Substituted pyrido[4,3-d]pyrimidines as 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

Attorney Docket No.62619-738601 SUBSTITUTED PYRIDO[4,3-d]PYRIMIDINES AS KRAS MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application No. 63 / 668,967, filed on July 9,2024; U.S. Patent Application No.63 / 710,370, filed on October 22, 2024; and U.S. Patent Application No.63 / 774,493, filed on March 19, 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 theRAS / 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 saidinhibitory 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 apharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl;Attorney Docket No.62619-738601 R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is selected from: (a) optionally substituted monocyclic aryl; (b) optionally substituted bicyclic aryl; (c) optionally substituted monocyclic heteroaryl; (d) optionally substituted bicyclic heteroaryl; (e) optionally substituted monocyclic aryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (f) optionally substituted bicyclic aryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (g) optionally substituted monocyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (h) optionally substituted bicyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; and (i) optionally substituted tricyclic heteroaryl; Q is a heterocyclyl selected from: (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclyl; or R5and R6together form an optionally substituted methylidene; or R5and R6together form an optionally substituted oxygen-containing heterocyclylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; or R5and R6join to form an optionally substituted heterocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10Attorney Docket No.62619-738601 and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; W is N-R40or C(R12)(R13); R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; R40is H or optionally substituted C1-C4 alkyl; m is 0, 1, or 2; and n is 0, 1, or 2.

[0005] One embodiment provides a compound having the structure of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; or R5and R6join to form an optionally substituted heterocyclyl;Attorney Docket No.62619-738601 R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; m is 0, 1, or 2; and n is 0, 1, or 2.

[0006] One embodiment provides a compound having the structure of Formula (Ib), or apharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl;Attorney Docket No.62619-738601 R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (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; G is selected from:wherein, R2and R3are independently selected from H or D;Attorney Docket No.62619-738601 R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; m is 0 or 1; and n is 0 or 1.

[0007] One embodiment provides a compound having the structure of Formula (Ic), or apharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-R, C-F, or C-Cl; X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; R is selected from optionally substituted alkyl or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl;Attorney Docket No.62619-738601 Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl;Attorney Docket No.62619-738601 R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; m is 0 or 1; and n is 0 or 1.

[0008] One embodiment provides a pharmaceutical composition comprising a compound of Formula(I), (Ia), (Ib), or (Ic), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0009] One embodiment provides a method of treating cancer in a patient in need thereof comprisingadministering to the patient a compound of Formula (I), (Ia), (Ib), or (Ic), or pharmaceutically acceptable salt or solvate thereof.

[0010] One embodiment provides a method of inhibiting KRAS protein activity comprising contactingthe KRAS protein with a compound of Formula (I), (Ia), (Ib), or (Ic), wherein the KRAS protein is contacted in an in vitro setting.

[0011] One embodiment provides a method of inhibiting KRAS protein activity comprising contactingthe KRAS protein with a compound of Formula (I), (Ia), (Ib), or (Ic), wherein the KRAS protein is contacted in an in vivo setting. INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are hereinincorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0013] As used herein and in the appended claims, the singular forms “a,” “and,” and “the” includeplural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-Attorney Docket No.62619-738601 combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. Definitions

[0014] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below.

[0015] “Amino” refers to the –NH2 radical.

[0016] “Cyano” refers to the -CN radical.

[0017] “Nitro” refers to the -NO2 radical.

[0018] “Oxa” refers to the -O- radical.

[0019] “Oxo” refers to the =O radical.

[0020] “Thioxo” refers to the =S radical.

[0021] “Imino” refers to the =N-H radical.

[0022] “Oximo” refers to the =N-OH radical.

[0023] “Hydrazino” refers to the =N-NH2 radical.

[0024] “Methylidene” refers to the =CH2 radical. An optionally substituted methylidene refers to themethylidene radical wherein one or two of the hydrogens are replaced with an alkyl chain as defined below.

[0025] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbonand hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1- C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, anAttorney Docket No.62619-738601 alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: 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 heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3group.

[0026] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula –O-alkyl, wherealkyl is an alkyl chain as defined above.

[0027] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely ofcarbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -Attorney Docket No.62619-738601 N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely ofcarbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).Attorney Docket No.62619-738601

[0029] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chainlinking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (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-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., 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 heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0030] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chainlinking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbonAttorney Docket No.62619-738601 atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). 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., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0031] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chainlinking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing 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-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In otherAttorney Docket No.62619-738601 embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0032] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ringsystem by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy,Attorney Docket No.62619-738601 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.

[0033] “Aralkyl” refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as definedabove, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0034] “Aralkenyl” refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain asdefined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0035] “Aralkynyl” refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain asdefined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0036] “Aralkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl whereRcis 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.

[0037] “Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radicalconsisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as “cycloalkyl.” Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,Attorney Docket No.62619-738601 cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted exocyclic alkylidene, halo, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb- OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0038] “Carbocyclylalkyl” refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylenechain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0039] “Carbocyclylalkynyl” refers to a radical of the formula –Rc-carbocyclyl where Rc is analkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0040] “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.Attorney Docket No.62619-738601

[0041] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

[0042] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or morefluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0043] “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprisestwo to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted exocyclic alkylidene, 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, orAttorney Docket No.62619-738601 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.

[0044] “N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0045] “C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining 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.

[0046] “Heterocyclylalkyl” refers to a radical of the formula –Rc-heterocyclyl where Rc is an alkylenechain 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.

[0047] “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.

[0048] “Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical thatcomprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance withAttorney Docket No.62619-738601 the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, 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, -Attorney Docket No.62619-738601 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.

[0049] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogenand where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0050] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachmentof the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0051] “Heteroarylalkyl” refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylenechain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0052] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted asAttorney Docket No.62619-738601 defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0053] The compounds disclosed herein, in some embodiments, contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pureforms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term“positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0054] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule toanother atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0055] The compounds disclosed herein, in some embodiments, are used in different enriched isotopicforms, 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 canAttorney Docket No.62619-738601 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.

[0056] Unless otherwise stated, structures depicted herein are intended to include compounds whichdiffer only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0057] The compounds of the present disclosure optionally contain unnatural proportions of atomicisotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N, 16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0058] In certain embodiments, the compounds disclosed herein have some or all of the 1H atomsreplaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0059] 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.

[0060] Deuterated starting materials are readily available and are subjected to the synthetic methodsdescribed herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0061] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such asiodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reactionAttorney Docket No.62619-738601 substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0062] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed totransfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0063] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbonlinkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0064] In one embodiment, the compounds disclosed herein contain one deuterium atom. In anotherembodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0065] “Pharmaceutically acceptable salt” includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the KRAS inhibitory compounds describedAttorney Docket No.62619-738601 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.

[0066] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. Aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0067] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biologicaleffectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine,Attorney Docket No.62619-738601 triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0068] “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solventaddition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0069] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but arenot 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.

[0070] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are usedinterchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0071] The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In some embodiments, the term “treating” includes slowing or delaying the progression of the disease or disorder to which the term is applied. Additionally, in some embodiments, the term “treating” is applied to one orAttorney Docket No.62619-738601 more of the complications resulting from the disease or disorder to which the term is applied. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. In some embodiments, the treatment provides a partial response. A partial response, or partial remission, is a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. In some embodiments, the treatment provides a complete response. A complete response, or complete remission, is the disappearance of all signs of cancer in response to treatment. In some embodiments, the treatment provides a slowing of disease progression.

[0072] The term "tumor," or “cancer” as used herein, and unless otherwise specified, refers to aneoplastic cell growth, and includes pre-cancerous and cancerous cells and tissues. Tumors usually present as a lesion or lump. As used herein, “treating” a tumor means that has one or more symptoms of the disease, such as the tumor itself, vascularization of the tumor, or other parameters by which the disease is characterized, are reduced, ameliorated, inhibited, placed in a state of remission, or maintained in a state of remission. “Treating” a tumor also means that one or more hallmarks of the tumor may be eliminated, reduced, or prevented by the treatment. Non-limiting examples of such hallmarks include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of the endothelial cells into new functioning capillaries, and the persistence of such functioning capillaries.

[0073] The term “refractory” or “refractory to therapy” indicates that the patients have neverresponded to therapy.

[0074] The term “relapsed” or “relapsed after therapy” indicates that patients, after initially respondingto prior therapy, have progressive disease due to acquired resistance and / or intolerance.

[0075] The term “resistance to therapy” or “acquired resistance to therapy” indicates the patients, afterinitially responding to prior therapy, have progressive disease due to clinical or molecular resistance to the therapy. The acquired resistance can result from emergence of resistant mutations in the molecular target of the therapy, or in the development of physiological functions such as efflux pumps.

[0076] The phrase "therapeutically effective amount", as used herein, refers to that amount of drug orpharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other. KRAS Protein and Function

[0077] RAS mutation is frequent in cancer, with approximately 19% of patients with cancer harboringRAS mutations (I.A. Prior et al., Cancer Res 2020; 80:2969-74). Ras proteins are important forAttorney Docket No.62619-738601 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.

[0078] The KRAS gene encodes two highly related protein isoforms, KRAS-4A and KRAS-4B, whichcomprise 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).

[0079] KRAS G domain is the basis of biological function of GTPase proteins. The G domaincomprises 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.

[0080] The RAS family comprises three isoforms, but about 85% of RAS-related cancers are causedby 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.

[0081] KRAS protein functions as a molecular switch in growth factor signaling pathways byregulating proliferation by alternating between a GDP-bound inactive form and a GTP-bound active form. The GTP-bound active form is capable of engaging downstream effector proteins to trigger a pro-proliferative response. This regulation cycle is impaired by mutations in codon 12 which disrupts association of GTPase activating proteins, which impairs the inactivation of KRAS, which leads to accumulation of the pro-proliferative form. Many growth factors such as but not limited to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and fibroblast growth factors (FGF) can activate KRAS proteins through intermediary molecules after activating receptor tyrosine kinases. Upstream regulation can promote binding of GTP and KRAS, converting KRAS from an inactive to an active state. Molecules upstream of KRAS mainly mediate the activation or inactivation of KRAS by regulating guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386). Another molecule in KRAS activation is Src homology phosphatase 2 (SHP2) which plays a role in KRAS activation. SHP2 is aAttorney Docket No.62619-738601 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.

[0082] The RAF-MEK-ERK pathway is a downstream target of KRAS signaling. Another pathwayKRAS involved in is the PI3K-AKT-mTOR pathway (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386).

[0083] KRAS was previously considered to be an undruggable protein, but recently there have beenadvances 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.

[0084] KRAS mutations are frequently found in colorectal cancer, pancreatic cancer, and non-smallcell 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

[0085] There have been advances for KRAS G12C inhibitors such as sotorasib (AMG510) andadagrasib (MRTX849). Sotorasib is the first to be approved for clinical use. Both inhibitors rely on the interaction with the nucleophilic cysteine 12 in the GDP state and occupy the switch II pocket.

[0086] NMR studies have shown that MRTX849 can engage mutant KRAS proteins lacking thenucleophilic mutant cysteine 12, but that the engagement is selected for inactive GDP-loaded state of KRAS protein, but that AMG510 had weak binding and relies on irreversible reaction of the mutant cysteine12 for KRAS (G12C) inhibitory activity (J.D. Vasta et al., Nature Chemical Biology, 2022, 18, 596-604).

[0087] AMG510 and additional KRAS inhibitors are described in Discovery of a Covalent Inhibitor ofKRASG12C (AMG 510) for the Treatment of Solid Tumors (B.A Lanman et al., J. Med. Chem.2020, 63, 52-65).Attorney Docket No.62619-738601 Novel Compounds Inhibiting KRAS

[0088] In one aspect, provided herein are KRAS inhibitory compounds.

[0089] One embodiment provides a compound having the structure of Formula (I), or apharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is selected from: (a) optionally substituted monocyclic aryl; (b) optionally substituted bicyclic aryl; (c) optionally substituted monocyclic heteroaryl; (d) optionally substituted bicyclic heteroaryl; (e) optionally substituted monocyclic aryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (f) optionally substituted bicyclic aryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (g) optionally substituted monocyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl;Attorney Docket No.62619-738601 (h) optionally substituted bicyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; and (i) optionally substituted tricyclic heteroaryl; Q is a heterocyclyl selected from: (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; G is selected from:wherein, R2and R3are independently selected from H or D;Attorney Docket No.62619-738601 R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclyl; or R5and R6together form an optionally substituted methylidene; or R5and R6together form an optionally substituted oxygen-containing heterocyclylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; or R5and R6join to form an optionally substituted heterocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; W is N-R40or C(R12)(R13); R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; R40is H or optionally substituted C1-C4 alkyl; m is 0, 1, or 2; and n is 0, 1, or 2.

[0090] One embodiment provides a compound of Formula (I) having the structure of Formula (Ia), ora pharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN;Attorney Docket No.62619-738601 X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; or R5and R6join to form an optionally substituted heterocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; m is 0, 1, or 2; and n is 0, 1, or 2.Attorney Docket No.62619-738601

[0091] One embodiment provides a compound of Formula (I), or (Ia) 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-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (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;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl;Attorney Docket No.62619-738601 R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; m is 0 or 1; and n is 0 or 1.

[0092] One embodiment provides a compound of Formula (I), (Ia), or (Ib) having the structure ofFormula (Ic), or a pharmaceutically acceptable salt or solvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-R, C-F, or C-Cl; X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; R is selected from optionally substituted alkyl or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (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;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; m is 0 or 1; and n is 0 or 1.

[0093] In some embodiments, X1 is N. In some embodiments, X1 is C-CN.

[0094] In some embodiments, X2 is N. In some embodiments, X2 is C-H, C-R, C-F, or C-Cl. In someembodiments, X2is C-F.

[0095] In some embodiments, X3 is N. In some embodiments, X3 is C-H, C-F, or C-Cl.

[0096] In some embodiments, R1 is H or D.Attorney Docket No.62619-738601

[0097] In some embodiments, 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.

[0098] In some embodiments, the optionally substituted phenyl is selected from:.

[0099] In some embodiments, the optionally substituted phenyl is substituted with an -NH2 group atthe meta position.

[0100] In some embodiments, the optionally substituted phenyl is selected from:.

[0101] In some embodiments, the optionally substituted phenyl is selected from:.Attorney Docket No.62619-738601

[0102] In some embodiments, the optionally substituted phenyl is:some embodiments, Ar is a bicyclic optionally substituted aryl. In someembodiments, the bicyclic optionally substituted aryl is an optionally substituted naphthyl. In some embodiments, the optionally substituted naphthyl is an optionally substituted 1-naphthyl. In some embodiments, the optionally substituted 1-naphthyl is further substituted at the 8- position. In some embodiments, the optionally substituted 1-naphthyl is substituted with an - OH group at the 3-position.

[0104] In some embodiments, the optionally substituted naphthyl is selected from:.

[0105] In some embodiments, the optionally substituted naphthyl is selected from:.

[0106] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601.

[0107] In some embodiments, the optionally substituted naphthyl is selected from:.

[0108] In some embodiments, the optionally substituted naphthyl is selected from:.

[0109] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0110] In some embodiments, the optionally substituted naphthyl is selected from:

[0111] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0112] In some embodiments, the optionally substituted naphthyl is selected from:.

[0113] In some embodiments, the optionally substituted naphthyl is selected from:

[0114] In some embodiments, the optionally substituted naphthyl is selected from:.

[0115] In some embodiments, the optionally substituted naphthyl is selected from:

[0116] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0117] In some embodiments, the optionally substituted naphthyl is selected from:

[0119] In some embodiments, the optionally substituted 1-naphthyl is substituted at the 3-position withan -OH or an optionally substituted alkoxy. In some embodiments, the group at the 3-position is an optionally substituted alkoxy.

[0120] In some embodiments, the optionally substituted naphthyl is selected from:.

[0121] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0122] In some embodiments, the optionally substituted naphthyl is selected from:

[0123] In some embodiments, the optionally substituted naphthyl is selected from:.

[0124] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0126] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0127] In some embodiments, the optionally substituted 1-naphthyl is substituted with an -NH2 groupat the 3-position. In some embodiments, the optionally substituted naphthyl is selected from:.

[0128] In some embodiments, the optionally substituted naphthyl is selected from:.

[0129] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0130] In some embodiments, the optionally substituted naphthyl is selected from:.

[0131] In some embodiments, the optionally substituted naphthyl is selected from:

[0132] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0133] In some embodiments, the optionally substituted naphthyl is selected from:.

[0134] In some embodiments, the optionally substituted naphthyl is selected from:

[0135] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0136] In some embodiments, the optionally substituted naphthyl is selected from:

[0137] In some embodiments, the optionally substituted naphthyl is selected from:

[0138] In some embodiments, the optionally substituted naphthyl is selected from:

[0139] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601

[0140] In some embodiments, the optionally substituted naphthyl is selected from:

[0141] In some embodiments, the optionally substituted 1-naphthyl is substituted with a halogen at the3-position. In some embodiments, the optionally substituted naphthyl is selected from:.

[0142] In some embodiments, the optionally substituted 1-naphthyl is unsubstituted at the 3-position.

[0143] In some embodiments, the optionally substituted naphthyl is selected from:.

[0144] In some embodiments, the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601.

[0145] In some embodiments, the optionally substituted naphthyl is selected from:.

[0146] In some embodiments, the optionally substituted naphthyl is selected from:.

[0147] In some embodiments, the optionally substituted bicyclic aryl is described by Formula (b):wherein: R16is H, D, or F; R17is H, D, -OH, -NH2, Cl, F, -CN, -OCONHMe, OCOH(Me)2, or -NHCO2Me; R18is H, D, F, Cl, or Br; R19is H, D, F, Cl, or Br; R20is H, D, F, Cl, Br, -CN, or -CH3;Attorney Docket No.62619-738601 R21is H, D, F, Cl, -CH3, -CD3, CF3, or -CN; and R22is H, D, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

[0148] In some embodiments, R22 -C≡CH.

[0149] In some embodiments, R21 is F.

[0150] In some embodiments, Ar is an optionally substituted monocyclic heteroaryl. In someembodiments, the optionally substituted monocyclic heteroaryl is an optionally substituted 2- pyridinyl. In some embodiments, the optionally substituted 2-pyridinyl is the optionally substituted monocyclic heteroaryl is an optionally substituted 4-pyridinyl.

[0151] In some embodiments, the optionally substituted 4-pyridinyl is.

[0152] In some embodiments, the optionally substituted 4-pyridinyl is:.

[0153] In some embodiments, Ar is an optionally substituted bicyclic heteroaryl. In someembodiments, the optionally substituted bicyclic heteroaryl is selected from:.

[0154] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-738601.

[0155] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:.

[0156] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:.

[0157] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-738601

[0158] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:

[0159] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:

[0160] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-738601.

[0161] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:.

[0162] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:

[0163] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:.

[0164] In some embodiments, the optionally substituted bicyclic heteroaryl is selected from:.

[0165] In some embodiments, Ar is an optionally substituted bicyclic heteroaryl further substitutedwith an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0166] In some embodiments, Ar is:Attorney Docket No.62619-738601.

[0169] In some embodiments, Q is selected from:(a) optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl; (b) optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl; (c) optionally substituted 2-azabicyclo[5.1.0]octan-2-yl; (d) optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl; (e) optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl; (f) optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl; (g) optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl; (h) optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (i) optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (j) optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl; (k) optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl; (l) optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl; (m) optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl; (n) optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl; and (o) optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl;

[0170] In some embodiments, Q is described by Formula (I-1):wherein: Y is O or CR27R28, and Z is O or CR29R30, provided that -Y-Z- is not -O-O-; or optionally -Y-Z- is -C(R28)=C(R29)-;Attorney Docket No.62619-738601 R23, R24, R25, R26, R27, R28, R29, R30, R33, R34, R35, R36each is independently selected from H or optionally substituted C1-C6 alkyl; or R26and R27are taken together with the carbon atoms to which they are attached to form a double bond; or R34and R35together form an optionally substituted carbocyclyl ring.

[0171] In some embodiments, Q is described by Formula (I-2):wherein: Y is O or CR27R28, and Z is O or CR29R30, provided that -Y-Z- is not -O-O-; or optionally -Y-Z- is -C(R28)=C(R29)-; R23, R24, R25, R26, R27, R28, R29, and R30each is independently selected from H or optionally substituted C1-C6 alkyl; or R26and R27are taken together with the carbon atoms to which they are attached to form a double bond; R31is H; and R32is selected from H, D, fluoro, chloro, -CN, or -OH.

[0172] In some embodiments, Q is an optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl.

[0173] In some embodiments, Q is an optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl.

[0174] In some embodiments, Q is an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl.

[0175] In some embodiments, Q is an optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl.

[0176] In some embodiments, Q is an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl.

[0177] In some embodiments, Q is an optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl.

[0178] In some embodiments, Q is an optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl.

[0179] In some embodiments, Q is an optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl.

[0180] In some embodiments, Q is an optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl.

[0181] In some embodiments, Q is an optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl.

[0182] In some embodiments, Q is an optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl.

[0183] In some embodiments, Q is an optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl.

[0184] In some embodiments, Q is an optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl.

[0185] In some embodiments, Q is an optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl

[0186] In some embodiments, Q is an optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl.Attorney Docket No.62619-738601

[0187] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0188] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0189] In some embodiments, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclylhas a structure selected from:.

[0190] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0191] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0192] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.Attorney Docket No.62619-738601

[0193] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0194] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0195] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0196] In some embodiments, the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0197] In some embodiments, Q is selected from:

[0198] In some embodiments, Q is selected from:

[0199] In some embodiments, Q is selected from:Attorney Docket No.62619-738601

[0200] In some embodiments, Q is selected from:

[0201] In some embodiments, Q is selected from:

[0202] In some embodiments, Q is selected from:

[0203] In some embodiments, the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0204] In some embodiments, the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0205] In some embodiments, the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has astructure selected from:.

[0206] In some embodiments, Q is selected from:Attorney Docket No.62619-738601

[0207] In some embodiments, Q is selected from:

[0208] In some embodiments, Q is an optionally substituted azabicyclo[4.1.0]heptane heterocyclyl.

[0209] In some embodiments, Q is an optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl.

[0210] In some embodiments, Q is an optionally substituted azabicyclo[6.1.0]nonane heterocyclyl.

[0211] In some embodiments, Q is an optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl.

[0212] In some embodiments, Q is a group selected from:optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl.

[0213] In some embodiments, the group is optionally substituted with a halogen.

[0214] In some embodiments, Q is a group selected from:.

[0215] In some embodiments, n is 2, and m is 2. In some embodiments, n is 1, and m is 2. In someembodiments, n is 0, and m is 2. In some embodiments, n is 2, and m is 1. In some embodiments, n is 2, and m is 0. In some embodiments, n is 1, and m is 1. In some embodiments, m is 0, and n is 1. In some embodiments, m is 1, and n is 0.Attorney Docket No.62619-738601

[0216] In some embodiments, R4 is H or D. In some embodiments, R4 is optionally substituted C1-C4alkyl. In some embodiments, R4is optionally substituted C1 alkyl. In some embodiments, R4is CH3or CD3.

[0217] In some embodiments, R9 is H or D. In some embodiments, R9 is optionally substituted C1-C4alkyl. In some embodiments, R9is optionally substituted C1-C2 alkyl. In some embodiments, R9is optionally substituted C1 alkyl. In some embodiments, R9is CH3 or CD3. In some embodiments, R9is optionally substituted C3-C6 carbocyclyl. In some embodiments, R9is optionally substituted C3 carbocyclyl.

[0218] In some embodiments, R5 and R6 together form an optionally substituted methylidene. In someembodiments, the optionally substituted methylidene is substituted with at least one halogen. In some embodiments, R5and R6join to form an optionally substituted C3-C6 carbocyclyl. In some embodiments, the optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl. In some embodiments, the carbocyclyl is substituted with at least one halogen.

[0219] In some embodiments, R5 and R6 join to form an optionally substituted heterocyclyl. In someembodiments, R5and R6join to form an optionally substituted oxetane.

[0220] In some embodiments, R5 is an optionally substituted C1-C4 alkyl, and R6 is H or D. In someembodiments, the optionally substituted C1-C4 alkyl is substituted with at least one halogen. In some embodiments, the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl.

[0221] In some embodiments, R5 and R6 are both selected from H or D. In some embodiments, R5 andR6are both halogen. In some embodiments, R5and R6are both optionally substituted C1-C4 alkyl. In some embodiments, R5is a halogen and R6is H or D.

[0222] In some embodiments, R5 is an optionally substituted C1-C4 alkoxy and R6 is H or D. In someembodiments, R5is an optionally substituted C1-C4 alkynyl and R6is H or D. In some embodiments, R5is -CN and R6is H or D. In some embodiments, R5and R6join to form an optionally substituted C3-C6 carbocyclyl. In some embodiments, R5and R6join to form an optionally substituted heterocyclyl.

[0223] In some embodiments, R7 and R8 together form an optionally substituted methylidene. In someembodiments, the optionally substituted methylidene is substituted with at least one halogen. In some embodiments, R7and R8join to form an optionally substituted C3-C6 carbocyclyl. In some embodiments, the optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl. In some embodiments, the carbocyclyl is substituted with at least one halogen.

[0224] In some embodiments, R7 is an optionally substituted C1-C4 alkyl, and R8 is H or D. In someembodiments, the optionally substituted C1-C4 alkyl is substituted with at least one halogen. InAttorney Docket No.62619-738601 some embodiments, the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl.

[0225] In some embodiments, R7 and R8 are both selected from H or D. In some embodiments, R7 andR8are both halogen. In some embodiments, R7and R8are both optionally substituted C1-C4 alkyl. In some embodiments, R7is a halogen and R8is H or D. In some embodiments, R7is an optionally substituted C1-C4 alkoxy and R8is H or D. In some embodiments, R7is an optionally substituted C1-C4 alkynyl and R8is H or D. In some embodiments, R7is -CN and R8is H or D.

[0226] In some embodiments, R2 and R3 are H. In some embodiments, R2 and R3 are D. In someembodiments, R2is H and R3is D.

[0227] In some embodiments, R10 is an optionally substituted C1-C4 alkyl, and R11 is H or D. In someembodiments, R10and R11are both optionally substituted C1-C4 alkyl. In some embodiments, the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl. In some embodiments, R10and R11are both selected from H or D. In some embodiments, R10and R11join to form an optionally substituted C3-C6 carbocyclyl. In some embodiments, the optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl.

[0228] In some embodiments, R12 is an optionally substituted C1-C4 alkyl, and R13 is H or D. In someembodiments, R12and R13are both optionally substituted C1-C4 alkyl. In some embodiments, the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl. In some embodiments, R12and R13are both selected from H or D.

[0229] In some embodiments, R10 and R11 join to form an optionally substituted C3-C6 carbocyclyl. Insome embodiments, the optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl.

[0230] In some embodiments, G is selected from:

[0231] In some embodiments, G is selected from:Attorney Docket No.62619-738601

[0232] In some embodiments, G is selected from:

[0233] In some embodiments, G is selected from:

[0234] In some embodiments, G is selected from:Attorney Docket No.62619-738601

[0235] In some embodiments, G is selected from:

[0236] In some embodiments, G is selected from:or .

[0237] In some embodiments, G is selected from:

[0238] In some embodiments, G is selected from:

[0239] In some embodiments, G is selected from:Attorney Docket No.62619-738601

[0240] In some embodiments, G is selected from:

[0241] In some embodiments, G is selected from:

[0243] In some embodiments, G is selected from:Attorney Docket No.62619-738601

[0244] In some embodiments, G is selected from:

[0245] In some embodiments, G is selected from:

[0246] In some embodiments, G is selected from:Attorney Docket No.62619-738601

[0247] In some embodiments, G is selected from:

[0248] In some embodiments, G is selected from:

[0249] In some embodiments, G is selected from:Attorney Docket No.62619-738601

[0252] In some embodiments, G is selected from:Attorney Docket No.62619-738601.

[0253] In some embodiments, G is selected from:

[0254] In some embodiments, G is selected from:.

[0255] In some embodiments, G is selected from:.Attorney Docket No.62619-738601

[0256] In some embodiments, G is selected from:.

[0257] In some embodiments, R5 and R6 together form an optionally substituted oxygen-containingheterocyclylidene.

[0258] In some embodiments, G is:.

[0259] In some embodiments, G is:.

[0260] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable saltor solvate thereof, wherein W is N-R40, m is 1 and n is 1.

[0261] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable saltor solvate thereof, wherein, wherein G is:.

[0262] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein

[0263] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof whereinAttorney Docket No.62619-738601

[0264] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,

[0265] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F.

[0266] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; and X3is N.

[0267] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; X3is N; and X4is C-R1.

[0268] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; X3is N; X4is C-R1; and R1is -H or optionally substituted C2-C6 alkynyl.

[0269] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; X3is N; X4is C-R1; and R1is C3 alkynyl.

[0270] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; X3is N; X4is C-R1; R1is -H or optionally substituted C2-C6 alkynyl; and X1is N.Attorney Docket No.62619-738601

[0271] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,or -CH2F; X3is N; X4is C-R1; R1is -H or optionally substituted C2-C6 alkynyl; X1is N; and G is selected from:

[0272] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; X3is N; X4is C-R1; R1is -H or optionally substituted C2-C6 alkynyl; X1is N; and Ar is selected from:.

[0273] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,Attorney Docket No.62619-738601 CH2F; X3is N; X4is C-R1; R1is -H or optionally substituted C2-C6 alkynyl; X1is N; and Ar is.

[0274] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,CH2F; X3is N; X4is C-R1; R1is -H or optionally substituted C2-C6 alkynyl; X1is N; Ar is selected from:

[0275] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof wherein,Attorney Docket No.62619-738601 CH2F; X3is N; X4is C-R1; R1is -H or optionally substituted C2-C6 alkynyl; X1is N; Ar is

[0276] One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable saltor solvate thereof, having a structure presented in Table 1. Table 1Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601

[0277] Another embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptablesalt or solvate thereof, having a structure presented in Table 2. Table 2Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Attorney Docket No.62619-738601Preparation of Compounds

[0278] The compounds used in the synthetic chemistry reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art, starting from commerciallyAttorney Docket No.62619-738601 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).

[0279] Suitable reference books and treatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2ndEd., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2ndEd., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4thEd., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of rectants useful in the prepaation 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” 2ndEdition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4thEdition (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” 7thEdition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C.,Attorney Docket No.62619-738601 “Intermediate Organic Chemistry” 2ndEdition (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.

[0280] Specific and analogous reactants are optionally identified through the indices of knownchemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G.Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions

[0281] In certain embodiments, the KRAS inhibitory compound described herein is administered as apure 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)).

[0282] Provided herein is a pharmaceutical composition comprising at least one KRAS inhibitorycompound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0283] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.62619-738601

[0284] One embodiment provides a method of preparing a pharmaceutical composition comprisingmixing a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0285] In certain embodiments, the KRAS inhibitory compound as described by Formula (I), (Ia), (Ib),or (Ic), 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.

[0286] One embodiment provides a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0287] One embodiment provides a method of preparing a pharmaceutical composition comprisingmixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0288] In certain embodiments, the KRAS inhibitory compound as described by Table 1, or apharmaceutically 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.

[0289] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard orsoft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0290] In some embodiments, the KRAS inhibitory compound as described by Formula (I), (Ia), (Ib),or (Ic), 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.Attorney Docket No.62619-738601

[0291] The dose of the composition comprising at least one KRAS inhibitory compound as describedherein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0292] Pharmaceutical compositions are administered in a manner appropriate to the disease to betreated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0293] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, perday. Methods of Treatment

[0294] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0295] One embodiment provides a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treating cancer.

[0296] One embodiment provides a pharmaceutical composition comprising a compound of Formula(I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0297] One embodiment provides a use of a compound of Formula (I), (Ia), (Ib), or (Ic), or apharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0298] 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), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.Attorney Docket No.62619-738601

[0299] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt orsolvate thereof, for use in a method of treatment of the human or animal body.

[0300] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt orsolvate thereof, for use in a method of treating cancer.

[0301] One embodiment provides a pharmaceutical composition comprising a compound of Table 1,or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0302] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptablesalt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0303] 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.

[0304] One embodiment provides a method of inhibiting KRAS protein activity comprising contactingthe KRAS protein with a compound of Formula (I), (Ia), (Ib), or (Ic), 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.

[0305] One embodiment provides a method of treating cancer in a patient in need thereof, the methodcomprising administering to the patient a compound of Formula (I), (Ia), (Ib), or (Ic), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0306] One embodiment provides a method of treating cancer in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Formula (I), (Ia), (Ib), or (Ic), or Table 1, or pharmaceutically acceptable salt or solvate thereof.

[0307] One embodiment provides the method wherein the cancer is breast cancer. Anotherembodiment 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.

[0308] One embodiment provides the method wherein the cancer is uterine cancer. Anotherembodiment provides the method wherein the cancer is uterine sarcoma.

[0309] One embodiment provides the method wherein the cancer is endometrial cancer. Anotherembodiment provides the method wherein the endometrial cancer is selected fromAttorney Docket No.62619-738601 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.

[0310] One embodiment provides the method wherein the cancer is cervical cancer. Anotherembodiment 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.

[0311] 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.

[0312] One embodiment provides the method wherein the cancer is prostate cancer. Anotherembodiment 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.

[0313] One embodiment provides the method wherein the cancer is bladder cancer. Anotherembodiment 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.

[0314] One embodiment provides the method wherein the cancer is lung cancer.

[0315] 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 theAttorney Docket No.62619-738601 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.

[0316] One embodiment provides the method wherein the cancer is colon cancer (CRC). Anotherembodiment 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.

[0317] One embodiment provides the method wherein the cancer is anal cancer. Another embodimentprovides the method wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

[0318] One embodiment provides the method wherein the cancer is biliary cancer. Anotherembodiment 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.

[0319] One embodiment provides the method wherein the cancer is a meningioma.

[0320] One embodiment provides the method wherein the cancer is a glioma.

[0321] One embodiment provides the method wherein the cancer is pancreatic cancer. Anotherembodiment 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.Attorney Docket No.62619-738601

[0322] One embodiment provides the method wherein the cancer is thyroid cancer. Anotherembodiment provides the method wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

[0323] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0324] One embodiment provides the method wherein the cancer is esophageal cancer, esophagealadenocarcinoma, or esophageal squamous cell carcinoma.

[0325] 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.

[0326] 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.

[0327] One embodiment provides the method wherein the cancer is skin cancer. Another embodimentprovides 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.

[0328] One embodiment provides the method wherein the cancer is melanoma. Another embodimentprovides the method wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

[0329] One embodiment provides the method wherein the cancer is ovarian cancer. Anotherembodiment provides the method wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

[0330] One embodiment provides the method wherein the cancer is renal cell cancer.

[0331] One embodiment provides the method wherein the cancer is an appendiceal cancer. Anotherembodiment 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 orAttorney Docket No.62619-738601 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.

[0332] One embodiment provides the method wherein the cancer is a peritoneal cancer or primaryperitoneal carcinoma.

[0333] One embodiment provides the method wherein the cancer is a bone cancer, osteosarcoma,chondrosarcoma, or chordoma.

[0334] One embodiment provides the method wherein the cancer is a sarcoma.

[0335] One embodiment provides the method wherein the cancer is a primary brain tumor. Anotherembodiment provides the method wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

[0336] One embodiment provides the method wherein the cancer is gallbladder cancer. Anotherembodiment 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.

[0337] One embodiment provides the method wherein the cancer is soft tissue sarcoma, orundifferentiated pleomorphic sarcoma.

[0338] One embodiment provides the method wherein the cancer is germ cell tumor. Anotherembodiment 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.

[0339] One embodiment provides the method wherein the cancer is plasma cell neoplasm. Anotherembodiment 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).

[0340] One embodiment provides the method wherein the cancer ismyelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0341] One embodiment provides the method wherein the cancer is myelodysplastic neoplasm,myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

[0342] One embodiment provides the method wherein the cancer is acute leukemia, acute lymphocyticleukemia, or acute myelogenous leukemia.

[0343] One embodiment provides the method wherein the cancer is neuroendocrine carcinomaAttorney Docket No.62619-738601

[0344] One embodiment provides the method wherein the cancer is cancer of unknown primary(CUP).

[0345] One embodiment provides the method wherein the cancer is locally advanced.

[0346] One embodiment provides the method wherein the cancer is metastatic.

[0347] One embodiment provides the method wherein the method is adjuvant therapy followingsurgical resection.

[0348] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0349] One embodiment provides the method wherein the method is first-line systemic therapy forlocally advanced or metastatic disease.

[0350] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0351] One embodiment provides the method wherein the patient has acquired resistance to priortherapy.

[0352] One embodiment provides the method wherein the patient is refractory to therapy.

[0353] Other embodiments and uses will be apparent to one skilled in the art in light of the presentdisclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis

[0354] In some embodiments, the KRAS inhibitory compounds disclosed herein are synthesizedaccording to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile oC degrees Celsius δH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionizationAttorney Docket No.62619-738601 Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometryμ microm multiplet (spectral); meter(s); milli M molar M+parent molecular ion Me methyl MsCl methanesulfonyl chloride MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid THF tetrahydrofuran TPP Triphenylphosphine Experimental ProceduresAttorney Docket No.62619-738601

[0355] Intermediate 1 & 2: Benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2H-1,4-oxazepine-4-carboxylate

[0356] Step 1: Benzyl 1,4-oxazepane-4-carboxylate

[0357] To an ice-cooled mixture of 1,4-oxazepane (20 g, 197.73 mmol) and K2CO3 (54.65 g, 395.45mmol) 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]+. 1H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.29 (m, 5H), 5.15 (s, 2H), 3.75 - 3.56 (m, 8H), 1.93 - 1.79 (m, 2H).

[0358] Step 2: Benzyl 3-methoxy-1,4-oxazepane-4-carboxylate & benzyl 5-methoxy-1,4-oxazepane-4-carboxylate

[0359] To a solution of benzyl 1,4-oxazepane-4-carboxylate (40 g, 170.00 mmol) in MeOH (200 mL)was added tetraethylammonium tosylate (25.62 g, 85.00 mmol) at room temperature. The reaction mixture was electrolysis with C (+) I C(-) electrodes at constant current 200 mA. The resulting mixture was stirred at 20 °C for 72 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) δ 7.39 - 7.31 (m, 5H), 5.53 - 5.09 (m, 3H), 4.12 - 3.20 (m, 9H), 2.72 - 2.22 (m, 1H), 2.12 - 1.24 (m, 1H).

[0360] Step 3: Benzyl 6,7-dihydro-5H-1,4-oxazepine-4-carboxylate & benzyl 3,7-dihydro-2H-1,4-oxazepine-4-carboxylate

[0361] To an ice-cooled solution of benzyl 3-methoxy-1,4-oxazepane-4-carboxylate and benzyl 5-methoxy-1,4-oxazepane-4-carboxylate (8.3 g, 31.28 mmol) in DCM (830 mL) were added DIEA (4.85 g, 37.54 mmol) and TMSOTf (8.34 g, 37.54 mmol 1.2) under N2. The reaction mixture was stirred in an ice bath for 0.5 hour. The solid was filtered out, and the filter cake was washed with hexane (1660 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 42% EA in PE toAttorney Docket No.62619-738601 afford two peaks. The first eluting peak was collected and concentrated under reduced pressure to afford the title compound (Intermediate 1, 2.18 g, 29% yield) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.40 - 7.29 (m, 5H), 5.96 - 5.74 (m, 2H), 5.18 (s, 2H), 4.11 - 4.07 (m, 2H), 3.84 - 3.87 (m, 2H), 2.04 - 1.94 (m, 2H). The second eluting peak was collected and concentrated under reduced pressure to afford the title compound (Intermediate 2, 2.52 g, 34% yield) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.28 (m, 5H), 5.26 - 4.85 (m, 4H), 4.22 - 4.20 (m, 2H), 3.93 - 3.70 (m, 4H).

[0362] Intermediate 3 & 4: Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (transmixture) & Benzyl 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)

[0363] Step 1: Benzyl 8-bromo-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate

[0364] To an ice-cooled solution of Intermediate 2 (2.0 g, 8.58 mmol) and TBAI (0.65 g, 1.76 mmol)in DCM (10 mL) under N2 were added 33wt% aq. NaOH solution (20 mL) and dibromofluoromethane (4.94 g, 25.74 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with iced water (50 mL), extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-30% EA in PE to afford the title compound (2.4 g, 82% yield) as an off-white semi-solid. MS: m / z = 361.10, 363.10 [M + NH4]+.

[0365] 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)

[0366] 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 NH4Cl (3.37 g, 63.00 mmol) and Zn (4.12 g, 63.00 mmol) at room temperature. The reaction mixture was heated at 70 °C for 16 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 (trans mixture) (Intermediate 3, 700 mg, 38% yield) as an off-white semi-solid. MS: m / z = 283.20 [M + NH4]+.1H NMR (300 MHz, Chloroform-d) δ 7.39 - 7.32 (m, 5H), 5.30 - 5.21 (m, 2H), 4.72 - 4.52 (m, 1H), 4.41 - 4.35 (m, 1H), 4.06 - 4.01 (m, 1H), 3.85 - 3.80 (m, 1H), 3.49 -Attorney Docket No.62619-738601 3.30 (m, 1H), 3.25 - 3.14 (m, 3H), 2.05 - 1.92 (m, 1H).19F NMR (282 MHz, Chloroform-d) δ - 207.85 (s, 1F). The second eluting mixtures were collected and concentrated under reduced pressure to give the title compound (cis mixture) (Intermediate 4, 360 mg, 19% yield) as a yellow oil. MS: m / z = 283.20 [M + NH4]+.1H NMR (300 MHz, Chloroform-d) δ 7.38 - 7.30 (m, 5H), 5.15 (s, 2H), 4.67 - 4.46 (m, 1H), 4.33 - 4.26 (m, 1H), 4.19 - 4.14 (m, 1H) 4.02 - 3.91 (m, 1H), 3.69 - 3.55 (m, 2H), 3.37 - 3.29 (m, 1H), 2.74 - 2.72 (m, 1H) 1.64 - 1.51 (m, 1H).19F NMR (282 MHz, Chloroform-d) δ -232.23 (s, 1F).

[0367] Intermediate 5 & 6: (1R,7R,8R)-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin- 4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0368] Step 1: 8-Fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture)

[0369] Intermediate 3 (trans mixture) (2.6 g, 9.81 mmol) in 33 wt% HBr in AcOH (26 mL) under N2was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was trituration with hexane (3 x 50 mL) to afford the title compound (trans mixture, HBr salt) (1.9 g, crude used through) as a light-yellow solid.

[0370] Step 2: 2-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

[0371] To a stirred solution of 8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture)(600 mg, crude) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1154.94 mg, 4.57 mmol) in DCM (11 mL) was added DIEA (1773.88 mg, 13.72 mmol) dropwise at -40 °C under N2. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with 10% citric solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by silica gel flashAttorney Docket No.62619-738601 chromatography, eluted with CH2Cl2 / EA (5 : 1) to afford the title compound (trans mixture) (800 mg, 50% yield) as a light yellow solid. MS: m / z = 347.10, 349.10 [M + H]+.

[0372] 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)

[0373] 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 hours. 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with DCM / EA (5 : 1) to afford the title compound (2 g, 43% yield) as a light-yellow solid. MS: m / z = 331.05 [M + H]+.

[0374] Step 4: (1R,7R,8R)-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8- fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0375] 2-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (2.7 g, 8.16 mmol) was separated by Prep-SFC with the following conditions: Column: CHIRAL ART Cellulose-SB 5 x 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 M NH3-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 5, 1 g, 37% yield) as a light-yellow solid. MS: m / z = 331.10 [M + H]+. The second eluting peak (RT2: 9.5 min) wasAttorney Docket No.62619-738601 concentrated and lyophilized to give the title compound (Intermediate 6, 970 mg, 35% yield) as a light-yellow solid. MS: m / z = 331.10 [M + H]+.

[0376] Intermediate 7 & 8: N-(6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine & 6-Fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0377] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0378] To a solution of 7-fluoronaphthalene-1,3-diol (50 g, 281 mmol) and 2-bromoethynyl(triisopropyl)silane (77 g, 295 mmol) in 1,4-dioxane (334 mL) were added KOAc (55.1 g, 561 mmol) and dichlororuthenium:1-isopropyl-4-methyl-benzene (17.2 g, 28.1 mmol). The mixture was stirred at 110 °C for 2 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 5% of EtOAc in petroleum ether) to give the title compound (70 g, 194 mmol, 69% yield) as a brown solid. MS: m / z = 359.1 [M+ H]+.1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 7.59 (dd, J = 5.6, 9.2 Hz, 1H), 7.17 (t, J = 8.8 Hz, 1H), 6.77 - 6.62 (m, 2H), 1.21 - 1.15 (m, 21H).19F NMR (376 MHz, Chloroform-d) δ -112.51.

[0379] Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate)

[0380] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (140 g, 390 mmol)and DIPEA (408 mL, 2.34 mol) in CH2Cl2 (3.5 L) was added Tf2O (258 ml, 1.56 mol) dropwise under N2atmosphere at 0 °C. The mixture was stirred at 0 °C under N2atmosphere for 2 h. The reaction mixture was partitioned between CH2Cl2 (500 mL) and H2O (2 L). The organic phase was separated, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the title compound (218 g, 340 mmol, 87% yield) as a brown solid.1H NMR (400 MHz, Chloroform-d) δ 7.87 (dd, J =Attorney Docket No.62619-738601 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).

[0381] Step 3: 3-((Diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonate

[0382] A mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate) (94 g, 151 mmol), diphenylmethanimine (54.7 g, 302 mmol, 50.7 mL), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (17.5 g, 30.2 mmol), Pd2(dba)3(6.91 g, 7.55 mmol) and Cs2CO3(148 g, 453 mmol) in toluene (1800 mL) was degassed, purged with N2 three times, and stirred at 100 °C under N2 for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the crude product (80 g) as a brown solid. The crude was triturated with MeOH (150 mL) at 25°C for 20 min and filtered. The filter cake was dried under reduced pressure to give the title compound (70 g, 94.2 mmol, 62% yield) as a yellow solid. MS: m / z = 654.3 [M+ H]+.1H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 8.0 Hz, 2H), 7.57 - 7.51 (m, 2H), 7.48 - 7.41 (m, 2H), 7.27 (s, 2H), 7.26 - 7.19 (m, 2H), 7.17 - 7.01 (m, 4H), 1.22 - 1.13 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -71.40, -104.22.

[0383] Step 4: N-(6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine & 6-Fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0384] A mixture of 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (50 g, 76.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (39 g, 153 mmol), KOAc (30 g, 306 mmol), and Pd(dppf)Cl2(11.2 g, 15.3 mmol) in 1,4-dioxane (600 mL) was degassed, purged with N2three times, and stirred at 100 °C under N2 for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0~100% of EtOAc in petroleum ether) to give the title compound (Intermediate 7, 9 g, 14.3 mmol, 19% yield) as a yellow solid and the other title compound(Intermediate 8, 10 g, 21.4 mmol, 28% yield) as a brown oil. Spectra for Intermediate 7: MS:m / z = 632.4 [M+ H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.86 - 7.79 (m, 1H), 7.72 - 7.67 (m, 2H), 7.60 - 7.53 (m, 1H), 7.53 - 7.47 (m, 2H), 7.42 (t, J = 9.2 Hz, 1H), 7.34 - 7.27 (m, 4H), 7.22 - 7.16 (m, 2H), 7.14 - 7.10 (m, 1H), 1.27 (s, 12H), 1.14 - 1.08 (m, 21H),19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -106.71. Spectra for Intermediate 8: MS: m / z = 468.3 [M+ H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.67 - 7.57 (m, 1H), 7.27 (t, J = 9.0 Hz, 1H),Attorney Docket No.62619-738601 7.23 - 7.17 (m, 1H), 6.89 (d, J = 2.4 Hz, 1H), 5.48 (s, 2H), 1.33 (s, 12H), 1.17 - 1.11 (m, 21H). 19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -112.20.

[0385] Intermediate 9: 4-(2,8-Difluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0386] A mixture of Intermediate 6 (12 g, 36.28 mmol), Intermediate 8 (36.58 g, 72.58 mmol, HCl),Ad2nBuP-Pd-G3 (cataCXiumAPdG3) (5.28 g, 7.26 mmol), and K3PO4 (23.1 g, 108.86 mmol) in THF (240 mL) and H2O (48 mL) was degassed, purged with N2three times, and stirred at 80 °C for 5 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of MeOH in CH2Cl2) to give the crude product. The crude was purified by prep-HPLC (column: XPT C18250 × 70 × 7 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 65% ~ 95% B over 23 min) to give the title compound (Intermediate 9, 13.239 g, 60% purity) as a yellow solid.MS: m / z = 636.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.56 (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-d6) δ - 41.05, -41.78, -110.77, -111.09, -138.96, -207.86.

[0387] Intermediate 10 & 11: 1-(tert-Butyl) 3-methyl (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylate& (tert-butyl) 3-methyl (S)-3-methyl-4-oxopiperidine-1,3-dicarboxylate

[0388] To a solution of 1-(tert-butyl) 3-methyl 4-oxopiperidine-1,3-dicarboxylate (90 g, 350 mmol) inACN (900 mL) were added K2CO3 (145 g, 1.05 mol) and CH3I (108.9 mL, 1.75 mol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with sat. NH4Cl (1000 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% Ethyl acetate in Petroleum ether) to give 1-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate (95 g). Then it wasAttorney Docket No.62619-738601 separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [CO2 - MeOH (0.1% NH3•H2O)]; B%: 10%, isocratic elution mode) to give the title compound (Intermediate 10, 42.3 g, 42.3% yield) as a colorless oil and the other title compound (Intermediate 11, 33.7 g, 33.7% yield) as a colorless oil. Spectra for Intermediate 10:1H NMR (400 MHz, Chloroform-d) δ 4.48 (d, J = 13.6 Hz, 1H), 4.20 - 3.99 (m, 1H), 3.71 (s, 3H), 3.37 - 3.27 (m, 1H), 3.07 (d, J = 13.6 Hz, 1H), 2.74 (s, 1H), 2.56 - 2.42 (m, 1H), 1.47 (s, 9H), 1.29 (s, 3H). Spectra for Intermediate 11:1H NMR (400 MHz, Chloroform-d) δ 4.49 (d, J = 13.6 Hz, 1H), 4.22 - 4.02 (m, 1H), 3.72 (s, 3H), 3.37 - 3.28 (m, 1H), 3.08 (d, J = 13.6 Hz, 1H), 2.84 - 2.69 (m, 1H), 2.54 - 2.42 (m, 1H), 1.52 - 1.46 (m, 9H), 1.31 (s, 3H).

[0389] Intermediate 12 & 13: 1-(tert-Butyl) 3-methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylate & 1-(tert-butyl) 3-methyl (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3- dicarboxylate

[0390] A mixture of fluoromethyl(triphenyl)phosphonium tetrafluoroborate (31.7 g, 82.9 mmol) inTHF (100 mL) was degassed and purged with N2 three times. Then t-BuOK (1 M in THF, 82.9 mL) was added into the mixture at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. Intermediate 10 (15 g, 55.3 mmol) was added to the mixture at -70 °C under N2. The mixture was warmed to 25 °C and continued to stir at 25 °C for 16 h under N2. The reaction mixture was quenched with sat. NH4Cl (1000 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica flash gel chromatography (eluent: 0 ~ 9% of Ethyl acetate in Petroleum ether) to give the title compound (Intermediate 12, 9.6 g, 60% yield, spot 1 less polar) as a colorless oil and the other title compound (Intermediate 13, 3.8 g, 23% yield, spot 2 more polar) as a colorless oil. Spectra for Intermediate 12:1H NMR (400 MHz, Chloroform-d) δ 6.70 - 6.38 (m, 1H), 4.34 (d, J = 12.0 Hz, 1H), 4.06 - 3.83 (m, 1H), 3.68 (s, 3H), 2.88 (t, J = 10.4 Hz, 1H), 2.75 (d, J = 13.2 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.17 (s, 1H), 1.46 (s, 9H), 1.28 (s, 3H).19F NMR (376 MHz, Chloroform- d) δ. -137.93. Spectra for Intermediate 13:1H NMR (400 MHz, Chloroform-d) δ 6.57 - 6.27Attorney Docket No.62619-738601 (m, 1H), 3.83 - 3.73 (m, 1H), 3.73 - 3.68 (m, 3H), 3.57 - 3.32 (m, 3H), 2.19 - 2.07 (m, 2H), 1.45 (s, 9H), 1.42 - 1.39 (m, 3H).19F NMR (376 MHz, Chloroform-d) δ -128.86, -129.31.

[0391] Intermediate 14: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0392] Step 1: Methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate

[0393] A solution of Intermediate 12 (8.6 g, 30.0 mmol) in 2M HCl (in EtOAC, 100 mL) was stirred at25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (6.6 g, crude) as a colorless oil, which was used in the next step without further purification.

[0394] Step 2: Methyl (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate

[0395] To a mixture of methyl (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (5.6 g, 25mmol) in THF (40 mL) was added NaH (3 g, 75.1 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C under N2for 0.5 h. Then CD3I (1.71 mL, 27.5 mmol) was added dropwise into the reaction at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 5 h. The reaction mixture was quenched with sat. NH4Cl (100 mL) at 0 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous MgSO4,filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 3% MeOH in CH2Cl2).to give methyl (S,E)-4-(fluoromethylene)- 3-methyl-1-(methyl-d3)piperidine-3-carboxylate (3.3 g, 65% yield over 2 steps) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 6.66 - 6.38 (m, 1H), 3.71 (s, 3H), 3.23 (d, J = 11.2 Hz, 1H), 2.84 - 2.72 (m, 2H), 2.19 - 2.08 (m, 1H), 1.92 - 1.83 (m, 1H), 1.75 (d, J = 11.2 Hz, 1H), 1.24 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -139.59.

[0396] Step 3: (S,E)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0397] To a solution of methyl (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate (3.3 g, 16.2 mmol) in THF (30 mL) was added LiAlD4 (736 mg, 19.4 mmol) at 0 °C under N2. The mixture was stirred at 0 °C under N2for 1 h. The reaction mixture was quenched slowly with Na2SO4•10H2O (1 g) at 0 °C. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (CH2Cl2: MeOH = 20 / 1 to 10 / 1) to give the title compuond (Intermediate 14, 1.8 g, 59% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 6.63 - 6.35 (m, 1H), 4.80 - 4.20 (m, 1H), 2.89 - 2.81 (m, 1H), 2.79 - 2.71 (m,Attorney Docket No.62619-738601 2H), 2.53 - 2.40 (m, 1H), 2.01 - 1.88 (m, 2H), 0.91 (s, 3H).19F NMR (376 MHz, Chloroform- d) δ -139.78.

[0398] Intermediate 15: (S,Z)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0399] Step 1: Methyl (S,Z)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate

[0400] A solution of Intermediate 13 (3.78 g, 13.2 mmol) in 2M HCl (in EtOAC, 50 mL) was stirred at25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (2.5 g, crude) as a colorless oil, which was used in the next step without further purification.

[0401] Step 2: Methyl (S,Z)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate

[0402] To a mixture of methyl (S,Z)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylate (2.5 g,8.94 mmol) in THF (20 mL) was added NaH (1.1 g, 26.8 mmol, 60% purity) at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 0.5 h. Then CD3I (1.22 mL, 19.67 mmol) was added dropwise to the reaction mixture at 0 °C under N2. The mixture was stirred at 0 °C for 5 h. The reaction was quenched with sat. NH4Cl (100 mL) aq. at 0 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% MeOH in CH2Cl2) to give the title compound (2.0 g, 79% yield over 2 steps) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 6.58 - 6.25 (m, 1H), 3.73 (s, 3H), 3.00 (d, J = 11.2 Hz, 1H), 2.65 - 2.54 (m, 1H), 2.26 - 2.15 (m, 1H), 2.14 - 1.97 (m, 3H), 1.49 (d, J = 4.4 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -130.69.

[0403] Step 3: (S,Z)-(4-(Fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0404] To a solution of methyl (S,Z)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate (2.0 g, 9.79 mmol) in THF (20 mL) was added LiAlD4(675 mg, 14.7 mmol) at 0 °C under N2. The mixture was stirred at 0 °C under N2 for 1 h. The reaction mixture was quenched slowly with Na2SO4•10H2O (600 mg) at 0 °C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (CH2Cl2: MeOH = 20 / 1 to 10 / 1) to give the title compound (Intermediate 15, 1.6 g, 91% yield) as a white solid. MS: m / z = 179.2 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 6.58 - 6.24 (m, 1H),Attorney Docket No.62619-738601 2.71 - 2.57 (m, 2H), 2.55 - 2.44 (m, 1H), 2.12 - 2.02 (m, 3H), 1.15 (d, J = 4.4 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -130.78.

[0405] Intermediate 16: 1-(tert-Butyl) 3-methyl (S)-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate

[0406] A solution of Intermediate 10 (27 g, 99.5 mmol) and 2-((difluoromethyl)sulfonyl)pyridine(28.9 g, 149.3 mmol) in DMF (270 mL) was degassed and purged with N2 three times at -70 °C. A solution of t-BuOK (179 Ml, 1 M in THF) was added dropwise to the mixture at -70 °C under N2. The mixture was stirred at -70 °C for 1 h. The reaction mixture was quenched with sat. NH4Cl (270 mL) at -70 °C. The mixture was warmed up to -40 °C. To the above reaction mixture was added slowly 12N HCl (60 mL). The reaction mixture was stirred at 70 °C for 16 h. The pH of the mixture was adjusted to 9 with Na2CO3. Then Boc2O (45 mL, 193.8 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with sat. NaCl (1000 mL) and extracted with EtOAc (1500 mL × 3). The combined organic layerswere dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 3% of EtOAc in petroleum ether) to give the title compound (Intermediate 16, 11 g, 38% yield) as a yellow oil. MS: m / z = 250.0 [M + H - tBu]+.1H NMR (400 MHz, Chloroform-d) δ 4.01 - 3.90 (m, 1H), 3.71 (s, 3H), 3.62 - 3.48 (m, 1H), 3.35 - 3.24 (m, 1H), 3.18 (d, J = 13.6 Hz, 1H), 2.41 - 2.24 (m, 2H), 1.45 (s, 9H), 1.38 (d, J = 3.2 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -88.29, -88.43, -90.18, - 90.33, -90.46.

[0407] Intermediate 17: (S)-(4-(difluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0408] Step 1: Methyl (S)-4-(difluoromethylene)-3-methylpiperidine-3-carboxylate

[0409] A mixture of Intermediate 16 (2 g, 6.55 mmol) in HCl (20 mL, 2 M in EtOAc) was stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the titleAttorney Docket No.62619-738601 compound (1.58 g, HCl salt) as a white solid, which was used in next step without further purification.

[0410] Step 2: Methyl (S)-4-(difluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate

[0411] To a suspension of NaH (745 mg, 18.6 mmol, 60% purity) in THF (20 mL) was added methyl(S)-4-(difluoromethylene)-3-methylpiperidine-3-carboxylate (1.58 g, 6.54 mmol, HCl salt) at 0 °C under N2. The mixture was stirred at 0 °C under N2 for 0.5 h. Then trideuterio(iodo)methane (1.08 g, 7.45 mmol) was added to the mixture at 0 °C under N2, and the mixture was stirred at 0 °C under N2for 5 h. The reaction mixture was quenched with sat. NH4Cl (20 mL) at 0 °C, diluted with H2O (20 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 3% of MeOH in CH2Cl2) to give the title compound (320 mg, 22% yield over 2 steps) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 3.72 (s, 3H), 3.09 (d, J = 11.2 Hz, 1H), 2.72 - 2.64 (m, 1H), 2.45 - 2.31 (m, 1H), 2.28 - 2.14 (m, 1H), 2.04 - 1.94 (m, 1H), 1.88 (d, J = 11.2 Hz, 1H), 1.39 (d, J = 5.2 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -89.48, -89.63, -89.80, -89.95

[0412] Step 3: (S)-(4-(difluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0413] To a solution of methyl (S)-4-(difluoromethylene)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate (320 mg, 1.44 mmol) in THF (3 mL) was added dropwise LiAlD4 (80 mg, 1.73 mmol) at 0 °C under N2. The mixture was stirred at 0 °C under N2for 1 h. The reaction mixture was slowly quenched with Na2SO4•10H2O (100 mg) at 0 °C and filtered. The filter cake was washed with 10% of CH3OH in CH2Cl2 (20 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 8% of MeOH in CH2Cl2) to give the title compound (Intermediate 17, 250 mg, 84% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 4.94 - 4.30 (m, 1H), 2.84 - 2.77 (m, 1H), 2.72 - 2.66 (m, 1H), 2.63 - 2.52 (m, 1H), 2.45 - 2.37 (m, 1H), 2.04 (d, J = 11.2 Hz, 1H), 2.00 - 1.91 (m, 1H), 1.06 (d, J = 5.6 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -88.59, -88.75, - 89.17, -89.33.

[0414] Intermediate 18: ((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-olAttorney Docket No.62619-738601

[0415] Step 1: 1-(tert-Butyl) 3-methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate

[0416] A solution of Intermediate 16 (1.0 g, 3.27 mmol) in MeOH (10mL) was added to a suspensionof Pd / C (500 mg, 10%) in MeOH (5 mL) at 25 °C under Ar. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 35 °C for 5 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (CH2Cl2: MeOH = 20 / 1 to 10 / 1) to give the title compound (900 mg, 86% yield) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 6.36 - 5.97 (m, 1H), 4.41 - 4.01 (m, 2H), 3.77 - 3.60 (m, 3H), 2.90 - 2.52 (m, 2H), 1.93 - 1.78 (m, 2H), 1.76 - 1.66 (m, 1H), 1.44 (s, 9H), 1.29 (d, J = 3.2 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ - 113.96, -113.97, -114.11, -114.74, -114.76, -114.89, -117.96, -117.98, 118.34.

[0417] Step 2: Methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate

[0418] A solution of 1-(tert-butyl) 3-methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (900 mg, 2.93 mmol) in HCl (2M in EtOAC, 20 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (700 mg, crude) as a white solid, which was used in the next step without further purification.

[0419] Step 3: Methyl (3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate

[0420] To a mixture of methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate (700 mg,2.87 mmol) in THF (10 mL) was added NaH (345 mg, 8.62 mmol, 60% purity) at 0 °C under N2, and the mixture was stirred at 0 °C under N2for 0.5 h. Then CD3I (268 μL, 4.31 mmol) was added at 0 °C under N2, and the mixture was stirred at 0 °C for 5 h. The reaction mixture was quenched with sat. NH4Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous MgSO4,filtered and concentrated under reduced pressure. The residue was purified by silica flash gel chromatography (eluent: 0 ~ 4% MeOH in CH2Cl2) to give the title compound (500 mg, 83% yield over 2 steps) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 6.56 - 6.13 (m, 1H), 3.72 (s, 3H), 3.10 (d, J = 11.6 Hz, 1H), 2.97 - 2.82 (m, 1H), 1.96 - 1.84 (m, 2H), 1.77 - 1.70 (m, 2H), 1.65 - 1.56 (m, 1H), 1.26 (d, J = 3.6 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -112.73, -113.50, -116.61, 117.38.

[0421] Step 4: ((3S,4S)-4-(Difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0422] To a solution of methyl (3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidine-3-carboxylate (500 mg, 2.23 mmol) in THF (5 mL) was added LiAlD4 (154 mg, 3.34 mmol) at 0 °C under N2. The mixture was stirred at 0 °C under N2for 1 h. The reaction mixture was quenched slowly with Na2SO4•10H2O (150 mg). The organic layer was dried over anhydrousAttorney Docket No.62619-738601 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (CH2Cl2 : MeOH = 20:1 to 10:1) to give the title compound (Intermediate 18, 400 mg, 90% yield) as a white solid. MS: m / z = 199.3 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 5.95 (dt, J = 5.6, 56.4 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 2.22 - 2.08 (m, 1H), 2.00 - 1.87 (m, 2H), 1.77 - 1.66 (m, 2H), 0.85 (d, J = 2.0 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -114.61, -115.37, -120.05, 120.81.

[0423] Intermediate 19: N-(6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine

[0424] Step 1: 5-(2-(4-Chlorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0425] To an ice-cooled solution of (4-chlorophenyl)acetic acid (10 g, 58.62 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (8.5 g, 58.97 mmol) in DCM (100 mL) under N2were added N-(N- cyclohexylcarboximidoyl)cyclohexanamine (13.3 g, 64.45 mmol) and DMAP (7.9 g, 64.66 mmol). The reaction mixture was stirred in an ice bath for 16 hours. The resulting mixture was warmed to room temperature, filtered, diluted with DCM (300 mL), and washed with saturated aqueous NaHSO4 (3 x 100 mL) and brine (100 mL). The organic layer was concentrated under reduced pressure to afford the title compound (19 g, crude used through) as a yellow solid. MS: m / z = 295.00 [M - H]-.

[0426] Step 2: tert-Butyl 4-(4-chlorophenyl)-3-oxobutanoate

[0427] A solution of 5-(2-(4-chlorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 33.70mmol) in tert-Butanol (100 mL) was heated at 88 °C for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 20% EA in PE) to afford the title compound (6.5 g, 79% yield for two steps) as an orange oil. MS: m / z = 267.05 [M - H]-.1H NMR (300Attorney Docket No.62619-738601 MHz, Chloroform-d) δ 7.32 - 7.29 (m, 2H), 7.17 - 7.11 (m, 2H), 3.80 (s, 2H), 3.38 (s, 2H), 1.49 - 1.44 (m, 9H).

[0428] Step 3: 4-(4-Chlorophenyl)-3-oxobutanoic acid

[0429] To a solution of tert-butyl 4-(4-chlorophenyl)-3-oxobutanoate (12.4 g, 46.14 mmol) in DCM(124 mL) under N2 was added trifluoroacetic acid (124 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and then co-evaporated with toluene (three times, 200 mL each) to afford the title compound (11.2 g, crude used through) as a yellow solid. MS: m / z = 211.05 [M - H]-.

[0430] Step 4: 7-Chloronaphthalene-1,3-diol

[0431] A solution of 4-(4-chlorophenyl)-3-oxobutanoic acid (11.7 g, crude) intrifluoromethanesulfonic acid (351 mL) was stirred at room temperature for 16 hours. The resulting mixture was quenched with sat. NaHCO3 (700 mL) in an ice bath and extracted with ethyl acetate (3 x 700 mL). The combined organic layers were washed with brine (4 x 1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 22% EA in PE) to afford the title compound (8 g, 85% yield for two steps) as a yellow solid. MS: m / z = 193.05 [M - H]-.1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.66 (s, 1H), 7.91 - 7.90 (m, 1H), 7.62 - 7.60 (m, 1H), 7.38 - 7.31 (m, 1H), 6.63 - 6.48 (m, 2H).

[0432] Step 5: 7-Chloro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0433] To a solution of 7-chloronaphthalene-1,3-diol (7.8 g, 40.08 mmol) and (2-bromoethynyl)triisopropylsilane (11.00 g, 42.08 mmol) in 1,4-dioxane (78 mL) were added [Ru(p-Cymene)Cl2]2 (2.45 g, 4.00 mmol) and KOAc (7.87 g, 80.16 mmol) at room temperature. The reaction mixture was heated at 110 °C for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 10% EA in PE) to afford the title compound (11.7 g, 73% yield) as a brown oil. MS: m / z = 373.05 [M - H]-.1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.75 (s, 1H), 7.60 - 7.58 (m, 1H), 7.41 - 7.36 (m, 1H), 6.63 - 6.60 (m, 2H), 1.21 - 1.03 (m, 21H).

[0434] Step 6: 7-Chloro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate)

[0435] To an ice-cooled solution of 7-chloro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (4.6 g,12.26 mmol) in DCM (46 mL) under N2 were added DIEA (9.53 g, 73.72 mmol) and (trifluoromethane)sulfonyl trifluoromethanesulfonate (13.88 g, 49.19 mmol). The reaction mixture was stirred in an ice bath for 2 hours. The resulting mixture was diluted with H2OAttorney Docket No.62619-738601 (150 mL) and extracted with DCM (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 PE) to afford the title compound (7 g, 89% yield) as a brown oil. MS: m / z = 637.15 [M - H]-.

[0436] Step 7: 7-Chloro-3-((diphenylmethylene)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonate

[0437] To a solution of 7-chloro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diylbis(trifluoromethanesulfonate) (7 g, 10.95 mmol) and diphenylmethanimine (2.44 g, 13.47 mmol) in toluene (70 mL) under N2 were added XantPhos (380.27 mg, 0.65 mmol), Pd2(dba)3 (100.30 mg, 0.11 mmol) and Cs2CO3(7.14 g, 21.90 mmol) under N2. The reaction mixture was heated at 100 °C for 2 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by trituration with MeOH (3 x 30 mL) to afford the title compound (3.5 g, 48% yield) as a yellow solid. MS: m / z = 670.15 [M + H]+.

[0438] Step 8: N-(6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine

[0439] To a solution of 7-chloro-3-((diphenylmethylene)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3.5 g, 5.22 mmol) and bis(pinacolato)diboron (3.33 g, 13.10 mmol) in 1,4-dioxane (35 mL) under N2 were added Pd(dppf)Cl2•CH2Cl2(111.14 mg, 1.04 mmol) and KOAc (2.07 g, 21.04 mmol) at room temperature. The reaction mixture was heated at 100 °C for 3 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 3% EA in PE) to afford the title compound (Intermediate 19, 1.21 g, 36% yield) as a yellow solid. MS: m / z = 648.45 [M + H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.79 - 7.75 (m, 2H), 7.56 - 7.36 (m, 6H), 7.25 - 7.14 (m, 6H), 1.29 - 1.27 (m, 12H), 1.17 - 1.12 (m, 21H).

[0440] Intermediate 20: N-(6-Chloro-4-(2,8-difluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimineAttorney Docket No.62619-738601

[0441] To a solution of Intermediate 6 (94.6 mg, 0.29 mmol) and Intermediate 19 (278.12 mg, 0.43mmol) in THF (5.73 mL) and H2O (1.15 mL) under N2 were added CataCXium A Pd G3 (41.67 mg, 0.06 mmol) and K3PO4(364.93 mg, 1.72 mmol) at room temperature. The reaction mixture was heated at 80 °C for 1 hour. The resulting mixture was cooled to room temperature, diluted with H2O (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep- TLC (PE : EA = 1 : 1) to afford a crude product. The crude product was purified by Prep- HPLC with following conditions: Column: X-bridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; Mobile Phase A: 10 mM aq. NH4HCO3; Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 70% B to 95% B in 12 min; Detector: UV 254 & 220 nm. The product-containing fractions were combined, concentrated and then lyophilized overnight to give the title compound (Intermediate 20, 30 mg, 13% yield) as a yellow solid. MS: m / z = 816.25 [M + H]+.

[0442] Intermediate 21: (1S,7S,8S)-2-(7-Chloro-2-fluoro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0443] Step 1: (1S,7S,8S)-2-(2,7-Dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0444] To a stirred solution of 2,4,7-trichloro-8-methylpyrido[4,3-d]pyrimidine (200 mg, 0.81 mmol)and (1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (refer to Intermediate 5 & 6 for detail procedures, 170.68 mg, 0.81 mmol) in DCM (5 mL) was added DIEA (312.08 mg, 2.42 mmol) dropwise at -40 °C under N2. The reaction mixture was stirred at -40 °C for 1 hour. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3 x 30 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 Prep- TLC (PE / EA 3 : 1) to afford the title compound (Intermediate 21, 200 mg, 72% yield) as a light yellow solid. MS: m / z = 343.05, 345.05 [M + H]+.1H NMR (400 MHz, Chloroform-d) δAttorney Docket No.62619-738601 9.40 (s, 1H), 4.67 - 4.62 (m, 1H), 4.43 - 4.22 (m, 2H), 3.96 - 3.82 (m, 3H), 3.69 - 3.62 (m, 1H), 3.28 (s, 1H), 2.67 (s, 3H), 2.35 - 2.30 (m, 1H).

[0445] Step 2: (1S,7S,8S)-2-(7-Chloro-2-fluoro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0446] To a stirred solution of (1S,7S,8S)-2-(2,7-dichloro-8-methylpyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (220 mg, 0.64 mmol) in DMSO (3.0 mL) under N2 was added KF (55.87 mg, 0.96 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with EA (100 mL), washed with water (3 x 30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with DCM / EA (5 : 1)) to afford the title compound (Intermediate 21, 180 mg, 85% yield) as a light yellow solid. MS: m / z = 327.05 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.43 - 9.40 (m, 1H), 4.69 - 4.61 (m, 1H), 4.42 - 4.22 (m, 2H), 3.98 - 3.86 (m, 3H), 3.71 - 3.62 (m, 1H), 3.29 (bs, 1H), 2.67 - 2.65 (m, 3H), 2.35 (bs, 1H).19F NMR (376 MHz, Chloroform-d) δ -39.85 (s, 1F), -207.11 (s, 1F).

[0447] Intermediate 22: (S)-(3-Methyl-1-(methyl-d3)-4-methylenepiperidin-3-yl)methan-d2-ol

[0448] Step 1: 1-(tert-Butyl) 3-methyl (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate

[0449] To a suspension of CH3PPh3Br (16.5 g, 46.07 mmol) in THF (50 mL) was added t-BuOK (5.17g, 46.07 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h. Intermediate 10 (5 g, 18.43 mmol) was added to the above mixture at 25 °C under N2. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with H2O (50 mL) at 25 °C, diluted with EtOAc (20 mL), and extracted with EtOAc (25 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Petroleum ether / Ethyl acetate = 10 / 1) to give the title compound (4.5 g, 91% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 4.92 (s, 1H), 4.80 (s, 1H), 4.24 (d, J = 12.4 Hz, 1H), 3.90-3.78 (m, 1H),Attorney Docket No.62619-738601 3.63 (s, 3H), 3.00-2.89 (m, 1H), 2.74 (d, J = 12.8 Hz, 1H), 2.42-2.16 (m, 2H), 1.41 (s, 9H), 1.27 (s, 3H)

[0450] Step 2: Methyl (S)-3-methyl-4-methylenepiperidine-3-carboxylate hydrochloride

[0451] A mixture of 1-(tert-butyl) 3-methyl (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate(2.2 g, 8.17 mmol) in HCl (2 M in 1,4-dioxane, 24 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the title compound (2.2 g, crude) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 10.46 (s, 1H), 9.00-8.60 (m, 1H), 5.15 (s, 1H), 5.10 (s, 1H), 3.82 (s, 3H), 2.99-2.86 (m, 1H), 2.82-2.70 (m, 1H), 2.68-2.56 (m, 1H), 2.55- 2.44 (m, 1H), 1.98 (brs, 2H), 1.42 (s, 3H).

[0452] Step 3: Methyl (S)-3-methyl-1-(methyl-d3)-4-methylenepiperidine-3-carboxylate

[0453] To a solution of methyl (S)-3-methyl-4-methylenepiperidine-3-carboxylate hydrochloride (1.3g, 6.32 mmol) in THF (25 mL) was added NaH (759 mg, 18.96 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. CD3I (393 μL, 6.32 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, quenched with aq. NH4Cl (10 mL) at 0 °C, diluted with EtOAc (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent: 0 ~ 15% CH2Cl2 in MeOH) to give the title compound (610 mg, 52% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 4.89 (s, 1H), 4.77 (s, 1H), 3.59 (s, 3H), 3.07 (dd, J = 1.6, 10.8 Hz, 1H), 2.76-2.61 (m, 1H), 2.41-2.27 (m, 1H), 2.24-2.16 (m, 1H), 1.87 (dt, J = 3.6, 11.2 Hz, 1H), 1.71 (d, J = 10.8 Hz, 1H), 1.21 (s, 3H)

[0454] Step 4: (S)-(3-Methyl-1-(methyl-d3)-4-methylenepiperidin-3-yl)methan-d2-ol

[0455] To a solution of methyl (S)-3-methyl-1-(methyl-d3)-4-methylenepiperidine-3-carboxylate (610mg, 3.27 mmol) in THF (8 mL) was added LiAlD4 (226 mg, 4.91 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was quenched slowly with Na2SO4•10H2O (0.2 g), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (MeOH / CH2Cl2 = 1 / 10) to give the title compound (Intermediate 22, 210 mg, 40% yield) as a yellow oil. MS: m / z = 161.3 [M+ H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 4.67 (d, J = 34.0 Hz, 2H), 2.60-2.54 (m, 1H), 2.48-2.42Attorney Docket No.62619-738601 (m, 1H), 2.37-2.26 (m, 1H), 2.20-2.12 (m, 1H), 2.06-1.92 (m, 1H), 1.74 (d, J = 10.8 Hz, 1H), 0.95 (s, 3H).

[0456] Intermediate 23 & 24: 1-(tert-Butyl) 2-ethyl (R)-2-methyl-3-oxopyrrolidine-1,2-dicarboxylate& 1-(tert-butyl) 2-ethyl (S)-2-methyl-3-oxopyrrolidine-1,2-dicarboxylate

[0457] To a solution of 1-(tert-butyl) 2-ethyl 3-oxopyrrolidine-1,2-dicarboxylate (95 g, 369 mmol) inACN (950 mL) were added K2CO3(127 g, 9.23 mol) and CH3I (57.5 mL, 9.23 mol) at 0 °C. The mixture was stirred at 45 °C for 16 h. The reaction mixture was quenched with sat. NH4Cl aq. (1000 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% of ethyl acetate in petroleum ether) to give 1-(tert-butyl) 2-ethyl 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate (48 g). Then it was was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [CO2- MeOH (0.1% NH3•H2O)]; B%: 10%, isocratic elution mode) to give the title compound (Intermediate 23, SFC peak 1, 21.4 g, 23% yield over 2 steps) as a yellow oiland the other title compound (Intermediate 24, SFC peak 2, 22.7 g, 25% yield over 2 steps) as ayellow oil. Spectra for Intermediate 23:1H NMR (400 MHz, Chloroform-d) δ 4.31 - 4.04 (m, 2H), 3.91 - 3.77 (m, 1H), 3.75 - 3.65 (m, 1H), 2.81 - 2.56 (m, 2H), 1.64 - 1.54 (m, 3H), 1.51 - 1.36 (m, 9H), 1.30 - 1.15 (m, 3H). Spectra for Intermediate 24:1H NMR (400 MHz, Chloroform-d) δ 4.23 - 4.06 (m, 2H), 3.92 - 3.77 (m, 1H), 3.75 - 3.63 (m, 1H), 2.81 - 2.51 (m, 2H), 1.56 (s, 3H), 1.48 - 1.37 (m, 9H), 1.31 - 1.15 (m, 3H).

[0458] Intermediate 25 & 26: 1-(tert-Butyl) 2-ethyl (R,E)-3-(fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylate & 1-(tert-butyl) 2-ethyl (R,Z)-3-(fluoromethylene)-2-methylpyrrolidine-1,2- dicarboxylate

[0459] A mixture of fluoromethyl(triphenyl)phosphonium tetrafluoroborate (6.34 g, 16.6 mmol) inTHF (30 mL) was degassed and purged with N2three times. t-BuOK (16.6 mL, 1 M in THF) was added dropwise to the above mixture at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. A solution of Intermediate 23 (3 g, 11.1 mmol) in THF (15 mL) was added to the mixture at -70 °C under N2. The mixture was stirred at 25 °C for 16 h under N2.Attorney Docket No.62619-738601 The reaction mixture was quenched with sat. NH4Cl aq. (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% of ethyl acetate in petroleum ether) to give the title compound (Intermediate 25, 930 mg, 29% yield, spot 1 with lower polarity) as a yellow oil and the other title compound (Intermediate 26, 980 mg, 31% yield, spot 2 with larger polarity) as a yellow oil. Spectra for Intermediate 25:1H NMR (400 MHz, Chloroform-d) δ 6.78 - 6.50 (m, 1H), 4.29 - 4.04 (m, 2H), 3.77 - 3.47 (m, 2H), 2.77 - 2.61 (m, 2H), 1.72 - 1.61 (m, 3H), 1.48 - 1.38 (m, 9H), 1.30 - 1.17 (m, 3H).19F NMR (376 MHz, Chloroform-d) δ. -134.08, -134.40. Spectra for Intermediate 26:1H NMR (400 MHz, Chloroform-d) δ1H NMR (400 MHz, Chloroform-d) δ 6.57 - 6.33 (m, 1H), 4.30 - 4.08 (m, 2H), 3.71 - 3.52 (m, 2H), 2.56 - 2.45 (m, 2H), 1.73 - 1.66 (m, 3H), 1.45 - 1.41 (m, 9H), 1.28 - 1.22 (m, 3H).19F NMR (376 MHz, Chloroform-d) δ - 129.92, -130.03.

[0460] Intermediate 27: (R,E)-(3-(Fluoromethylene)-2-methyl-1-(methyl-d3)pyrrolidin-2-yl)methan-d2-ol

[0461] To a solution of Intermediate 25 (600 mg, 2.09 mmol) in THF (15 mL) was added LiAlD4 (396mg, 10.4 mmol) slowly at 0 °C under N2. The mixture was stirred at 70 °C for 3 h. D2O (0.4 mL) was added dropwise to the reaction mixture at 0 °C under N2. 15 wt% NaOH (0.4 mL) and water (1.2 mL) were added dropwise. The mixture was stirred at 20 °C for another 0.5 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% of MeOH in CH2Cl2) to the title compound (Intermediate 27, 262 mg, 76% yield) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 6.69 - 6.43 (m, 1H), 3.09 - 3.02 (m, 1H), 2.63 - 2.55 (m, 2H), 2.52 - 2.38 (m, 1H), 0.95 (s, 3H). 19F NMR (376 MHz, Chloroform-d) δ. -137.97.

[0462] Intermdiate 28: (R,Z)-(3-(Fluoromethylene)-2-methyl-1-(methyl-d3)pyrrolidin-2-yl)methan-d2-ol

[0463] Intermediate 28 was prepared in a similar manner to Example 27. MS: m / z = 165.3 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 6.64 - 6.27 (m, 1H), 3.06 - 2.99 (m, 1H), 2.65 - 2.55 (m,Attorney Docket No.62619-738601 1H), 2.44 - 2.31 (m, 1H), 2.30 - 2.23 (m, 1H), 1.06 (s, 3H).19F NMR (376 MHz, Chloroform- d) δ -135.25.

[0464] Intermediate 29 & 30: Benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (transmixture) & benzyl 8-chloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (cis mixture)

[0465] Step 1: Benzyl 8,8-dichloro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate

[0466] To an ice-cooled solution of Intermediate 2 (20 g, 85.73 mmol) and TBAI (6.33 g, 17.14mmol) in DCM (100 mL) and NaOH (200 mL, 50% aq.) under N2was 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]+.1H NMR (400 MHz, Chloroform-d) δ 7.50 - 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).

[0467] 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 nitrogen atmosphere 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 (trans mixture) (Intermediate 29, 4.8 g, 53% yield) as an off-white semi-solid. MS: m / z = 282.05 [M + H]+.1H NMR (300 MHz, Chloroform-d) δ 7.46 - 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 title compound (cis mixture) (Intermediate 30, 2.2 g, 24% yield) as a yellow oil.1H NMR (300Attorney Docket No.62619-738601 MHz, Chloroform-d) δ 7.41 - 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).

[0468] Intermediate 31: 8-Chloro-2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

[0469] Step 1: 8-Chloro-5-oxa-2-azabicyclo[5.1.0]octane hydrobromide (trans mixture)

[0470] A mixture of Intermediate 29 (1.8 g, 6.39 mmol) in HBr (33wt% in AcOH, 18 mL) undernitrogen atmosphere was stirred in an ice bath for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was triturated with hexane (3 x 50 mL) to afford the title compound (1.2 g, crude used through) as a yellow solid.

[0471] Step 2: 8-Chloro-2-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

[0472] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1027.43 mg, 4.07 mmol) inDCM (10 mL) under N2were added DIEA (1578.05 mg, 12.21 mmol) and 8-Chloro-5-oxa-2- azabicyclo[5.1.0]octane hydrobromide (trans mixture) (930 mg, crude) at -40 °C. The reaction mixture was stirred at - 40 °C for 1 hour. The resulting mixture was quenched with water (50 mL) and extracted with DCM (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 30% EA in PE) to give the title compound (Intermediate 31, 1.4 g, 94% yield) as a light yellow solid. MS: m / z = 362.90, 364.90 [M + H]+.

[0473] Intermediate 32 & 33: (1R,7R,8R)-8-Chloro-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-8-chloro-2-(7-chloro-2,8-difluoropyrido[4,3- d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octaneAttorney Docket No.62619-738601

[0474] Step 1: 8-Chloro-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture)

[0475] To a solution of Intermediate 31 (2.5 g, 6.876 mmol) in DMSO (10 mL) was added KF (0.60 g,10.314 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 CH2Cl2 (200 mL), washed with water (3 x 80 mL) and brine (80 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 (2 g, 83% yield) as a yellow solid. MS: m / z = 347.00, 349.00 [M + H]+.

[0476] Step 2: (1R,7R,8R)-8-Chloro-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane & (1S,7S,8S)-8-chloro-2-(7-chloro-2,8-difluoropyrido[4,3- d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane

[0477] 8-Chloro-2-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-5-oxa-2-azabicyclo[5.1.0]octane (trans mixture) (2 g, 5.76 mmol) was separated by Prep-SFC with the following conditions: Column: CHIRAL ART Cellulose-SJ, 3 x 25 cm, 5 μm; Mobile Phase A: CO2; Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 30% B; RT1: 3.8 min; RT2: 4.8 min. The first eluting peak (RT1: 3.8 min) was concentrated and lyophilized to give the title compound (Intermediate 32, 850 mg, 42% yield) as a yellow lyophilized powder. MS: m / z = 346.95, 348.95 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.38 (s, 1H), 4.76 - 4.42 (m, 2H), 4.10 - 3.89 (m, 2H), 3.88 - 3.63 (m, 3H), 3.10 - 2.92 (m, 1H), 2.20 (s, 1H).19F NMR (376 MHz, Chloroform-d) δ -38.41 (s, 1F), - 133.42- -134.51 (d, 1F). The second eluting peak (RT2: 4.8 min) was concentrated and lyophilized to give the title compound (Intermediate 33, 670 mg, 33%yield) as a yellow lyophilized powder. MS: m / z = 346.95, 348.95 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.38 (s, 1H), 4.67 - 4.42 (m, 2H), 4.08 - 3.65 (m, 5H), 3.03 (s, 1H), 2.20 (s, 1H).19F NMR (376 MHz, CDCl3) δ 38.41 (s, 1F), -132.41 - -133.50 (m, 1F).

[0478] Intermediate 34: 6-Fluoro-4-(2-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amineAttorney Docket No.62619-738601

[0479] A mixture of Intermediate 21 (1.85 g, 5.66 mmol), K3PO4 (3.61 g, 17.0 mmol), Intermediate 8(3.97 g, 8.49 mmol) and Ad2nBuP-Pd-G3 (cataCXiumAPdG3) (412 mg, 566 μmol) in 1,4- dioxane (20 mL) and H2O (4 mL) was purged, degassed with N2three times, and stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 4% of MeOH in CH2Cl2) to give the title compound (Intermediate 34, 4.05 g, 96% yield) as a brown solid. MS: m / z = 632.4 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.78 - 9.61 (m, 1H), 7.70 - 7.57 (m, 1H), 7.23 - 7.14 (m, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 4.60 (d, J = 14.0 Hz, 1H), 4.55 - 4.34 (m, 2H), 3.95 - 3.85 (m, 3H), 3.72 - 3.67 (m, 1H), 3.37 - 3.18 (m, 1H), 2.41 (s, 3H), 2.37 - 2.26 (m, 1H), 0.90 - 0.84 (m, 18H), 0.54 - 0.39 (m, 3H).19F NMR (376 MHz, Chloroform-d) δ -41.11, -107.86, -206.59.

[0480] Intermediate 35 & 36: Benzyl (1R,7S,8R)-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate &Benzyl (1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate

[0481] Benzyl-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (trans) (35 g) was separated by SFC(column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2 - MeOH (0.1% NH3•H2O)]; B% : 20%, isocratic elution mode) to give the title compound (Intermediate 35, SFC peak 2, retention time: 1.236 min, 13.7 g, 39% yield) as a colorless oil and the other title compound (Intermediate 36, SFC peak 1, retention time: 1.002 min, 14.0 g, 40% yield) as a colorless oil. Spectra for Intermediate 35:1H NMR (400 MHz, Chloroform-d) δ 7.45 - 7.28 (m, 5H), 5.27 - 5.08 (m, 2H), 4.74 - 4.30 (m, 1H), 4.13 - 3.90 (m, 1H), 2.99 - 2.84 (m, 2H), 2.37 - 2.19 (m, 1H), 1.80 - 1.67 (m, 2H), 1.66 - 1.53 (m, 1H), 1.59 - 1.53 (m, 2H), 1.12 - 0.98 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -203.93, -204.35. Spectra for Intermediate 36: MS: m / z = 264.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.47 - 7.28 (m, 5H), 5.28 - 5.06 (m, 2H), 4.75 - 4.32 (m, 1H), 4.15 - 3.90 (m, 1H), 2.99 - 2.82 (m, 2H), 2.35 - 2.22 (m,Attorney Docket No.62619-738601 1H), 1.81 - 1.68 (m, 2H), 1.67 - 1.58 (m, 1H), 1.51 - 1.37 (m, 2H), 1.12 - 0.97 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -204.36.

[0482] Intermediate 37: 7-Chloro-2,8-difluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine

[0483] Step 1: tert-Butyl (1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate

[0484] To a solution of Intermediate 36 (10 g, 37.9 mmol) in MeOH (110 mL) was added wet Pd / C(4.04 g, 10% purity) and Boc2O (10.5 mL, 45.5 mmol) under Ar. The suspension was degassed and purged with H2 three 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. Pd / C was filtered off and washed with MeOH (100 mL x 3). The combined organic phases were evaporated. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of ethyl acetate in petroleum ether) to give the title compound (8.4 g, 96% yield) as a colorless oil. MS: m / z = 174.2 [M + H - t-Bu]+. 1H NMR (400 MHz, Chloroform-d) δ 4.51 - 4.24 (m,1H), 4.04 - 3.87 (m, 1H), 2.90 - 2.70 (m, 2H), 2.34 - 2.19 (m, 1H), 1.80 - 1.64 (m, 2H), 1.53 - 1.37 (m, 12H), 1.13 - 0.99 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -204.12, -205.16.

[0485] Step 2: (1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octane

[0486] To a solution of tert-butyl (1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (9.4 g,41.0 mmol) in CH2Cl2(50 mL) was added TFA (23.5 mL, 316 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (9.97 g, TFA salt) as a yellow oil.1H NMR (400 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.08 (s, 1H), 4.99 - 4.72 (m, 1H), 3.61 (m, 1H), 3.28 - 2.96 (m, 2H), 2.60 - 2.44 (m, 1H), 2.10 - 1.82 (m, 3H), 1.74 - 1.50 (m, 2H), 1.38 - 1.17 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -204.00.

[0487] Step 3: 2,7-Dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine

[0488] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.08 g, 8.22 mmol) in CH2Cl2(10 mL) was added DIPEA (7.2 mL, 41.1 mmol) at –40 °C under N2. A solution ofAttorney Docket No.62619-738601 (1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octane (2 g, 8.22 mmol, TFA salt) in CH2Cl2(10 mL) was added dropwise and then the mixture was stirred at -40 °C for 1 h under N2. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of ethyl acetate in petroleum ether) to give the title compound (2.6 g, 92% yield) as a yellow solid. MS: m / z = 345.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.30 (s, 1H), 4.78 - 4.50 (m, 1H), 4.39 (d, J = 13.2 Hz, 1H), 4.18 - 4.07 (m, 1H), 3.45 - 3.37 (m, 1H), 2.30 - 2.19 (m, 1H), 2.10 - 1.94 (m, 1H), 1.91 - 1.62 (m, 3H), 1.55 - 1.36 (m, 1H), 1.11 - 0.97 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ - 135.80, -205.38.

[0489] Step 4: 7-Chloro-2,8-difluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine

[0490] To a solution of 2,7-dichloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidine (2.7 g, 7.82 mmol) in DMSO (10 mL) was added KF (2.27 g, 39.1 mmol). The mixture was stirred at 100 °C for 1 h under N2. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 100% of dichloromethane) to give the title compound (Intermediate 37, 2 g, 71% yield) as a yellow solid. MS: m / z = 329.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.31 (s, 1H), 4.76 - 4.52 (m, 1H), 4.37 (d, J = 13.6 Hz, 1H), 4.21 - 4.05 (m, 1H), 3.33 - 3.25 (m, 1H), 2.31 - 2.18 (m, 1H), 2.12 - 2.00 (m, 1H), 1.93 - 1.57 (m, 3H), 1.54 - 1.34 (m, 1H), 1.12 - 0.91 (m, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -40.87, -136.17, -205.36.

[0491] Intermediate 38 & 39: 1-(tert-Butyl) 3-methyl (6R)-3,6-dimethyl-4-oxopiperidine-1,3-dicarboxylate & 1-(tert-butyl) 3-methyl (2R,3S)-2,3-dimethyl-4-oxopiperidine-1,3- dicarboxylateAttorney Docket No.62619-738601

[0492] Step 1: Methyl (R)-3-aminobutanoate

[0493] To a solution of (R)-3-aminobutanoic acid (25 g, 242 mmol) in MeOH (250 mL) was addedSOCl2(20 mL, 275 mmol) slowly at 0 °C under N2. The mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (38 g, HCl salt) as a brown solid, which was used in the next step without further purification. 1HNMR (400 MHz, Chloroform-d) δ 3.83 - 3.77 (m, 1H), 3.74 (s, 3H), 2.99 - 2.91 (m, 1H), 2.80 - 2.72 (m, 1H), 2.64 - 2.08 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H).

[0494] Step 2: Methyl (R)-3-((tert-butoxycarbonyl)(3-methoxy-3-oxopropyl)amino)butanoate

[0495] To a solution of methyl (R)-3-aminobutanoate (38 g, HCl salt) and methyl acrylate (23.2 mL,258 mmol) in CH2Cl2(360 mL) was added TEA (81.55 mL, 586 mmol) and DBU (1.77 mL, 11.72 mmol) at 25 °C. The mixture was stirred at 40 °C for 16 h. Boc2O (106 mL, 463 mmol) was added dropwise into the mixture at 0 °C and stirred at 25 °C for 1 h. The reaction mixture was quenched with citric acid aq. (500 mL) and extracted with CH2Cl2(250 mL × 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 ~ 20% of EtOAc in petroleum ether) to give the title compound (68 g, 90% yield of 2 steps) as a colorless oil.1HNMR (400 MHz, Chloroform-d) δ 4.51 - 4.13 (m, 1H), 3.70 - 3.64 (m, 6H), 3.50 - 3.30 (m, 2H), 2.70 - 2.57 (m, 2H), 2.56 - 2.41 (m, 2H), 1.46 (s, 9H), 1.23 (d, J = 7.2 Hz, 3H).

[0496] Step 3: 1-(tert-Butyl) 3-methyl (6R)-6-methyl-4-oxopiperidine-1,3-dicarboxylate &1-(tert-butyl) 3-methyl (2R)-2-methyl-4-oxopiperidine-1,3-dicarboxylate

[0497] A mixture of methyl (R)-3-((tert-butoxycarbonyl)(3-methoxy-3-oxopropyl)amino)butanoate(26 g, 77.14 mmol) in THF (500 mL) was degassed and purged with N2three times. t-BuOK (154 mL, 1 M in THF) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with sat. NH4Cl aq. (500 mL) and extracted with EtOAc (250 mL × 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 a mixture of the title compounds (20 g, 96% yield) as a colorless oil. MS: m / z = 216.1 [M + H - t-Bu]+.

[0498] Step 4: 1-(tert-Butyl) 3-methyl (6R)-3,6-dimethyl-4-oxopiperidine-1,3-dicarboxylate & 1-(tert-butyl) 3-methyl (2R,3S)-2,3-dimethyl-4-oxopiperidine-1,3-dicarboxylate

[0499] A mixture of 1-(tert-butyl) 3-methyl (6R)-6-methyl-4-oxopiperidine-1,3-dicarboxylate and 1-(tert-butyl) 3-methyl (2R)-2-methyl-4-oxopiperidine-1,3-dicarboxylate (20 g, 73.7 mmol) andAttorney Docket No.62619-738601 K2CO3(32.6 g, 236 mmol) in ACN (300 mL) was degassed and purged with N2three times. CH3I (14.7 mL, 236 mmol) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 25 °C for 16 h under N2. The reaction mixture was diluted with NH4Cl aq. (300 mL) and extracted with EtOAc (200 mL × 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 over 6 h) to give the title compound (Intermediate 38, spot 1 with lower polarity, 9.1 g, 54 % yield) as a colorless oil and the other title compound (Intermediate 39, spot 2 with larger polarity, 2.3 g, 14% yield) as a colorless oil. Spectra for Intermediate 38: MS: m / z = 230.1 [M + H - t-Bu]+. Spectra for Intermediate 39: MS: m / z = 186.1 [M + H - Boc]+.

[0500] Intermediate 40 & 41: 1-(tert-Butyl) 3-methyl (3R,6R)-3,6-dimethyl-4-oxopiperidine-1,3-dicarboxylate & 1-(tert-butyl) 3-methyl (3S,6R)-3,6-dimethyl-4-oxopiperidine-1,3- dicarboxylate

[0501] Intermediate 38 (9 g, 31.54 mmol) was separated by SFC (column: DAICEL CHIRALPAK IG(250 mm × 30 mm, 10 μm); mobile phase: [CO2- MeOH (0.1% NH3•H2O)]; B%: 10%, isocratic elution mode) to give the title compound (Intermediate 40, SFC peak 2, retention time: 0.558 min, 5.2 g, 57% yield) as a colorless oil and 1-(tert-butyl) 3-methyl (3S,6R)-3,6- dimethyl-4-oxopiperidine-1,3-dicarboxylate (Intermediate 41, SFC peak 1, retention time: 0.436 min, 1.45 g, 16% yield) as a colorless oil. Spectra for Intermediate 40:1HNMR (400 MHz, Chloroform-d) δ 4.67 - 4.50 (m, 1H), 4.11 (d, J = 14.0 Hz, 1H), 3.78 (d, J = 14.4 Hz, 1H), 3.75 (s, 3H), 2.80 - 2.67 (m, 1H), 2.46 - 2.32 (m, 1H), 1.60 - 1.57 (m, 1H), 1.47 (s, 9H), 1.40 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H). Spectra for Intermediate 41:1HNMR (400 MHz, Chloroform-d) δ 5.03 - 4.46 (m, 2H), 3.70 (s, 3H), 3.00 - 2.86 (m, 2H), 2.32 - 2.20 (m, 1H), 1.48 (s, 9H), 1.26 (s, 3H), 1.12 (d, J = 7.2 Hz, 3H).

[0502] Intermediate 42: ((3S,6R,E)-4-(Fluoromethylene)-3,6-dimethyl-1-(methyl-d3)piperidin-3-yl)methan-d2-olAttorney Docket No.62619-738601

[0503] Step 1: 1-(tert-Butyl) 3-methyl (3S,6R,E)-4-(fluoromethylene)-3,6-dimethylpiperidine-1,3-dicarboxylate

[0504] A mixture of fluoromethyl(triphenyl)phosphonium;tetrafluoroborate (8.04 g, 21. mmol) in THF(30 mL) was degassed and purged with N2three times. t-BuOK (18.9 mL, 1 M in THF) was added dropwise to the mixture at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. A solution of Intermediate 40 (3 g, 10.5 mmol) in THF (10 mL) was added dropwise to the mixture at -70 °C under N2. The mixture was warmed to 25 °C slowly and stirred at 25 °C for another 2 h under N2. The reaction mixture was quenched with sat. NH4Cl aq. (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of EtOAc in petroleum ether) to give the title compound (2.3 g, 69% yield) as a colorless oil.1HNMR (400 MHz, Chloroform-d) δ 6.68 - 6.41 (m, 1H), 4.35 - 4.22 (m, 1H), 3.87 - 3.79 (m, 1H), 3.74 (s, 3H), 3.45 (d, J = 13.6 Hz, 1H), 2.61 - 2.45 (m, 1H), 2.33 - 2.15 (m, 1H), 1.46 (s, 9H), 1.34 (s, 3H), 1.15 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -136.74.

[0505] Step 2: ((3S,6R,E)-4-(fluoromethylene)-3,6-dimethyl-1-(methyl-d3)piperidin-3-yl)methan-d2-ol

[0506] To a solution of methyl 1-(tert-butyl) 3-methyl 1-(tert-butyl) 3-methyl (3S,6R,E)-4-(fluoromethylene)-3,6-dimethylpiperidine-1,3-dicarboxylate (2.3 g, 6.87 mmol) in THF (30 mL) was added LiAlD4 (1.26 g, 27.5 mmol) at 0 °C under N2. The mixture was stirred at 70 °C under N2 for 15 h. The reaction mixture was quenched with D2O (1.3 ml) at 0 ~ 5 °C till no air bubbles released. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 5% of MeOH in CH2Cl2) to give the title compound (Intermediate 42, 1.03 g, 78% yield) as a colorless oil. MS: m / z = 193.2 [M + H]+.1HNMR (400 MHz, Chloroform-d) δ 6.62 - 6.33 (m, 1H), 2.80 - 2.71 (m, 2H), 2.20 - 2.10 (m, 2H), 1.99 - 1.89 (m, 1H), 1.13 (d, J = 6.0 Hz, 3H), 0.89 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -140.77.

[0507] Intermediate 43: ((3S,6R)-3,6-Dimethyl-1-(methyl-d3)-4-methylenepiperidin-3-yl)methan-d2-ol

[0508] Step 1: 1-(tert-Butyl) 3-methyl (3S,6R)-3,6-dimethyl-4-methylenepiperidine-1,3-dicarboxylate

[0509] A mixture of PPh3CH3Br (9.39 g, 26.3 mmol) in THF (25 mL) was added t-BuOK (26 mL, 1M in THF) at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h. A solution ofAttorney Docket No.62619-738601 Intermediate 40 (3 g, 10.5 mmol) in THF (10 mL) was added to the above mixture at 25 °C. The resulting mixture was stirred at 25 °C for another 2 h. The reaction mixture was quenched with sat. NH4Cl aq. (100 mL) at 25 °C and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 8% of EtOAc in petrol ether) to give the title compound (2 g, 67% yield) as a yellow oil. MS: m / z = 284.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 4.93 - 4.77 (m, 2H), 4.28 (s, 1H), 3.80 (d, J = 13.6 Hz, 1H), 3.73 (s, 3H), 3.50 (d, J = 14.0 Hz, 1H), 2.59 - 2.50 (m, 1H), 2.13 - 2.04 (m, 1H), 1.45 (s, 9H), 1.34 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H).

[0510] Step 2: ((3S,6R)-3,6-Dimethyl-1-(methyl-d3)-4-methylenepiperidin-3-yl)methan-d2-ol

[0511] To a mixture of 1-(tert-butyl) 3-methyl (3S,6R)-3,6-dimethyl-4-methylenepiperidine-1,3-dicarboxylate (2 g, 7.06 mmol) in THF (20 mL) was added LiAlD4 (1.34 g, 35.2 mmol) slowly at 0 °C under N2. The mixture was stirred at 70 °C for 16 h under N2. The reaction mixture was quenched with D2O (2.5 mL) at 0 ~ 5 °C till no air bubbles released. The mixture was filtered and filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% of MeOH in CH2Cl2) to give the title compound (Intermediate 43, 1 g, 81% yield) as a yellow oil. MS: m / z = 175.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 4.87 - 4.73 (m, 2H), 2.83 (d, J = 11.2 Hz, 1H), 2.61 - 2.46 (m, 1H), 2.24 (d, J = 14.4 Hz, 1H), 2.10 (d, J = 11.6 Hz, 1H), 2.05 - 1.95 (m, 1H), 1.11 (d, J = 3.2 Hz, 3H), 0.95 (s, 3H).

[0512] Intermediate 44: 7-Chloro-2-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methylpyrido[4,3-d]pyrimidine

[0513] Step 1: 2,7-Dichloro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methylpyrido[4,3-d]pyrimidine

[0514] To a solution of 2,4,7-trichloro-8-methylpyrido[4,3-d]pyrimidine (800 mg, 3.22 mmol) inCH2Cl2 (16 mL) were added DIPEA (1.66 g, 12.9 mmol) and (1S,7R,8S)-8-fluoro-2- azabicyclo[5.1.0]octane) (900 mg, 2.96 mmol, TFA salt) at -40 °C under N2. The reaction mixture was stirred at -40 °C for 1 h, then diluted with water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give aAttorney Docket No.62619-738601 residue. The residue was purified by flash silica gel chromatography (eluent: 0 ~ 15% ethyl acetate in petroleum ether) to give the title compound (1.1 g, crude) as a yellow solid. MS: m / z = 341.1 [M + H]+.

[0515] Step 2: 7-Chloro-2-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methylpyrido[4,3-d]pyrimidine

[0516] To a solution of 2,7-dichloro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methylpyrido[4,3-d]pyrimidine (1.1 g, 3.22 mmol) in DMSO (15 mL) was added KF (1.0 g, 17.6 mmol) at 25 ℃ under N2. The mixture was stirred at 100 ℃ for 10 h. The reaction mixture was quenched with H2O (50 mL) and EtOAc (20 mL × 3). The combined layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 7% ethyl acetate in petroleum ether) to give the title compound (Intermediate 44, 800 mg, 76% yield for two steps) as a yellow solid. MS: m / z = 325.1 [M + H]+.

[0517] Intermediate 45: (1S,7S,8S)-8-Fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0518] A mixture of benzyl (1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane-2-carboxylate (2.0 g,102 mmol, refer to Intermediate 3 and 4 for detail procedures) and HBr (10 mL, 30% in AcOH) was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 45, 1.6 g, HBr salt), which was used in the next step without further purification.

[0519] Intermediate 46: (1S,7S,8S)-2-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0520] To 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 N2was added Intermediate 45 (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 flashAttorney Docket No.62619-738601 chromatography (eluted with PE / EA (3 : 1) to afford the title compound (Intermediate 46, 1 g, 76% yield). MS: m / z = 407.85, 409.85 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.96 - 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-d) δ -106.59 (s, 1F), - 111.46 (s, 1F).

[0521] Intermediate 47: 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol

[0522] Step 1: Ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate

[0523] To a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (36 g, 164.7 mmol) and DMAP (2.0g, 16.5 mmol) in CH2Cl2 (300 mL) in a 1 L three-necked flask were added Boc2O (83 mL, 362.3 mmol) dropwise and TEA (69 mL, 494 mmol). The mixture was at 25 °C for 2 h. The reaction mixture was quenched with sat. NH4Cl aq. (1 L) and extracted with CH2Cl2 (500 mL× 3). The combined organic layers were washed with brine (2 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (70 g, 93 % yield), which was used in the next step without further purification. MS: m / z = 419.2 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.46 - 1.36 (m, 21H).19F NMR (376 MHz, Chloroform-d) δ -126.24.

[0524] Step 2: Ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate & ethyl2-bromo-4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate

[0525] To a solution of ethyl 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinate (14 g,33.4 mmol) in THF (100 mL) was added lithium:chloro-(2,2,6,6-tetramethyl-1- piperidyl)magnesium:chloride (60 mL, 1 M in THF) dropwise at -40 °C under N2 over 30 min. The mixture was stirred at this temperature for 4 h under N2. 1,2-Dibromo-1,1,2,2-tetrachloro-Attorney Docket No.62619-738601 ethane (4.81 mL, 40.1 mmol) was added dropwise at -40 °C under N2. The resulting mixture was stirred at -40 °C for an additional 4 h under N2. The mixture was quenched with sat. NH4Cl aq. (100 mL) slowly at -40 °C under N2and extracted with EtOAc (100 mL × 4). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 25% of CH2Cl2 in n-hexane) to give the title compound (8.2 g, 47% yield, spot 1). MS: m / z = 519.0, 521.1 [M + Na]+.1H NMR (400 MHz, Chloroform-d) δ 4.40 (q, J = 7.2 Hz, 2H), 1.46 (s, 18H), 1.38 (t, J = 7.2 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -127.79. Ethyl 2-bromo-4-((tert-butoxycarbonyl)amino)-6-chloro-5- fluoronicotinate (2.7 g, 20% yield, spot 2) was obtained. MS: m / z = 397.0, 398.9 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.13 (s, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.49 (s, 9H), 1.42 (t, J = 7.2 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ -130.03.

[0526] Step 3: Ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate

[0527] A solution of ethyl 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinate (21g, 42.2 mmol) in HCl (200 mL, 2M in EtOAc) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (13.5 g, 93% yield, HCl salt). MS: m / z = 296.9, 299.0 [M + H]+.1H NMR (Dimethylsulfoxide-d6) δ 7.21 (s, 2H), 4.36 - 4.32 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -131.18.

[0528] Step 4: Ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate

[0529] A mixture of ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate (13.5 g, 40.4 mmol, HClsalt), Pd(PPh3)2Cl2 (2.3 g,) and CuI (1.15 g, 6.1 mmol) in THF (120 mL) were added TEA (161.7 mmol, 22.5 mL) and ethynyl(triisopropyl)silane (48.5 mmol, 10.9 mL). The mixture was degassed and purged with N2three times. The mixture was stirred at 40 °C under N2for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15% of EtOAc in petroleum ether) to give the title compound (12.6 g, 76% yield). MS: m / z = 399.3 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 6.11 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.18 - 1.07 (m, 21H).19F NMR (376 MHz, Chloroform-d) δ -143.40.

[0530] Step 5: 4-Amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinic acid

[0531] To a solution of ethyl 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinate (7 g,17.5 mmol) in MeOH (20 mL) and THF (20 mL) was added NaOH (15 mL, 3 M in H2O). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The mixture was neutralized with 3M HCl aq. and extracted with EtOAc (80 mL xAttorney Docket No.62619-738601 3). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (6.5 g, 98% yield). MS: m / z = 371.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.28 (s, 2H), 1.11 - 1.09 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -143.63.

[0532] Step 6: 7-Chloro-8-fluoro-2-mercapto-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol

[0533] A mixture of 4-amino-6-chloro-5-fluoro-2-((triisopropylsilyl)ethynyl)nicotinic acid (20 g, 54mmol) in SOCl2(150 mL) was stirred at 50 °C under N2for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetone (150 mL) under N2and NH4SCN (8.2 g, 108 mmol) was added at 25 °C. The mixture was stirred at this temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15% of EtOAc in petroleum ether) to give the title compound (17.5 g, 77% yield). MS: m / z = 412.2 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 13.19 (s, 1H), 12.75 (s, 1H), 1.11-1.08 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -132.06.

[0534] Step 7: 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol

[0535] To a mixture of 7-chloro-8-fluoro-2-mercapto-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol (20 g, 42 mmol) and NaOH (62.6 mL, 1 M in H2O) in MeOH (150 mL) was added CH3I (2.4 mL, 39.1 mmol) dropwise at 25 °C under N2. The mixture was stirred at 25 °C under N2 for 1 h. The reaction mixture was quenched with water (150 mL) at 20 °C and neutralized with 3M HCl aq. to give a precipitate. The precipitate was filtered. The filter cake was washed with water (120 mL) and dried under reduced pressure to give the title compound (Intermediate 47, 115.5 g, 85% yield) as a yellow solid. MS: m / z = 426.1 [M + H]+.1H NMRAttorney Docket No.62619-738601 (400 MHz, Dimethylsulfoxide-d6) δ 9.31 (s, 1H), 2.70 (s, 3H), 1.16 - 1.05 (m, 21H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -131.17.

[0536] Intermediate 48: 2,4,7-Trichloro-8-fluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidine

[0537] Step 1: Ethyl 4-amino-6-chloro-5-fluoro-2-(prop-1-yn-1-yl)nicotinate

[0538] A mixture of ethyl 4-amino-2-bromo-6-chloro-5-fluoronicotinate (18.5 g, 57.8 mmol, refer toIntermediate 47 for detail procedures), Pd(PPh3)2Cl2(4.0 g, 5.8 mmol), and CuI (2.2 g, 11.6 mmol) in THF (60 mL) was degassed and purged with N2 three times. To the mixture were added TEA (48.3 mL, 347 mmol), trimethyl(prop-1-ynyl)silane (10.3 mL, 69.4 mmol), and TABF (69.4 mL, 1 M in THF). The mixture was stirred at 50 °C under N2for 6 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 20% ~ 53% of CH2Cl2 in n- hexane) to give a crude product. The crude was triturated with a mixture solvent of CH2Cl2(30 mL) and n-hexane (300 mL) at 20 °C for 30 min to give the title compound (12.4 g, 77% yield). MS: m / z = 257.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 6.26 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 2.08 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).19F NMR (376 MHz, Chloroform-d) δ - 144.56.

[0539] Step 2: Ethyl 6-chloro-5-fluoro-2-(prop-1-yn-1-yl)-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0540] To a solution of ethyl 4-amino-6-chloro-5-fluoro-2-(prop-1-yn-1-yl)nicotinate (12.4 g, 42.4mmol) in THF (120 mL) was added 2,2,2-trichloroacetyl isocyanate (12 g, 63.5 mmol) slowly under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (20 g, crude), which was used in the next step without further purification. MS: m / z = 444.0, 446.0 [M + H]+.

[0541] Step 3: 7-Chloro-8-fluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidine-2,4-diol

[0542] To a solution of ethyl 6-chloro-5-fluoro-2-(prop-1-yn-1-yl)-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (20 g, 41.2 mmol) in MeOH (50 mL) was added NH3(60 mL, 7 M in MeOH). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated underAttorney Docket No.62619-738601 reduced pressure. The residue was triturated with MTBE (200 mL) at 20 °C for 30 min and filtered. The filter cake was dried under reduced pressure to give the title compound (11 g, 90% yield for 2 steps). MS: m / z = 254.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 2.05 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -138.64.

[0543] Step 4: 2,4,7-Trichloro-8-fluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidine

[0544] A mixture of ethyl 7-chloro-8-fluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidine-2,4-diol (10 g,39.43 mmol) and DIPEA (27.5 mL, 158 mmol) in toluene (100 mL) was degassed and purged with N2. POCl3(18.38 mL, 197.15 mmol) was added to the mixture at 25 °C under N2. The mixture was stirred at 100 °C under N2 for 3 h. The mixture was concentrateed and azeotroped with toluene (50 mL) to remove excess POCl3. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 35% of CH2Cl2in n-hexane) to give the title compound (Intermediate 48, 5.2 g, 45% yield). MS: m / z = 289.9, 291.9 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 2.25 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -133.48.

[0545] Intermediate 49: (1S,7S,8S)-2-(7-Chloro-2,8-difluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0546] Step 1: (1S,7S,8S)-2-(2,7-Dichloro-8-fluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0547] To a solution of Intermediate 48 (2.8 g, 9.64 mmol) and DIPEA (6.7 mL, 38.6 mmol) inCH2Cl2 (30 mL) was added a solution of Intermediate 45 (2.04 g, 9.64 mmol, HBr salt) in CH2Cl2(10 mL) at -78 °C under N2. The reaction mixture was stirred at -78 °C under N2for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (60 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% of EtOAc in petroleum ether) to give the title compound (3.4 g, 82% yield). MS: m / z = 385.1 [M + H]+.1H NMR (400 MHz, Chloroform-d)Attorney Docket No.62619-738601 δ 4.65 (d, J = 13.6 Hz, 1H), 4.51 - 4.38 (m, 1H), 4.34 - 4.20 (m, 1H), 4.06 - 3.97 (m, 1H), 3.88 (t, J = 11.6 Hz, 1H), 3.73 - 3.53 (m, 2H), 2.77 - 2.63 (m, 1H), 2.34 - 2.15 (m, 4H).

[0548] Step 2: (1S,7S,8S)-2-(7-Chloro-2,8-difluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0549] To a solution of (1S,7S,8S)-2-(2,7-dichloro-8-fluoro-5-(prop-1-yn-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (3.2 g, 8.31 mmol) in dry DMSO (30 mL) was added KF (965 mg, 16.6 mmol) at 25 °C under N2. The mixture was stirred at 100 °C under N2for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 40% of CH2Cl2in petroleum ether) to give the title compound (Intermediate 49, 1.9 g, 59% yield). MS: m / z = 369.0 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 4.61 (d, J = 14.0 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.37 - 4.24 (m, 1H), 4.06 - 3.98 (m, 1H), 3.93 - 3.85 (m, 1H), 3.75 - 3.58 (m, 2H), 2.78 - 2.62 (m, 1H), 2.33 - 2.23 (m, 1H), 2.21 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -41.49, -134.04, - 205.36.

[0550] Intermediate 50: (1S,7S,8S)-2-(7-Chloro-8-fluoro-2-(methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane

[0551] Step 1: 4,7-Dichloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine

[0552] To a solution of Intermediate 47 (5 g, 11.7 mmol) in CH2Cl2 (50 mL) were added DIPEA (6.13mL, 35.2 mmol) and POCl3 (5.47 mL, 58.7 mmol) dropwise at 0 °C under N2. The mixture was stirred at 25 °C under N2for 2 h. The reaction mixture was concentrated under reducedAttorney Docket No.62619-738601 pressure to give the title compound (5.2 g, crude), which was used in the next step without further purification. MS: m / z = 444.0 [M + H]+.

[0553] Step 2: (1S,7S,8S)-2-(7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane

[0554] To a solution of 4,7-dichloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine (5.1 g, 11.5 mmol) in CH2Cl2(70 mL) were added DIPEA (9.99 mL, 57.4 mmol) and Intermediate 45 (2.43 g, 11.5 mmol, HBr salt) at -40 °C under N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (150 mL) and extracted with CH2Cl2(100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% of EtOAc in petroleum ether) to give the title compound (Intermediate 50, 5.2 g, 84% yield for 2 steps) as a yellow solid. MS: m / z = 539.1 [M + H]+. 1H NMR (400 MHz, Chloroform-d) δ 4.63 - 4.38 (m, 3H), 4.03 - 3.82 (m, 2H), 3.67 - 3.47 (m, 2H), 2.73 - 2.60 (m, 1H), 2.58 (s, 3H), 2.27 - 2.10 (m, 1H), 1.20 - 1.10 (m, 21H).19F NMR (376 MHz, Chloroform-d) δ -134.16, -205.31.

[0555] Step 3: (1S,7S,8S)-2-(7-Chloro-8-fluoro-2-(methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane

[0556] To a solution of (1S,7S,8S)-2-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (2.1 g, 3.89 mmol) in CH2Cl2 (25 mL) was added m-CPBA (949 mg, 4.67 mmol, 85% purity) at 0 °C. The mixture was stirred under N2at 25 °C for 1 h. The reaction mixture was quenched with Na2S2O3aq. (30 mL) at 0 °C and extracted with CH2Cl2(60 mL × 3). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography(eluent: 0 ~ 10% of MeOH in CH2Cl2) to give the title compound (Intermediate 50, 2.2 g, 90% yield). MS: m / z = 555.3 [M + H]+.

[0557] Intermediate 51: 6-Fluoro-5-(fluoromethoxy-d2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-olAttorney Docket No.62619-738601

[0558] Step 1: 4-Bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-ol

[0559] To a solution of fluoromethyl-d24-methylbenzenesulfonate (700 mg, 3.39 mmol,) in DMF (20mL) was added K2CO3(938 mg, 6.79 mmol) and 8-bromo-2-fluoronaphthalene-1,6-diol (872 mg, 3.39 mmol). The mixture was stirred under N2at 50 °C for 16 h. 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). MS: m / z = 290.7 [M - H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 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-d6) δ -132.22, -132.26, -152.63, -152.65.

[0560] Step 2: 6-Fluoro-5-(fluoromethoxy-d2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol

[0561] A mixture of 4-bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-ol (70 mg, 240.48 μmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (122 mg, 480 μmol), K3PO4 (153 mg, 721 μmol), and Cy3P Pd G3 (31 mg, 48.1 μmol) in dioxane (3 mL) was degassed and purged with N2three 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 51, 67 mg, 81% yield). MS: m / z = 336.8 [M - H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.83 (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, Dimethylsulfoxide-d6) δ -137.18, -137.23, -149.87.

[0562] Intermediate 52: (1S,7S,8S)-2-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0563] To 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 N2was added Intermediate 45 (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 flashAttorney Docket No.62619-738601 chromatography (eluted with PE / EA (3 : 1) to afford the title compound (Intermediate 52, 1 g, 76% yield). MS: m / z = 407.85, 409.85 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 7.96 - 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-d) δ -106.59 (s, 1F), - 111.46 (s, 1F).

[0564] Intermediate 53: (1S,7S,8S)-2-(7-chloro-2-fluoro-8-(methyl-d3)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0565] Step 1: tert-Butyl (2-chloro-3-(methyl-d3)pyridin-4-yl)carbamate

[0566] A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (4 g, 17.5 mmol) in THF (120 mL)was added t-buLi (33.7 mL, 1.3 M in THF) dropwise at -78 °C under N2. The reaction mixture was stirred under N2at -78 °C for 4 h. CD3I (1.31 mL, 21.0 mmol) was added dropwise to the mixture at -78 °C under N2. The reaction mixture was stirred under N2 at 0 °C for 2 h. The reaction mixture was quenched with sat. NH4Cl aq. (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 12% of EtOAc in petroleum ether) to give the title compound (2.6 g, 57% yield). MS: m / z =246.0 [M + H]+.1H NMR (400 MHz, Methanol- d4) δ 8.05 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 1.54 (s, 9H).

[0567] Step 2: 2-Chloro-3-(methyl-d3)pyridin-4-amine

[0568] A mixture of tert-butyl (2-chloro-3-(methyl-d3)pyridin-4-yl)carbamate (2.6 g, 10.6 mmol) inHCl (25 mL, 2 M in EtOAc) was stirred at 25 °C for 1 h. The reaction mixture was diluted with sat. Na2CO3 aq. (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered andAttorney Docket No.62619-738601 concentrated under reduced pressure to give the title compound (1.5 g, 97% yield).1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 5.6 Hz, 1H), 6.51 - 6.43 (m, 1H), 4.26 (s, 2H).

[0569] Step 3: 2-Chloro-5-iodo-3-(methyl-d3)pyridin-4-amine

[0570] To a solution of 2-chloro-3-(methyl-d3)pyridin-4-amine (1.5 g, 10.3 mmol) in ACN (15 mL)was added NIS (2.78 g, 12.4 mmol) and TsOH•H2O (98 mg, 515 μmol) at 25 °C. The mixture was stirred at 70 °C for 4 h. The reaction mixture was quenched with sat. Na2CO3 aq. (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.7 g, 85% yield).1H NMR (400 MHz, Chloroform-d) δ 8.24 (s, 1H), 4.74 (s, 2H)

[0571] Step 4: Ethyl 4-amino-6-chloro-5-(methyl-d3)nicotinate

[0572] To a suspension of 2-chloro-5-iodo-3-(methyl-d3)pyridin-4-amine (2.7 g, 9.94 mmol) in EtOH(50 mL) were added TEA (27.7 mL, 199 mmol) and Pd(PPh3)2Cl2(698 mg, 994 μmol) under Ar. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (20 Psi) at 80 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2 g, 92% yield). MS: m / z = 218.3 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 4.44 - 4.27 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[0573] Step 5: Ethyl 6-chloro-5-(methyl-d3)-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0574] A mixture of ethyl 4-amino-6-chloro-5-(methyl-d3)nicotinate (2 g, 9.19 mmol) and 2,2,2-trichloroacetyl isocyanate (1.73 g, 9.19 mmol) in THF (20 mL) was degassed, purged with N2three times, and stirred under N2at 25 °C for 15 min. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE (60 mL) at 25 °C for 15 min. The solid was filtered, and the filter cake was concentrated under reduced pressure to give the title compound (3.5 g, 89% yield). MS: m / z = 405.0, 407.0, 408.9 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 10.97 (s, 1H), 8.80 (s, 1H), 8.68 (s, 1H), 4.53 - 4.37 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).

[0575] Step 6: 7-Chloro-8-(methyl-d3)pyrido[4,3-d]pyrimidine-2,4-diol

[0576] To a solution of ethyl 6-chloro-5-(methyl-d3)-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (3.5g, 8.62 mmol) in MeOH (30 mL) was added NH3 (8 mL, 7 M in MeOH). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was triturated with MTBE (60 mL) at 25 °C for 15 min. The solid wasAttorney Docket No.62619-738601 filtered, and the filter cake was concentrated under reduced pressure to give the title compound (1.85 g, 95% yield). MS: m / z = 215.1 [M + H]+.

[0577] Step 7: 2,4,7-Trichloro-8-(methyl-d3)pyrido[4,3-d]pyrimidine

[0578] A suspension of 7-Chloro-8-(methyl-d3)pyrido[4,3-d]pyrimidine-2,4-diol (1.85 g, 6.82 mmol)in DIPEA (4.50 mL, 25.9 mmol) was cooled to 0 °C under N2. POCl3 (10 mL) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred under N2 at 120 °C for 6 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 (900 mg, 41% yield). MS: m / z = 251.1, 253.1, 254.9 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.33 (s, 1H).

[0579] Step 8: (1S,7S,8S)-2-(2,7-Dichloro-8-(methyl-d3)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0580] To a suspension of (1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (337 mg, 1.59 mmol,HBr salt) in CH2Cl2(5 mL) was added DIPEA (1.39 mL, 7.95 mmol) at -40 °C under N2. Then a solution of 2,4,7-trichloro-8-(methyl-d3)pyrido[4,3-d]pyrimidine (400 mg, 1.59 mmol) in CH2Cl2 (5 mL) was added dropwise to the above mixture at -40 °C under N2. The mixture was stirred at -40 °C for 0.5 h. The reaction mixture was diluted with water (50 mL) at 0 °C and extracted with EtOAc (30 mL × 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 ~ 20% of EtOAc in petroleum ether) to give the title compound (520 mg, 94% yield). MS: m / z = 346.1, 348.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.40 (s, 1H), 4.64 (d, J = 14.0 Hz, 1H), 4.46 - 4.16 (m, 2H), 4.03 - 3.83 (m, 3H), 3.74 - 3.55 (m, 1H), 3.38 - 3.17 (m, 1H), 2.44 - 2.20 (m, 1H).

[0581] Step 9: (1S,7S,8S)-2-(7-chloro-2-fluoro-8-(methyl-d3)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0582] To a solution of (1S,7S,8S)-2-(2,7-dichloro-8-(methyl-d3)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (520 mg, 1.5 mmol) in DMSO (5 mL) was added KF (262 mg, 4.51 mmol) under N2 at 25 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (80 mL) at 25 °C and extracted with EtOAc (50 mL ×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 20% of EtOAc in petroleum ether) to give the title compound (Intermediate 53, 480 mg, 92% yield). MS: m / z = 330.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 4.70 - 4.55 (m, 1H), 4.47 - 4.24(m, 2H), 3.99 - 3.86 (m,Attorney Docket No.62619-738601 3H), 3.73 - 3.62 (m, 1H), 3.40 - 3.19 (m, 1H), 2.43 - 2.27 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -39.95, -207.09.

[0583] Intermediate 54: (S,E)-(4-(fluoromethylene)-1-methyl-3-(methyl-d3)piperidin-3-yl)methanol

[0584] Step 1: 1-(tert-Butyl) 3-methyl (R)-3-(methyl-d3)-4-oxopiperidine-1,3-dicarboxylate & 1-(tert-butyl) 3-methyl (S)-3-(methyl-d3)-4-oxopiperidine-1,3-dicarboxylate

[0585] To a solution of 1-(tert-butyl) 3-methyl 4-oxopiperidine-1,3-dicarboxylate (20 g, 77.7 mmol) inMeCN (200 mL) was added K2CO3 (32.2 g, 233.2 mmol). CD3I (7.3 mL, 116.6 mmol) was added dropwise to the mixture at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with sat. NH4Cl aq. (100 mL), diluted with H2O (100 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 15% of EtOAc in petroleum ether) to give a crude product 1-(tert-butyl) 3-methyl 3-(methyl-d3)-4-oxopiperidine-1,3-dicarboxylate (20 g, 94% yiled). The crude was further seperated by SFC (column: SFC-IG-30-Daicel ChiralPak IG (250 × 30 mm, 10 μm); mobile phase: [CO2 - MeOH (0.1% NH3•H2O)]; B%: 12%, isocratic elution mode) to give the title compound (SFC peak 1, retention time: 0.473 min, 9.5 g, 47.5% yield) and the other title compound (SFC peak 2, retention time: 0.651 min, 9.3 g, 46.5% yield). Spectra for peak1: MS: m / z = 219.2 [M + H - t-Bu]+. 1H NMR (400 MHz,Chloroform-d) δ 4.49 (d, J = 13.6 Hz, 1H), 4.18 - 4.01 (m, 1H), 3.72 (s, 3H), 3.37 - 3.27 (m, 1H), 3.08 (d, J = 13.6 Hz, 1H), 2.87 - 2.66 (m, 1H), 2.56 - 2.40 (m, 1H), 1.48 (s, 9H). Spectra for peak 2: MS: m / z = 219.2 [M + H - t-Bu]+.1H NMR (400 MHz, Chloroform-d) δ 4.48 (d, JAttorney Docket No.62619-738601 = 13.2 Hz, 1H), 4.19 - 4.02 (m, 1H), 3.72 (s, 3H), 3.37 - 3.26 (m, 1H), 3.08 (d, J = 13.6 Hz, 1H), 2.86 - 2.65 (m, 1H), 2.56 - 2.40 (m, 1H), 1.48 (s, 9H).

[0586] Step 2: 1-(tert-Butyl) 3-methyl (S,E)-4-(fluoromethylene)-3-(methyl-d3)piperidine-1,3-dicarboxylate

[0587] A mixture of (fluoromethyl)triphenylphosphonium (2.1 g, 5.5 mmol) in THF (10 mL) wasdegassed and purged with N2 three times. t-BuOK (6.6 mL, 1 M in THF) was added dropwise to the mixture at -70 °C. The mixture was stirred at this temperature for 0.5 h before a solution of 1-(tert-butyl) 3-methyl (R)-3-(methyl-d3)-4-oxopiperidine-1,3-dicarboxylate (1 g, 3.6 mmol) in THF (10 mL) was added to the above mixture slowly at -70 °C. The mixture was stirred under N2at 25 °C for 2 h. The reaction mixture was quenched with sat. NH4Cl aq. (30 mL) at 25 °C and extracted with EtOAc (30 mL × 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 ~ 10% of EtOAc in petroleum ether) to give 1-(tert-butyl) 3-methyl (S,E)-4-(fluoromethylene)-3-(methyl- d3)piperidine-1,3-dicarboxylate (0.34 g, 34% yield, spot 1 with less polarity) and 1-(tert-butyl) 3-methyl (S)-4-(fluoromethylene)-3-(methyl-d3)piperidine-1,3-dicarboxylate (0.41 g, 39% yield, spot 2 with more polarity, contained about 50% of spot 1 on TLC). Spectra for spot 1:MS: m / z = 235.2 [M + H - t-Bu]+.1H NMR (400 MHz, Chloroform-d) δ 6.54 (d, J = 84.4 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 3.95 (m, 1H), 3.68 (s, 3H), 2.88 (t, J = 10.4 Hz,1H), 2.82 - 2.57 (m, 2H), 2.17 (m, 1H), 1.45 (s, 9H).19F NMR (376 MHz, Chloroform-d) δ -137.94.

[0588] Step 3: (S,E)-(4-(fluoromethylene)-1-methyl-3-(methyl-d3)piperidin-3-yl)methanolTo a solution of 1-(tert-butyl) 3-methyl (S,E)-4-(fluoromethylene)-3-(methyl-d3)piperidine-1,3- dicarboxylate (340 mg, 1.2 mmol) in THF (5 mL) was added LiAlH4(2.3 mL, 2.5 M in THF) at 0 °C under N2. The mixture was stirred at 65 °C for 16 h under N2. The reaction mixture was quenched by addition Na2SO4•10H2O (1 g) slowly at 0 °C, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0 ~ 15% of MeOH in CH2Cl2) to give the title compound (Intermediate 54, 140 mg, 68% yield). MS: m / z = 177.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 6.61 - 6.36 (m, 1H), 3.77 (d, J = 10.4 Hz, 1H), 3.56 - 3.52 (m, 1H), 2.90 - 2.86 (m, 1H), 2.79 - 2.75 (m, 2H), 2.55 - 2.43 (m, 1H), 2.23 (s, 3H), 2.00-1.90 (m, 2H).19F NMR (376 MHz, Chloroform-d) - 139.75.Attorney Docket No.62619-738601

[0589] Intermediate 55: (1S,7S,8S)-2-(7-chloro-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane

[0590] To a solution of Intermediate 14 (50 mg, 280 μmol) in THF (2 mL) was added dropwise t-BuOK (337 μL, 1 M in THF) at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h under N2 before a solution of Intermediate 6 (93 mg, 280 μmol) in THF (2 mL) was added dropwise at -40 °C. The resulting mixture was stirred at 25 °C for 3 h under N2. The reaction mixture was quenched with sat. NH4Cl aq. (20 mL) at 0 °C and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% of MeOH in CH2Cl2) to give the title compound (Intermediate 55, 135 mg, 92.37% yield). MS: m / z = 489.1 [M + H]+.

[0591] Intermediate 56: 6-Fluoro-5-(fluoromethoxy-d2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-amine

[0592] Step 1: 4-Bromo-6-fluoro-5-methoxynaphthalen-2-ol

[0593] To a solution of 8-bromo-2-fluoronaphthalene-1,6-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 × 3). The combined organic layers were washed with brine (200 mL), dried over 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 (4.7 g, 88% yield). MS: m / z = 268.9,Attorney Docket No.62619-738601 270.9 [M - H]-.1H NMR (400 MHz, Chloroform-d) δ 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-d) δ -134.77.

[0594] Step 2: N-(4-Bromo-6-fluoro-5-methoxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide

[0595] To a solution of 4-bromo-6-fluoro-5-methoxynaphthalen-2-ol (4.6 g, 17.0 mmol) in DMA (10mL) 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 × 3). The combined organic layers were washed with brine (200 mL), dried over 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 (5.96 g, 87% yield). MS: m / z =354.0, 356.0 [M - H]-.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.95 (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, Dimethylsulfoxide-d6) δ -131.96.

[0596] Step 3: N-(4-Bromo-6-fluoro-5-hydroxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide

[0597] To a solution of N-(4-bromo-6-fluoro-5-methoxynaphthalen-2-yl)-2-hydroxy-2-methylpropanamide (5.86 g, 16.5 mmol) in CH2Cl2(0.5 mL) was added BBr3(10 mL, 2 M in CH2Cl2) 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 × 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). MS: m / z = 342.1, 344.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 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-d6) δ -138.38, -139.06.

[0598] Step 4: N-(4-Bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-yl)-2-hydroxy-2-methylpropanamide

[0599] To a solution of fluoromethyl-d24-methylbenzenesulfonate (1.22 g, 5.9 mmol) and N-(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 × 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 titleAttorney Docket No.62619-738601 compound (2.35 g, 99% yield). MS: m / z = 376.0, 378.0 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.99 (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-d6) δ -129.42, -152.72, -152.74.

[0600] Step 5: 4-Bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-amine

[0601] To a solution of N-(4-bromo-6-fluoro-5-(fluoromethoxy-d2)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). MS: m / z = 289.9, 290.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.50 (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-d6) δ -134.98, -152.39.

[0602] Step 6: 6-Fluoro-5-(fluoromethoxy-d2)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-amine

[0603] A mixture of 4-bromo-6-fluoro-5-(fluoromethoxy-d2)naphthalen-2-amine (1.4 g, 4.83 mmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.68 g, 14.5 mmol), Cy3PPdG3 (471 mg, 724 μmol), 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 56, 681 mg, 71% yield). MS: m / z = 337.9 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 7.38 (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-d6) δ -139.70, -149.68, -149.72.

[0604] Intermediate 57: ((1R,3S,4S)-1-fluoro-4,6-dimethyl-6-azaspiro[2.5]octan-4-yl)methanol

[0605] Step 1: 6-(tert-Butyl) 4-methyl (2S,3S,4S)-1,1-dichloro-2-fluoro-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylate

[0606] A mixture of Intermediate 12 (800 mg, 2.78 mmol) and benzyl(triethyl)ammonium;chloride(63 mg, 278 μmol) in CHCl3(12 mL) and NaOH (3 mL, 50% in water) was degassed, purged with N2three times, and stirred at 60 °C for 16 h under N2. The reaction mixture was dilutedAttorney Docket No.62619-738601 with water (100 mL) and extracted with CH2Cl2(80 mL × 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% ~ 4% of EtOAc in Commercial hexanes) and further purified by prep-HPLC (column: CD24 - WePure Biotech XPT C18150 × 25 × 7 μm; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 45% ~ 75% B over 10.0 min) to give the title compound (160 mg, 16% yield). 1H NMR (400 MHz, Chloroform-d) δ 5.24 - 4.98 (m, 1H), 3.78 - 3.63 (m, 4H), 3.58 - 3.43 (m, 3H), 2.22 - 2.04 (m, 1H), 1.95 - 1.77 (m, 1H), 1.46 (s, 9H), 1.31 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -213.39. Step 2: ((1R,3S,4S)-1-fluoro-4,6-dimethyl-6-azaspiro[2.5]octan-4-yl)methanol To a solution of 6-(tert-butyl) 4-methyl (2S,3S,4S)-1,1-dichloro-2-fluoro-4-methyl-6- azaspiro[2.5]octane-4,6-dicarboxylate (160 mg, 432 μmol) in THF (10 mL) was added dropwise LiAlH4(1.73 mL, 2.5 M in THF) at 0 °C under N2. The mixture was stirred at 70 °C under N2for 4 h. The reaction mixture was quenched with Na2SO4•10 H2O (500 mg) slowly at 0 °C under N2. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0% ~ 5% of MeOH in CH2Cl2) to give the title compound (Intermediate 57, 61 mg, 61% yield). MS: m / z = 188.6 [M + H]+.

[0607] Intermediate 58: (S,E)-(4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol

[0608] To a solution of Intermediate 12 (2.0 g, 6.96 mmol) in THF (20 mL) was added LiAlH4 (13.9mL, 2.5 M in THF) at 0 °C under N2. The mixture was stirred at 70 °C for 1 h under N2before water (1.4 mL) was added dropwise to the above reaction at 0 °C. Then 15 wt% NaOH (1.4 mL) was added dropwise, and water (4.2 mL) was added. The resulting mixture was stirred at 20 °C for 0.5 h, dried over anhydrous MgSO4,filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 10% of MeOH in CH2Cl2) to give the title compound (Intermediate 58, 1.0 g, 83% yield). MS: m / z = 174.3 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 6.62 - 6.38 (m, 1H), 3.77 (dd, J = 1.2, 10.4 Hz, 1H),Attorney Docket No.62619-738601 3.54 (dd, J = 1.6, 10.4 Hz, 1H), 2.91 - 2.83 (m, 1H), 2.81 - 2.73 (m, 2H), 2.54 - 2.42 (m, 1H), 2.23 (s, 3H), 2.00 - 1.90 (m, 2H), 0.92 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -139.72.

[0609] Intermediate 59: 2-(7-Fluoro-8-(fluoromethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0610] Step 1: 8-Bromo-2-fluoronaphthalen-1-ol

[0611] To a solution of 7-bromo-2,3-dihydro-1H-inden-1-one (9.45 g, 44.8 mmol) in toluene (100 mL)were added TBAB (1.45 g, 4.50 mmol) and (bromodifluoromethyl)trimethylsilane (27.3 g, 134 mmol). The mixture was stirred under N2 at 110 °C for 16 h. The mixture was cooled to 25 °C before TBAF (9 mL, 9 mmol, 1 M in THF) was added. The mixture was stirred for another 1 h. The reaction mixture was quenched with water (50 mL). The orgaic phase was seperated, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 6% of EtOAc in petroleum ether) to give the title compound (10 g, 90% yield). MS: m / z = 238.8 [M - H]-.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 10.11 (s, 1H), 7.93 -7.71 (m, 2H), 7.55 - 7.46 (m, 2H), 7.27 (t, J = 8.0, 1H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -136.16.

[0612] Step 2: 8-Bromo-2-fluoro-1-(fluoromethoxy)naphthalene

[0613] To a mixture of 8-bromo-2-fluoronaphthalen-1-ol (1 g, 4.15 mmol) and Cs2CO3 (3.38 g, 10.4mmol) in ACN (10 mL) was added bromo(fluoro)methane (1.40 g, 12.4 mmol) at 0 °C under N2. The mixture was stirred under N2at 0 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.1 g, 97% yield).1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 8.05 (d, J = 8.0 Hz, 1H), 8.00 - 7.92 (m, 2H), 7.66 (t, J = 9.6 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 5.90 - 5.72 (d, J = 53.6 Hz, 2H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -126.82, -126.86, -151.63, -151.68.

[0614] Step 3: 2-(7-Fluoro-8-(fluoromethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0615] A mixture of 8-bromo-2-fluoro-1-(fluoromethoxy)naphthalene (1 g, 3.66 mmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.02 g, 4.03 mmol), K3PO4(2.33 g, 11.0 mmol) and Cy3PPdG3(269 mg, 366 μmol) in 1,4-dioxane (10 mL) was degassed, purged with N2 three times, and stirred under N2 at 100 °C for 1 h. The reaction mixture wasAttorney Docket No.62619-738601 concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 2% of EtOAc in petroleum ether) to give the title compound (Intermediate 59, 388 mg, 30% yield).1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 8.04 - 7.96 (m, 1H), 7.89 - 7.82 (m, 1H), 7.62 - 7.50 (m, 3H), 5.92 - 5.72(d, J = 53.6 Hz, 2H), 1.36 (s, 12H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -132.00, -132.03, -148.73, -148.77.

[0616] Example 1: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0617] Step 1: 6-Fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0618] To a mixture of Intermediate 14 (50 mg, 280 μmol) in THF (1 mL) was added t-BuOK (280μL, 1 M in THF) under N2, and the mixture was stirred at 25 °C for 30 min under N2. Then a sulution of Intermediate 9 (162 mg, 255 μmol) in THF (3 mL) was added to the mixture at -40 °C under N2. The mixture was stirred at -40 °C for 1 h under N2. The reaction mixture was quenched with sat. NH4Cl (40 mL) at 25 °C, diluted with H2O (40 mL), and extracted with EtOAc (80 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 ~ 4% of MeOH in CH2Cl2) to give the title compound (98 mg, 48% yield) as a yellow solid. MS: m / z = 794.3 [M + H]+.

[0619] Step 2: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0620] To a solution of 6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (98 mg, 123 μmol) in DMSO (2 mL) was added CsF (56 mg, 370 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and purified by reversed-phase column (C18 column; mobile phase: [water (0.1% NH3•H2O) - ACN]; B%: 5% ~ 58%, 30 min) to give theAttorney Docket No.62619-738601 title compound (Example 1, 60.7 mg, 77% yield) as a yellow solid. MS: m / z = 638.4 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.43 - 9.32 (m, 1H), 7.82 - 7.73 (m, 1H), 7.39 - 7.29 (m, 1H), 7.11 - 7.00 (m, 2H), 6.82 - 6.55 (m, 1H), 5.70 - 5.58 (m, 2H), 4.98 - 4.71 (m, 1H), 4.51 (d, J = 14.0 Hz, 1H), 4.43 - 4.28 (m, 2H), 4.07 - 3.68 (m, 3H), 3.63 - 3.56 (m, 1H), 3.28 - 3.15 (m, 2H), 2.68 (t, J = 10.4 Hz, 2H), 2.39 - 2.28 (m, 1H), 2.25 - 2.14 (m, 1H), 1.92 - 1.79 (m, 2H), 1.12 - 1.05 (m, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.36, - 138.76, -139.77, -140.26, -207.64.

[0621] Example 2: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,Z)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0622] Step 1: 6-Fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,Z)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0623] To a mixture of Intermediate 15 (100 mg, 561 μmol) in THF (1 mL) was added t-BuOK (448μL, 1 M in THF) at 0 °C under N2. The mixture was stirred at 25 °C for 30 min under N2. A solution of Intermediate 9 (238 mg, 374 μmol) in THF (3 mL) was added to the mixture at -40 °C under N2. Then the mixture was stirred at -40 °C for 1 h under N2. The reaction mixture was quenched with sat. NH4Cl (40 mL) at 25 °C, diluted with H2O (40 mL), and extracted with EtOAc (80 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 ~ 4% of MeOH in CH2Cl2) to give the title compound (250 mg, 80% yield) as a yellow solid. MS: m / z = 794.4 [M + H]+.

[0624] Step 2: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,Z)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0625] To a solution of 6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,Z)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (250 mg, 315 μmol) in DMSO (2 mL) was added CsF (144 mg, 945 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and purified by reversed-phase column (column:Attorney Docket No.62619-738601 C18; mobile phase: [water (0.1% NH3•H2O) - ACN]; B%: 0% ~ 57%, 40 min). to give the title compound (Example 2, 165 mg, 79% yield) as a yellow solid. MS: m / z = 638.3 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.47 - 9.31 (m, 1H), 7.83 - 7.71 (m, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.06 (s, 2H), 6.80 - 6.44 (m, 1H), 5.63 (s, 2H), 4.99 - 4.71 (m, 1H), 4.50 (d, J = 14.0 Hz, 1H), 4.44 - 4.26 (m, 2H), 4.09 - 3.77 (m, 2H), 3.76 - 3.55 (m, 2H), 3.30 - 3.17 (m, 2H), 2.46 - 2.28 (m, 2H), 2.23 - 1.99 (m, 4H), 1.30 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.35, -113.39, -130.95, -131.07, -139.81, -140.33, -207.65.

[0626] Example 3: 4-(2-(((S)-4-(difluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

[0627] Example 3 was prepared in a similar manner to Example 1. MS: m / z = 656.2 [M + H]+. 1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 9.46 - 9.33 (m, 1H), 7.83 - 7.72 (m, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.06 (s, 2H), 5.64 (s, 2H), 4.98 - 4.71 (m, 1H), 4.51 (d, J = 13.6 Hz, 1H), 4.45 - 4.29 (m, 2H), 4.08 - 3.70 (m, 3H), 3.66 - 3.57 (m, 1H), 3.31 - 3.20 (m, 2H), 2.59 (d, J = 10.0 Hz, 2H), 2.30 - 2.21 (m, 2H), 2.04 - 1.91 (m, 2H), 1.28 - 1.18 (m, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -89.63, -89.71, -89.79, -89.87, -90.35, -90.44, -90.59, -113.35, - 139.76, -140.27, -207.66, -207.74.

[0628] Example 4: 4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

[0629] Example 4 was prepared in a similar manner to Example 1. MS: m / z = 658.1 [M + H]+. 1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 9.49 - 9.31 (m, 1H), 7.78 (dd, J = 6.0, 9.2 Hz, 1H), 7.43 - 7.27 (m, 1H), 7.06 (d, J = 2.8 Hz, 2H), 6.47 - 6.10 (m, 1H), 5.75 - 5.53 (m, 2H), 5.00 - 4.71 (m, 1H), 4.50 (d, J = 13.6 Hz, 1H), 4.43 - 4.28 (m, 2H), 4.11 - 3.78 (m, 2H), 3.78 - 3.57 (m, 2H), 3.30 - 3.18 (m, 1H), 2.89 - 2.78 (m, 2H), 2.42 - 2.28 (m, 1H), 1.87 - 1.57 (m, 5H),Attorney Docket No.62619-738601 1.14 - 1.05 (m, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.35, -113.41, -116.15, - 116.90, -117.01, -118.74, -118.82, -119.49, -119.57, -139.79, -140.23, -207.73.

[0630] Example 11: 6-Chloro-5-ethynyl-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0631] Step 1: N-(6-Chloro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine

[0632] To an ice-cooled solution of Intermediate 14 (9.83 mg, 0.06 mmol) in THF (0.3 mL) under N2was added t-BuOK (6.18 mg, 0.06 mmol). The mixture was stirred in an ice bath for 1 hr. Intermediate 20 (30 mg, 0.04 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE : EA = 1 : 3) to afford the title compound (30 mg, 83% yield) as ayellow solid. MS: m / z = 974.40 [M + H]+.

[0633] Step 2: 6-Chloro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0634] To a solution of N-(6-chloro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1- diphenylmethanimine (30 mg, 0.03 mmol) in EtOH (0.3 mL) was added NaOAc (5.6 mg, 0.07Attorney Docket No.62619-738601 mmol) and hydroxylamine hydrochloride (4.8 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aqueous NaHCO3(5 mL) and extracted with ethyl acetate (3 x 8 mL). The combined organic layers were washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep- TLC (DCM : MeOH = 17 : 1) to afford the title compound (21.2 mg, 84% yield) as a yellow solid. MS: m / z = 810.30 [M + H]+.

[0635] Step 3: 6-Chloro-5-ethynyl-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0636] To a solution of 6-chloro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (21.2 mg, 0.03 mmol) in DMF (0.25 mL) was added CsF (99.33 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered and purified by RP-Flash with the following conditions: Column: C18, 40 g, 20 - 35 μm; Mobile Phase A: 5 mM aq. NH4HCO3; Mobile Phase B: MeCN; Gradient: 5% B to 5% B in 3 min, 5% B to 68% B in 15 min, 68% B to 68% B in 3 min, 68% B to 95% B in 4 min; Flow rate: 40 mL / min; Detector: UV 254 & 210 nm. The product-containing fractions were collected, concentrated, and lyophilized overnight to give the title compound (Example 11, 7.2 mg, 42% yield) as a yellow lyophilized powder. MS: m / z = 654.20 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 9.42 - 9.36 (m, 1H), 7.73 - 7.71 (m, 1H), 7.46 - 7.44 (m, 1H), 7.05 - 7.03 (m, 2H), 6.79 - 6.58 (m, 1H), 5.78 (s, 2H), 4.94 - 4.75 (m, 1H), 4.53 - 4.29 (m, 3H), 4.15 - 3.84 (m, 2H), 3.74 - 3.57 (m, 2H), 3.33 - 3.21 (m, 1H), 2.79 - 2.61 (m, 2H), 2.43 - 2.08 (m, 2H), 1.96 - 1.78 (m, 2H), 1.20 - 1.10 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -138.74 (s, 1F), - 139.85 - -140.32 (d, 1F).

[0637] Example 12: 5-Ethynyl-6-fluoro-4-(4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-8- methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amineAttorney Docket No.62619-738601

[0638] Step 1: 6-Fluoro-4-(4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-8-methylpyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0639] To an ice-cooled solution of Intermediate 14 (33.86 mg, 0.19 mmol) in THF (1.0 mL) under N2was added t-BuOK (21.31 mg, 0.19 mmol). The mixture was stirred in an ice bath for 30 min. A solution of Intermediate 21 (80 mg, 0.12 mmol) in THF (0.5 mL) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with saturated aq. NH4Cl (20 mL) 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 Prep-TLC (CH2Cl2: MeOH= 10 :1) to afford the title compound (75 mg, 74% yield) as a light yellow solid. MS: m / z = 790.55 [M + H]+.

[0640] Step 2: 5-Ethynyl-6-fluoro-4-(4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-8- methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0641] To a stirred solution of 6-fluoro-4-(4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-8- methylpyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (75 mg, 0.09 mmol) in DMF (1.0 mL) was added CsF (144.20 mg, 0.95 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was filtered and purified by RP-Flash directly with the following conditions: C18 spherical, 20 - 30 um, 100 A, 25 g; Mobile Phase A: 5 mM aq. NH4HCO3; Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 5% B to 5% B in 3 min, 5% B to 65% B in 20 min, 65% B to 65% B in 3 min, 65% B to 95% B in 5 min; Detector: UV 254 & 210 nm. The collected fractions were combined, concentrated and lyophilized overnight to give the title compound (Example 12, 34.1 mg, 56% yield) as an off-white lyophilized powder. MS: m / z = 634.40 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 9.43 - 9.37 (m, 1H), 7.77 - 7.73 (m, 1H), 7.33 - 7.28 (m, 1H), 7.01 (s, 1H), 6.91 - 6.88 (m, 1H), 6.81 - 6.59 (m, 1H), 5.58 - 5.57 (m, 2H), 4.90 - 4.67 (m, 1H), 4.50 - 4.47 (m, 1H), 4.40 - 4.24 (m, 2H), 4.04 - 3.51 (m, 4H), 3.28 - 3.11 (m, 1H), 2.75 - 2.60Attorney Docket No.62619-738601 (m, 2H), 2.48 - 2.42 (m, 1H), 2.40 - 2.10 (m, 5H), 1.98 - 1.77 (m, 2H), 1.10 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -113.62 (s, 1F), -138.85 - -138.92 (d, 1F), -207.37 (s, 1F).

[0642] Example 13: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S)-3-methyl-1-(methyl-d3)-4-methylenepiperidin-3- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0643] Example 13 was prepared in a similar manner to Example 1. MS: m / z = 620.2 [M+ H]+. 1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 9.45 - 9.32 (m, 1H), 7.85 - 7.71 (m, 1H), 7.40 - 7.27 (m, 1H), 7.13 - 6.98 (m, 2H), 5.71 - 5.57 (m, 2H), 4.90 - 4.69 (m, 3H), 4.51 - 4.27 (m, 3H), 3.94 - 3.79 (m, 1H), 4.11 - 3.77 (m, 1H), 3.74 - 3.53 (m, 2H), 3.29 - 3.20 (m, 1H), 2.68 - 2.60 (m, 2H), 2.44 - 2.14 (m, 3H), 2.02 - 1.77 (m, 2H), 1.13 (s, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.36, -113.41, -139.81, -140.33.-207.69.

[0644] Example 14: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((R,E)-3-(fluoromethylene)-2-methyl-1-(methyl-d3)pyrrolidin- 2-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0645] Example 14 was prepared in a similar manner to Example 1. MS: m / z = 624.2 [M + H]+. 1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 9.46 - 9.32 (m, 1H), 7.82 - 7.73 (m, 1H), 7.39 - 7.28 (m, 1H), 7.08 - 6.78 (m, 3H), 5.73 - 5.54 (m, 2H), 5.00 - 4.66 (m, 1H), 4.55 - 4.45 (m, 1H), 4.44 - 4.27 (m, 2H), 4.11 - 3.49 (m, 4H), 3.45 - 3.38 (m, 1H), 2.95 - 2.85 (m, 1H), 2.68 - 2.60Attorney Docket No.62619-738601 (m, 1H), 2.45 - 2.22 (m, 3H), 1.18 - 1.09 (m, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.37, -136.21, -136.31, -139.82, -140.31, -207.80.

[0646] Example 15: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((R,Z)-3-(fluoromethylene)-2-methyl-1-(methyl-d3)pyrrolidin- 2-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0647] Example 15 was prepared in a similar manner to Example 1. MS: m / z = 624.2 [M + H]+. 1HNMR (400 MHz, Dimethylsulfoxide-d6) δ 8.62 - 8.49 (m, 1H), 6.95 (dd, J = 6.0, 9.2 Hz, 1H), 6.57 - 6.46 (m, 1H), 6.27 - 6.18 (m, 2H), 6.05 - 5.76 (m, 1H), 4.90 - 4.74 (m, 2H), 4.17 - 3.88 (m, 1H), 3.70 - 3.62 (m, 1H), 3.61 - 3.43 (m, 2H), 3.27 - 2.95 (m, 2H), 2.93 - 2.72 (m, 2H), 2.47 - 2.32 (m, 1H), 2.09 - 2.00 (m, 1H), 1.86 - 1.69 (m, 2H), 1.50 - 1.45 (m, 2H), 0.35 (s, 3H). 19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.37, -113.43, -135.44, -135.55, -139.96, - 140.47, -207.62.

[0648] Example 19: 4-(4-((1S,7S,8S)-8-Chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

[0649] Step 1: 4-(4-((1S,7S,8S)-8-Chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2,8-difluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0650] To a solution of Intermediate 33 (50 mg, 0.14 mmol) and Intermediate 8 (181.47 mg, 0.36mmol) in THF (3 mL) and H2O (0.6 mL) under N2were added CataCXium A Pd G3 (20.98 mg, 0.03 mmol) and K3PO4 (183.44 mg, 0.86 mmol) at room temperature. The reactionAttorney Docket No.62619-738601 mixture was heated at 80 °C for 2 h. The resulting mixture was cooled to room temperature, diluted with H2O (8 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15 : 1) to afford the title compound (65 mg, 69% yield) as a yellow solid. MS: m / z = 652.20 [M + H]+.

[0651] Step 2: 4-(4-((1S,7S,8S)-8-Chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3-d]pyrimidin- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0652] To an ice-cooled solution of Intermediate 14 (26.65 mg, 0.15 mmol) in THF (1.0 mL) under N2was added t-BuOK (16.77 mg, 0.15 mmol). The mixture was stirred in an ice bath for 30 min. 4-(4-((1S,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2,8-difluoropyrido[4,3- d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (65 mg, 0.100 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. NH4Cl aq. (20 mL) in an ice bath and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10 : 1) to afford the title compound (55 mg, 68% yield) as a yellow solid. MS: m / z = 810.30 [M + H]+.

[0653] Step 3: 4-(4-((1S,7S,8S)-8-Chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

[0654] To a solution of 4-(4-((1S,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (55 mg, 0.07 mmol) in DMF (1.0 mL) was added CsF (206.16 mg, 1.36 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The solid was filtered out. The filtrate was purified by RP-Flash directly with the following conditions: Column, C18; Mobile phase A: 5 mM aq. NH4HCO3; Mobile phase B: MeCN; Gradient: 2% B ~ 95% B in 40 min, 65% B hold 3 min; Flow rate: 25 mL / min; Detector: UV 254 & 210 nm. The collected fractions were combined, concentrated and lyophilized overnight to give the title compound (Example 19, 17.2 mg, 38% yield) as a yellow lyophilized powder. MS: m / z = 654.2, 656.2 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 9.36 - 9.31 (m, 1H), 7.80 - 7.76 (m, 1H), 7.36 - 7.32Attorney Docket No.62619-738601 (m, 1H), 7.06 - 7.02 (m, 2H), 6.81 - 6.58 (m, 1H), 5.67 - 5.65 (m, 2H), 4.49 - 4.40 (m, 2H), 4.23 - 4.18 (m, 1H), 4.07 - 3.73 (m, 3H), 3.66 - 3.56 (m, 2H), 3.31 - 3.25 (m, 1H), 2.71 - 2.66 (m, 2H), 2.49 (s, 1H), 2.23 - 2.18 (m, 2H), 1.91 - 1.78 (m, 2H), 1.10 - 1.08 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -113.40 (s, 1F), -138.73 - -138.74 (d, 1F), -140.13 - -140.42 (d, 1F).

[0655] Example 24: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0656] Step 1: 7-Chloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3-d]pyrimidine

[0657] To a solution of Intermediate 14 (100 mg, 561 μmol) in THF (3 mL) was added t-BuOK (189mg, 1.68 mmol) dropwise at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h. A solution of Intermediate 37 (184 mg, 561 μmol) in THF (2 mL) was added dropwise to the above mixture at 0 °C under N2. The resulting mixture was stirred at 25 °C for another 1 h under N2. The reaction mixture was quenched with sat. NH4Cl aq. (10 mL) at 25 °C, diluted with H2O (30 mL) and extracted with EtOAc (20 mL × 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 ~ 3% of MeOH in CH2Cl2) to give the title compound (260 mg, 95% yield) as a yellow solid. MS: m / z = 487.1 [M + H]+.1H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 6.65 - 6.33 (m, 1H), 4.53 (d, J = 13.6 Hz, 1H), 4.21 (s, 0.5H), 4.06 (s, 0.5H), 3.65 - 3.53 (m, 1H), 3.41 - 3.29 (m, 1H), 2.82 - 2.55 (m, 3H), 2.49 - 2.24 (m, 2H), 1.97 - 1.91 (m, 3H), 1.79 (s, 1H), 1.70 - 1.52 (m,Attorney Docket No.62619-738601 3H), 1.18 (s, 3H), 1.10 - 0.96 (m, 1H).19F NMR (376 MHz, Chloroform-d) δ -134.50, -138.87, -204.05.

[0658] Step 2: 6-Fluoro-4-(8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3-d]pyrimidin- 7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0659] A mixture of 7-chloro-8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidine (130 mg, 267 μmol), Intermediate 8 (137 mg, 294 μmol), K3PO4(170 mg, 800 μmol) and Ad2nBuP-Pd-G3 (cataCXiumAPdG3) (19 mg, 26.7 μmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was degassed, purged with N2three times, and stirred at 100 °C for 2 h under N2. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 4% of MeOH in CH2Cl2) to give the title compound (130 mg, 61% yield) as a yellow solid. MS: m / z = 792.3 [M + H]+.

[0660] Step 3: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-amine

[0661] To a solution of 6-fluoro-4-(8-fluoro-4-((1S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (130 mg, 164 μmol) in DMSO (1 mL) was added CsF (75 mg, 492 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved with CH2Cl2 (3 mL). n-Hexane (50 mL) was added to the solution to give precipitate. The precipitate was filtered, and the filter cake was washed with n-hexane (20 mL), dried under reduced pressure to give a crude product. The crude product was purified by reversed-phase column: (column C18; mobile phase: [Water (NH4HCO3) - ACN)]; B%: 5% ~ 66%, 35 min) to give the title compound (Example 24, 63.1 mg, 60% yield) as a yellow solid. MS: m / z = 636.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) 9.42 - 9.27 (m, 1H), 7.82 - 7.72 (m, 1H), 7.39 - 7.27 (m, 1H), 7.08 - 6.99 (m, 2H), 6.82 - 6.56 (m, 1H), 5.70 - 5.56 (m, 2H), 4.76 - 4.39 (m, 2H), 4.17 - 3.69 (m, 2H), 3.42 - 3.35 (m, 2H), 2.72 - 2.65 (m, 2H), 2.30 - 2.17 (m, 2H), 2.03 - 1.94 (m, 1H), 1.93 - 1.81 (m, 4H), 1.76 - 1.65 (m, 1H), 1.57 - 1.44 (m, 1H), 1.28 - 1.17Attorney Docket No.62619-738601 (m, 1H), 1.11 - 1.07 (m, 3H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ -113.41, -138.81, - 140.00, -140.44, -204.93.

[0662] Example 52: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((3S,6R,E)-4-(fluoromethylene)-3,6-dimethyl-1-(methyl- d3)piperidin-3-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0663] Step 1: 6-Fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((3S,6R,E)-4-(fluoromethylene)-3,6-dimethyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine

[0664] To a solution of Intermediate 42 (45 mg, 234 μmol) in THF (2 mL) was added t-BuOK (225μL, 1M in THF) at 25 °C under N2. The mixture was stirred at 25 °C for 30 min under N2. A solution of Intermediate 9 (135 mg, 212 μmol) in THF (2 mL) was added dropwise to the above mixture at -40 °C under N2. The mixture was stirred at 25 °C for another 30 min under N2. The reaction mixture was quenched with sat. NH4Cl aq. (20 mL) at 25 °C, diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 0 ~ 8% of MeOH in CH2Cl2) to give the title compound (125 mg, 71% yield) as a yellow solid. MS: m / z = 808.3 [M + H]+.

[0665] Step 2: 5-Ethynyl-6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((3S,6R,E)-4-(fluoromethylene)-3,6-dimethyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine

[0666] To a solution of 6-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((3S,6R,E)-4-(fluoromethylene)-3,6-dimethyl-1-(methyl-d3)piperidin-3-yl)methoxy- d2)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (120 mg, 148 μmol) in DMSO (3 mL) was added CsF (68 mg, 445 μmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase column (column: C18; mobile phase: [Water (NH4HCO3) - MeCN)]; B%: 5% ~Attorney Docket No.62619-738601 55% over 30 min) to give the title compound (Example 52, 35.8 mg, 37% yield) as a yellowsolid. MS: m / z = 652.1 [M + H]+.1H NMR (400 MHz, Dimethylsulfoxide-d6) δ 9.45 - 9.31 (m, 1H), 7.81 - 7.73 (m, 1H), 7.38 - 7.29 (m, 1H), 7.10 - 7.02 (m, 2H), 6.82 - 6.52 (m, 1H), 5.69 - 5.57 (m, 2H), 4.97 - 4.69 (m, 1H), 4.57-4.44 (m, 1H), 4.42 - 4.28 (m, 2H), 4.07 - 3.67 (m, 3H), 3.67 - 3.54 (m, 1H), 3.43-3.38 (m, 1H), 2.81 - 2.74 (m, 1H), 2.59-2.54 (m, 1H), 2.41 - 2.29 (m, 1H), 1.89 - 1.77 (m, 3H), 1.10 - 1.02 (m, 6H).19F NMR (376 MHz, Dimethylsulfoxide-d6) δ - 113.24, -113.43, -139.28, -139.33, -139.81, -140.36, -207.85.

[0667] Example 56 & 57: 2-Amino-7-fluoro-4-((R)-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile & 2- amino-7-fluoro-4-((S)-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2- (((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0668] Step 1: (1S,7S,8S)-2-(7-Bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane

[0669] To a stirred solution of (1S,7S,8S)-2-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane (2.8 g, 6.10 mmol) in DMSO (28 mL) under N2 was added KF (532.06 mg, 9.15 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 h. The resulting mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flashAttorney Docket No.62619-738601 chromatography (eluted with 30% EA in PE) to afford the title compound (2.2 g, 81% yield) as a light-yellow solid. MS: m / z = 441.85, 443.85 [M + H]+.

[0670] Step 2: (1S,7S,8S)-2-(7-Bromo-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-6-(trifluoromethyl)quinazolin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane

[0671] To an ice-cooled solution of Intermediate 14 (266.09 mg, 1.49 mmol) in THF (1.0 mL) underN2was added t-BuOK (167.50 mg, 1.49 mmol). The mixture was stirred in an ice bath for 30 min. (1S,7S,8S)-2-(7-Bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-8-fluoro-5-oxa- 2-azabicyclo[5.1.0]octane (550 mg, 1.24 mmol) was added to the above mixture. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with sat. NH4Cl aq. (10 mL) in an ice bath and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / EA 2 : 1) to afford the title compound (500 mg, 66% yield) as a light yellow solid. MS: m / z = 600.00, 602.00 [M + H]+.

[0672] Step 3: tert-Butyl (3-cyano-7-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophen-2-yl)carbamate

[0673] To a mixture of (1S,7S,8S)-2-(7-bromo-8-fluoro-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-6-(trifluoromethyl)quinazolin-4-yl)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octane (490 mg, 0.81 mmol) and tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2- dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (1.32 g, 3.26 mmol) in 1,4- dioxane (5.0 mL) under N2were added Pd(DPEPhos)Cl2(233.70 mg, 0.32 mmol) and Cs2CO3(664.75 mg, 2.04 mmol) at room temperature. The reaction mixture was heated at 100 °C for 3 h. The resulting mixture was cooled to room temperature, diluted with H2O (8 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-Achiral-SFC directly with the following conditions: Column: XA-GreenSep Naphthyl, 3 x 25 cm, 5 μm; Mobile Phase A: CO2; Mobile Phase B: MeOH (0.5% 2 M NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 31% B; Column Temperature (℃): 35; Back Pressure (bar): 100; Detector: UV 254 nm; RT1: 10.22 min; Sample Solvent: MeOH (1% 2 M NH3•MeOH). The collected fractions were combined,Attorney Docket No.62619-738601 concentrated and lyophilized overnight to give the title compound (80 mg, 12% yield) as a light-yellow lyophilized powder. MS: m / z = 812.15 [M + H]+.

[0674] Step 4: 2-Amino-7-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0675] To an ice-cooled solution of tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl- d3)piperidin-3-yl)methoxy-d2)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophen-2- yl)carbamate (80 mg, 0.09 mmol) in DCM (2.0 mL) under N2 was added TFA (1.0 mL). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was co-evaporated with toluene (20 mLx3). The residue was purified by RP-Flash with the following conditions: Column: C18, 40 g, 20 - 35 μm; Mobile Phase A: 5 mM aq. NH4HCO3; Mobile Phase B: MeCN; Gradient: 5% B to 5% B in 3 min, 5% B to 64% B in 30 min, 64% B to 64% B in 3 min, 64% B to 95% B in 2 min; Flow rate: 40 mL / min; Detector: UV 254 & 210 nm. The product-containing fractions were collected, concentrated and lyophilized overnight to give the title compound (60 mg, 85% yield) as a yellow lyophilized powder. MS: m / z = 712.10 [M + H]+.

[0676] Step 5: 2-Amino-7-fluoro-4-((R)-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3- yl)methoxy-d2)-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile & 2- amino-7-fluoro-4-((S)-8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2- (((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0677] 2-Amino-7-fluoro-4-(8-fluoro-4-((1S,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d3)piperidin-3-yl)methoxy-d2)-6- (trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile (60 mg, 0.08 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAKIC, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3•MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30%; Detector: UV 220 & 254 nm; RT1: 4.026 min; RT2: 10.83 min. The first eluting peak (RT1: 4.026 min) was concentrated and lyophilized to give the title compound (Example 57, 24.6 mg, 41% yield) as an off-white lyophilized powder. MS: m / z = 712.10 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 7.24 - 7.20 (m, 1H), 7.03 - 6.99 (m, 1H), 6.76 - 6.54 (m, 1H), 4.66 - 4.40 (m, 3H), 4.17 - 4.11 (m, 1H), 4.03 - 3.94 (m,Attorney Docket No.62619-738601 2H), 3.77 - 3.73 (m, 1H), 3.30 - 3.20 (m, 1H), 2.85 - 2.22 (m, 1H), 2.75 - 2.72 (m, 1H), 2.67 - 2.63 (m, 1H), 2.43 - 2.16 (m, 2H), 2.07 - 1.93 (m, 2H), 1.19 (s, 3H).19F NMR (376 MHz, Methanol-d4) δ -59.89 (s, 3F), -118.98 (s, 1F), -124.18 (s, 1F), -139.57 (s, 1F), -209.02 (s, 1F). The second eluting peak (RT2: 10.83 min) was concentrated and lyophilized to give the title compound (Example 56, 11.8 mg, 19% yield) as an off-white lyophilized powder. MS: m / z = 712.15 [M + H]+.1H NMR (400 MHz, Methanol-d4) δ 8.68 (s, 1H), 7.27 - 7.23 (m, 1H), 7.04 - 6.99 (m, 1H), 6.75 - 6.53 (m, 1H), 4.69 - 4.40 (m, 3H), 4.12 - 4.02 (m, 2H), 3.92 - 3.89 (m, 1H), 3.75 - 3.72 (m, 1H), 3.15 - 3.05 (m, 1H), 2.85 - 2.82 (m, 1H), 2.76 - 2.74 (m, 1H), 2.67 - 2.63 (m, 1H), 2.40 - 2.20 (m, 2H), 2.06 - 1.93 (m, 2H), 1.19 (s, 3H).19F NMR (376 MHz, Methanol-d4) δ -59.89 - 59.90 (d, 3F), -...

Claims

Attorney Docket No.62619-738601 CLAIMS We claim:

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is selected from: (a) optionally substituted monocyclic aryl; (b) optionally substituted bicyclic aryl; (c) optionally substituted monocyclic heteroaryl; (d) optionally substituted bicyclic heteroaryl; (e) optionally substituted monocyclic aryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (f) optionally substituted bicyclic aryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; (g) optionally substituted monocyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl;Attorney Docket No.62619-738601 (h) optionally substituted bicyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl; and (i) optionally substituted tricyclic heteroaryl; Q is a heterocyclyl selected from: (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; G is selected from:wherein, R2and R3are independently selected from H or D;Attorney Docket No.62619-738601 R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclyl; or R5and R6together form an optionally substituted methylidene; or R5and R6together form an optionally substituted oxygen-containing heterocyclylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; or R5and R6join to form an optionally substituted heterocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; W is N-R40or C(R12)(R13); R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; R40is H or optionally substituted C1-C4 alkyl; m is 0, 1, or 2; and n is 0, 1, or 2.

2. A compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof:wherein: X1is N or C-CN;Attorney Docket No.62619-738601 X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (a) optionally substituted azabicyclo[3.1.0]hexane; (b) optionally substituted azabicyclo[4.1.0]heptane; (c) optionally substituted oxazabicyclo[4.1.0]heptane; (d) optionally substituted azabicyclo[5.1.0]octane; (e) optionally substituted oxazabicyclo[5.1.0]octane; (f) optionally substituted azabicyclo[6.1.0]nonane; (g) optionally substituted oxazabicyclo[6.1.0]nonane; (h) optionally substituted azabicyclo[5.1.0]oct-5-en-2-yl; (i) optionally substituted azabicyclo[5.1.0]oct-4-en-2-yl; (j) optionally substituted azabicyclo[6.1.0]non-6-en-2-yl; (k) optionally substituted azabicyclo[6.1.0]non-5-en-2-yl; (l) optionally substituted azabicyclo[6.1.0]non-4-en-2-yl; (m) optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; (n) optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; (o) optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; (p) optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; (q) optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; (r) optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; or R5and R6join to form an optionally substituted heterocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl; R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; m is 0, 1, or 2; and n is 0, 1, or 2.Attorney Docket No.62619-7386013. A compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt orsolvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-D, C-CN, C-R, C-F, or C-Cl; X3is N, C-H, C-D, C-F, C-Cl, C-CN, C-R14, or C-CF3; X4is N or C-R1; R is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R14is selected from optionally substituted alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, N(R15)2, SR15, optionally substituted C2-C4 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; R15is independently selected from H or optionally substituted C1-C6 alkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (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;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R10and R11are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R10and R11together form an optionally substituted methylidene; or R10and R11together form an oxo, or R10and R11together form an optionally substituted C3-C6 carbocyclyl;Attorney Docket No.62619-738601 R12and R13are independently selected from H, D, -CN, optionally substituted C1-C4 alkyl; or R12and R13together form an optionally substituted methylidene; or R12and R13together form an oxo, or R12and R13together form an optionally substituted C3-C6 carbocyclyl; m is 0 or 1; and n is 0 or 1.

4. A compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt orsolvate thereof:wherein: X1is N or C-CN; X2is N, C-H, C-R, C-F, or C-Cl; X3is N, C-H, C-F, C-Cl, C-CN, or C-CF3; R is selected from optionally substituted alkyl or optionally substituted cycloalkyl; R1is selected from H, D, -CN, halogen, optionally substituted C1-C4 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl; Ar is an optionally substituted mono or bicyclic aryl, or optionally substituted mono or bicyclic heteroaryl ring system; Q is a heterocyclyl selected from: (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;Attorney Docket No.62619-738601 (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; G is selected from:wherein, R2and R3are independently selected from H or D; R4is selected from H, D, -CN, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; R5and R6are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R5and R6together form an optionally substituted methylidene; or R5and R6join to form an optionally substituted C3-C6 carbocyclyl; R7and R8are independently selected from H, D, halogen, -CN, -OH, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkynyl, or optionally substituted C1-C4 alkyl; or R7and R8together form an optionally substituted methylidene; or R7and R8join to form an optionally substituted C3-C6 carbocyclyl; R9is selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 carbocyclyl, or optionally substituted heterocyclyl; and m is 0 or 1; and n is 0 or 1.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvatethereof, wherein X1is N.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvatethereof, wherein X1is C-CN.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvatethereof, wherein X2is N.Attorney Docket No.62619-7386018. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvatethereof, wherein X2is C-H, C-R, C-F, or C-Cl.

9. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein X2is C-F.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvatethereof, wherein X3is N.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvatethereof, wherein X3is C-H, C-F, or C-Cl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvatethereof, wherein R1is H or D.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is a optionally substituted monocyclic aryl.

14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted monocyclic aryl is an optionally substituted phenyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted phenyl is substituted with an -OH group at the meta position.

16. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted phenyl is selected from:.

17. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted phenyl is substituted with an -NH2 group at the meta position.

18. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted phenyl is selected from:Attorney Docket No.62619-738601.

19. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted phenyl is selected from:.

20. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted phenyl is:.

21. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is an optionally substituted bicyclic aryl.

22. The compound of claim 21, or a pharmaceutically acceptable salt or solvate thereof, whereinthe bicyclic optionally substituted aryl is an optionally substituted naphthyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted naphthyl is an optionally substituted 1-naphthyl.

24. The compound of claim 23 or a pharmaceutically acceptable salt or solvate thereof, wherein theoptionally substituted 1-naphthyl is further substituted at the 8-position.Attorney Docket No.62619-73860125. The compound of claim 23 or 24, or a pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted 1-naphthyl is substituted with an -OH group at the 3- position.

26. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

27. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

28. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601.

29. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

30. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.Attorney Docket No.62619-73860131. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

32. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

33. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860134. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

35. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

36. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

37. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

38. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860139. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 1-naphthyl is substituted at the 3-position with an -OH or an optionally substituted alkoxy.

40. The compound of claim 39, or a pharmaceutically acceptable salt or solvate thereof, whereinthe group at the 3-position is an optionally substituted alkoxy.

41. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

42. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

43. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860144. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

45. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860146. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

47. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860148. The compound of any one of claims 23-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted 1-naphthyl is substituted with an -NH2 group at the 3-position.

49. The compound of any one of claims 22-24 or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

50. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

51. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860152. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

53. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860154. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

55. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

56. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

57. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-73860158. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

59. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:

60. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 1-naphthyl is substituted with a halogen at the 3-position.

61. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

62. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 1-naphthyl is unsubstituted at the 3-position.

63. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601.

64. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

65. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:.

66. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt or solvatethereof, wherein the optionally substituted naphthyl is selected from:Attorney Docket No.62619-738601.

67. The compound of claim 21, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic aryl is described by Formula (b):wherein: R16is H, D, or F; R17is H, D, -OH, -NH2, Cl, F, -CN, -OCONHMe, OCOH(Me)2, or -NHCO2Me; R18is H, D, F, Cl, or Br; R19is H, D, F, Cl, or Br; R20is H, D, F, Cl, Br, -CN, or -CH3; R21is H, D, F, Cl, -CH3, -CD3, CF3, or -CN; and R22is H, D, -CH3, -CH2CH3, -CD2CD3, -CH=CH2, -C≡CH, -OCHF2, -OCF3, -CH2F, -CHF2, -CF3, -CN, Cl, F, -OCH3, -OCD3, -OCH2F, or -OCD2F.

68. The compound of claim 67, or a pharmaceutically acceptable salt or solvate thereof, whereinR22-C≡CH.

69. The compound of claim 67, or a pharmaceutically acceptable salt or solvate thereof, whereinR21is F.

70. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is an optionally substituted monocyclic heteroaryl.

71. The compound of claim 70, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted monocyclic heteroaryl is an optionally substituted 2-pyridinyl.

72. The compound of claim 71, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 2-pyridinyl is.Attorney Docket No.62619-73860173. The compound of claim 71, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted monocyclic heteroaryl is an optionally substituted 4-pyridinyl.

74. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 4-pyridinyl is:.

75. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 4-pyridinyl is:.

76. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted 4-pyridinyl is:.

77. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is an optionally substituted bicyclic heteroaryl.

78. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:.

79. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-738601.

80. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:.

81. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-73860183. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:.

84. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-738601.

85. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:.

86. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:.

87. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:

88. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:Attorney Docket No.62619-738601.

89. The compound of claim 77, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted bicyclic heteroaryl is selected from:.

90. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is an optionally substituted bicyclic heteroaryl further substituted with an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

91. The compound of claim 90, or a pharmaceutically acceptable salt or solvate thereof, whereinAr is:.

92. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is an optionally substituted tricyclic heteroaryl.

93. The compound of claim 92, or a pharmaceutically acceptable salt or solvate thereof, whereinAr is:.

94. The compound of any one of claims 1-93, or a pharmaceutically acceptable salt or solvatethereof, wherein Q is selected from: (a) optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl; (b) optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl; (c) optionally substituted 2-azabicyclo[5.1.0]octan-2-yl; (d) optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl; (e) optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl;Attorney Docket No.62619-738601 (f) optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl; (g) optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl; (h) optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (i) optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl; (j) optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl; (k) optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl; (l) optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl; (m) optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl; (n) optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-yl; and (o) optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl;95. The compound of any one of claims 1-94, or a pharmaceutically accept salt or solvate thereof,wherein Q is described by Formula (I-1):wherein: Y is O or CR27R28, and Z is O or CR29R30, provided that -Y-Z- is not -O-O-; or optionally -Y-Z- is -C(R28)=C(R29)-; R23, R24, R25, R26, R27, R28, R29, R30, R33, R34, R35, R36each is independently selected from H or optionally substituted C1-C6 alkyl; or R26and R27are taken together with the carbon atoms to which they are attached to form a double bond; or R34and R35together form an optionally substituted carbocyclyl ring.

96. The compound of claim 95, or a pharmaceutically accept salt or solvate thereof, wherein Q isdescribed by Formula (I-2):wherein: Y is O or CR27R28, and Z is O or CR29R30, provided that -Y-Z- is not -O-O-; or optionally -Y-Z- is -C(R28)=C(R29)-;Attorney Docket No.62619-738601 R23, R24, R25, R26, R27, R28, R29, and R30each is independently selected from H or optionally substituted C1-C6 alkyl; or R26and R27are taken together with the carbon atoms to which they are attached to form a double bond; R31is H; and R32is selected from H, D, fluoro, chloro, -CN, or -OH.

97. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein Qis an optionally substituted 2-azabicyclo[4.1.0]heptan-2-yl.

98. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein Qis an optionally substituted 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl.

99. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof, wherein Qis an optionally substituted 2-azabicyclo[5.1.0]octan-2-yl.

100. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-oxa-6-azabicyclo[5.1.0]octan-6-yl.

101. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 5-oxa-2-azabicyclo[5.1.0]octan-2-yl.

102. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-azabicyclo[6.1.0]nonan-2-yl.

103. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-oxa-7-azabicyclo[6.1.0]nonan-7-yl.

104. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 6-oxa-2-azabicyclo[6.1.0]nonan-2-yl.

105. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 5-oxa-2-azabicyclo[6.1.0]nonan-2-yl.

106. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-azabicyclo[5.1.0]oct-5-en-2-yl.

107. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-azabicyclo[5.1.0]oct-4-en-2-yl.

108. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-azabicyclo[3.1.0]hexan-2-yl.

109. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-azabicyclo[6.1.0]non-4-en-2-yl.

110. The compound of claim 94, or a pharmaceutically acceptable salt or solvate thereof,wherein Q is an optionally substituted 2-azabicyclo[6.1.0]non-5-en-2-ylAttorney Docket No.62619-738601111. The compound of claim 94, or a pharmaceutically acceptable salt or solvatethereof, wherein Q is an optionally substituted 2-azabicyclo[6.1.0]non-6-en-2-yl.

112. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

113. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

114. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

115. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

116. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl is:Attorney Docket No.62619-738601.

117. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

118. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

119. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

120. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

121. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted azabicyclo[5.1.0]octane heterocyclyl has a structure selected from:Attorney Docket No.62619-738601.

122. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

123. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

124. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

125. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

126. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

127. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:Attorney Docket No.62619-738601128. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

129. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

130. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein the optionally substituted oxazabicyclo[5.1.0]octane heterocyclyl has a structure selected from:.

131. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

132. The compound of any one of claims 1-94, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is selected from:

133. The compound of any one of claims 1-93, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is an optionally substituted azabicyclo[4.1.0]heptane heterocyclyl.

134. The compound of any one of claims 1-93, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is an optionally substituted oxazabicyclo[4.1.0]heptane heterocyclyl.Attorney Docket No.62619-738601135. The compound of any one of claims 1-93, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is an optionally substituted azabicyclo[6.1.0]nonane heterocyclyl.

136. The compound of any one of claims 1-93, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is an optionally substituted oxazabicyclo[6.1.0]nonane heterocyclyl.

137. The compound of any one of claims 1-93, or a pharmaceutically acceptable salt orsolvate thereof, wherein Q is a group selected from: optionally substituted 3-oxa-2,6-diazabicyclo[5.1.0]oct-1-en-6-yl; optionally substituted 2-oxa-3,6-diazabicyclo[5.1.0]oct-3-en-6-yl; optionally substituted 4-oxa-2,5-diazabicyclo[5.1.0]oct-5-en-2-yl; optionally substituted 3-oxa-2,7-diazabicyclo[6.1.0]non-1-en-7-yl; optionally substituted 2-oxa-3,7-diazabicyclo[6.1.0]non-3-en-7-yl; optionally substituted 5-oxa-2,6-diazabicyclo[6.1.0]non-6-en-2-yl; optionally substituted 6-oxa-2,5-diazabicyclo[6.1.0]non-4-en-2-yl; and optionally substituted 4-oxa-2,5-diazabicyclo[6.1.0]non-5-en-2-yl.

138. The compound of claim 137, or a pharmaceutically acceptable salt or solvate thereof,wherein the group is optionally substituted with a halogen.

139. The compound of claim 137 or 138, or a pharmaceutically acceptable salt or solvatethereof, wherein Q is a group selected from:

140. The compound of any one of claims 1-139, or a pharmaceutically acceptable saltor solvate thereof, wherein W is C(R12)(R13), n is 2, and m is 2.

141. The compound of any one of claims 1-139, or a pharmaceutically acceptable saltor solvate thereof, wherein W is C(R12)(R13), n is 1, and m is 2.

142. The compound of any one of claims 1-139, or a pharmaceutically acceptable saltor solvate thereof, wherein n is 0, and m is 2.

143. The compound of any one of claims 1-139, or a pharmaceutically acceptable saltor solvate thereof, wherein W is C(R12)(R13), n is 2, and m is 1.Attorney Docket No.62619-738601144. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein W is C(R12)(R13), n is 2, and m is 0.

145. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein W is C(R12)(R13), n is 1, and m is 1.

146. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein W is C(R12)(R13), m is 0, and n is 1.

147. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein m is 1, and n is 0.

148. The compound of any one of claims 1-147, or a pharmaceutically acceptable salt or solvatethereof, wherein R4is H or D.

149. The compound of any one of claims 1-147, or a pharmaceutically acceptable salt or solvatethereof, wherein R4is optionally substituted C1-C4 alkyl.

150. The compound of any one of claims 1-147, or a pharmaceutically acceptable salt or solvatethereof, wherein R4is optionally substituted C1 alkyl.

151. The compound of any one of claims 1-147, or a pharmaceutically acceptable salt or solvatethereof, wherein R4is CH3 or CD3.

152. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is H or D.

153. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is optionally substituted C1-C4 alkyl.

154. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is optionally substituted C1-C2 alkyl.

155. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is optionally substituted C1 alkyl.

156. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is CH3 or CD3.

157. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is optionally substituted C3-C6 carbocyclyl.

158. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R9is optionally substituted C3 carbocyclyl.

159. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6together form an optionally substituted methylidene.

160. The compound of claim 159, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted methylidene is substituted with at least one halogen.Attorney Docket No.62619-738601161. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6join to form an optionally substituted C3-C6 carbocyclyl.

162. The compound of claim 161, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl.

163. The compound of claim 161 or 162, or a pharmaceutically acceptable salt or solvate thereof,wherein the carbocyclyl is substituted with at least one halogen.

164. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6join to form an optionally substituted heterocyclyl.

165. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6join to form an optionally substituted oxetane.

166. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5is an optionally substituted C1-C4 alkyl, and R6is H or D.

167. The compound of claim 166, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted C1-C4 alkyl is substituted with at least one halogen.

168. The compound of claim 166 or 167, or a pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl.

169. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6are both selected from H or D.

170. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6are both halogen.

171. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6are both optionally substituted C1-C4 alkyl.

172. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5is a halogen and R6is H or D.

173. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5is an optionally substituted C1-C4 alkoxy and R6is H or D.

174. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5is an optionally substituted C1-C4 alkynyl and R6is H or D.

175. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5is -CN and R6is H or D.

176. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6join to form an optionally substituted C3-C6 carbocyclyl.

177. The compound of any one of claims 1-158, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6join to form an optionally substituted heterocyclyl.Attorney Docket No.62619-738601178. The compound of any one of claim 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7and R8together form an optionally substituted methylidene.

179. The compound of claim 178, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted methylidene is substituted with at least one halogen.

180. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7and R8join to form an optionally substituted C3-C6 carbocyclyl.

181. The compound of claim 180, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl.

182. The compound of claim 179 or 180, or a pharmaceutically acceptable salt or solvate thereof,wherein the carbocyclyl is substituted with at least one halogen.

183. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7is an optionally substituted C1-C4 alkyl, and R8is H or D.

184. The compound of claim 183, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted C1-C4 alkyl is substituted with at least one halogen.

185. The compound of claim 183 or 184, or a pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl.

186. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7and R8are both selected from H or D.

187. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7and R8are both halogen.

188. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7and R8are both optionally substituted C1-C4 alkyl.

189. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7is a halogen and R8is H or D.

190. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7is an optionally substituted C1-C4 alkoxy and R8is H or D.

191. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7is an optionally substituted C1-C4 alkynyl and R8is H or D.

192. The compound of any one of claims 1-177, or a pharmaceutically acceptable salt or solvatethereof, wherein R7is -CN and R8is H or D.

193. The compound of any one of claims 1-192, or a pharmaceutically acceptable salt or solvatethereof, wherein R2and R3are H.

194. The compound of any one of claims 1-192, or a pharmaceutically acceptable salt or solvatethereof, wherein R2and R3are D.Attorney Docket No.62619-738601195. The compound of any one of claims 1-192, or a pharmaceutically acceptable salt or solvatethereof, wherein R2is H and R3is D.

196. The compound of any one of claims 1-195, or a pharmaceutically acceptable salt or solvatethereof, wherein R10is an optionally substituted C1-C4 alkyl, and R11is H or D.

197. The compound of any one of claims 1-195, or a pharmaceutically acceptable salt or solvatethereof, wherein R10and R11are both optionally substituted C1-C4 alkyl.

198. The compound of claim 196 or 197, or a pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl.

199. The compound of any one of claims 1-195, or a pharmaceutically acceptable salt or solvatethereof, wherein R10and R11are both selected from H or D.

200. The compound of any one of claims 1-195, or a pharmaceutically acceptable salt or solvatethereof, wherein R10and R11join to form an optionally substituted C3-C6 carbocyclyl.

201. The compound of claim 200, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl.

202. The compound of any one of claims 1-201, or a pharmaceutically acceptable salt or solvatethereof, wherein R12is an optionally substituted C1-C4 alkyl, and R13is H or D.

203. The compound of any one of claims 1-201, or a pharmaceutically acceptable salt or solvatethereof, wherein R12and R13are both optionally substituted C1-C4 alkyl.

204. The compound of claim 202 or 203, or a pharmaceutically acceptable salt or solvate thereof,wherein the optionally substituted C1-C4 alkyl is an optionally substituted C1 alkyl.

205. The compound of any one of claims 1-201, or a pharmaceutically acceptable salt or solvatethereof, wherein R12and R13are both selected from H or D.

206. The compound of any one of claims 1-201, or a pharmaceutically acceptable salt or solvatethereof, wherein R10and R11join to form an optionally substituted C3-C6 carbocyclyl.

207. The compound of claim 206, or a pharmaceutically acceptable salt or solvate thereof, whereinthe optionally substituted C3-C6 carbocyclyl is a C3 carbocyclyl.

208. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601209. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

210. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

211. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601212. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

213. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

214. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

215. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601216. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

217. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

218. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601219. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

220. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

221. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

222. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601223. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

224. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

225. The compound of any one of claims 139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

226. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601227. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

228. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

229. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601230. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:.

231. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

232. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:Attorney Docket No.62619-738601.

233. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:.

234. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:.

235. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein R5and R6together form an optionally substituted oxygen-containing heterocyclylidene.

236. The compound of claim 235, or a pharmaceutically acceptable salt or solvate thereof, wherein.

237. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt or solvatethereof, wherein G is:Attorney Docket No.62619-738601.

238. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,wherein.

239. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,wherein.

240. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,wherein.

241. The compound of any one of claims 238-240, or a pharmaceutically acceptable salt or solvatethereof, wherein X2is C-R.

242. The compound of claim 241, or a pharmaceutically acceptable salt or solvate thereof, whereinR is -CH3.

243. The compound of claim 241, or a pharmaceutically acceptable salt or solvate thereof, whereinR is -CH2F.

244. The compound of any one of claims 238-240, or a pharmaceutically acceptable salt or solvatethereof, wherein X2is C-F.

245. The compound of any one of claims 238-244, or a pharmaceutically acceptable salt or solvatethereof, wherein X3is N.

246. The compound of any one of claims 238-24, or a pharmaceutically acceptable salt or solvatethereof, wherein X4is C-R1.

247. The compound of claim 246, or a pharmaceutically acceptable salt or solvate thereof, whereinR1is -H.

248. The compound of claim 246, or a pharmaceutically acceptable salt or solvate thereof, whereinR1is optionally substituted C2-C6 alkynyl.Attorney Docket No.62619-738601249. The compound of claim 246, or a pharmaceutically acceptable salt or solvate thereof, whereinR1is C3 alkynyl.

250. The compound of any one of claims 238-249, or a pharmaceutically acceptable salt or solvatethereof, wherein X1is N.

251. The compound of any one of claims 238-250, or a pharmaceutically acceptable salt or solvatethereof, wherein G is selected from:

252. The compound of any one of claims 238-251, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is selected from:.

253. The compound of any one of claims 238-252, or a pharmaceutically acceptable salt or solvatethereof, wherein Ar is selected from:.

254. The compound of any one of claims 1, 5-139, 148-201, 206-207, and 238-250, or apharmaceutically acceptable salt or solvate thereof, wherein W is N-R40, m is 1 and n is 1.

255. The compound of claim 254, or a pharmaceutically acceptable salt or solvate thereof, whereinG is:Attorney Docket No.62619-738601.

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

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

258. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt orsolvate thereof, as described in any one of claims 1-257, and a pharmaceutically acceptable excipient.

259. A method of preparing a pharmaceutical composition comprising mixing a compound, orpharmaceutically acceptable salt or solvate thereof, of any one of claims 1-257, and a pharmaceutically acceptable carrier.

260. A compound of any one of claims 1-257, or pharmaceutically acceptable salt or solvate thereof,for use in a method of treatment of the human or animal body.

261. A compound of any one of claims 1-257, or pharmaceutically acceptable salt or solvate thereof,for use in a method of treatment of cancer.

262. Use of a compound of any one of claims 1-257, or pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for the treatment of cancer.

263. A method of treating cancer in a patient in need thereof, comprising administering to thepatient a compound as described in any one of claims 1-257, or pharmaceutically acceptable salt or solvate thereof.

264. A method of treating cancer in a patient in need thereof, comprising administering to thepatient a pharmaceutical composition comprising a compound as described in any one of claims 1-257, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

265. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any oneof claims 1-257, wherein KRAS is contacted in an in vitro setting.

266. A method of inhibiting KRAS comprising contacting the enzyme with a compound of any oneof claims 1-257, wherein KRAS is contacted in an in vivo setting.

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