Tethered spiro-heterocyclic inhibitors of KRAS g12c mutant proteins and uses thereof

Abstract

The present disclosure provides compounds having activity as inhibitors of the G12C mutant KRAS protein, pharmaceutical compositions comprising the compounds, and methods of treating certain disorders, such as cancer, including but not limited to lung cancer, pancreatic cancer, colorectal cancer, and solid tumors. In particular, the disclosure provides compounds of Formula (I):, and pharmaceutically acceptable salts thereof, wherein the substituents are as described.

Description

TETHERED, SPIRO-HETEROCYCLIC INHIBITORS OF KRAS G12C MUTANT PROTEINS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 632,091, filed on April 10, 2024. FIELD

[0002] The present disclosure relates generally to compounds having activity as inhibitors of the G12C-mutant KRAS protein, pharmaceutical compositions comprising the compounds, and uses and methods of treating disorders such as cancer, including but not limited to lung cancer, pancreatic cancer, and colorectal cancer. BACKGROUND

[0003] The KRAS oncoprotein is a G-protein that couples extracellular mitogenic signaling to intracellular, pro-proliferative responses. KRAS functions as a molecular "on / off" switch, alternating between an inactive GDP-bound state and an active GTP-bound state. Transition between these states is facilitated by guanine nucleotide-exchange factors. Mitogen stimulation can induce GTP binding, which results in a conformational change that enables KRAS to interact with downstream effector proteins, leading to cellular proliferation. In normal cells, the pro-proliferative signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non- proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP- and GTP-bound states, leading to the accumulation of the GTP-bound active state and dysregulated cellular proliferation. See Simanshu et al., Cell 2017, 170, 17-33.

[0004] Attempts to develop inhibitors of mutated KRAS proteins have historically been thwarted by the picomolar affinity with which KRAS binds to GDP and GTP, as well as the absence of druggable pockets on the surface of the protein. See Cox et al., Nat. Rev. Drug Discov.2014, 13, 828- 851. Covalent inhibitors of the G12C mutant of KRAS ("KRASG12C") have been identified. These inhibitors can bind to a previously unrecognized allosteric pocket on GDP-KRASG12C, preventing its subsequent activation. See O'Bryan, J. P. Pharmacol. Res.2019, 139, 503-511 and Ostrem et al., Nature 2013, 503, 548-551. This discovery brought about significant new efforts in KRAS inhibitor research, recently culminating in the entry of KRAS inhibitors into human clinical trials. SUMMARY

[0005] One aspect of the disclosure provides compounds of Formula (I):pharmaceutically acceptable salts thereof, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S, or heteroalkenylene having 3- 6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 3-5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused-heterocycloalkenylhaving 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; A is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; each of W1and W2independently is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C2-3alkenyl, C-C2-3alkynyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; Y’ is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; each of R1a, R1b, and R2independently is H, D, halo, C1-4alkyl, C1-4haloalkyl, C1-2alkylene- OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RN1)2, C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or R1band R2, together with the carbon atoms to which they are attached, form; each R3independently is C1-3alkyl, C1-3haloalkyl,, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or fused- heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, C1-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; R5is halo, C1-3haloalkyl, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3thioalkyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S,wherein each of the foregoing C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl; each R6independently is halo, CN, C1-3alkyl, C2-3alkenyl, C1-3haloalkyl, C0-3alkylene-OH, C0-3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, C1-4alkylene-N(RN1)2, oxo, =CH2, C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused- heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two non- neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl of each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN; each R7independently is halo, C0-3alkylene-CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, oxo, =CH2, C0-4alkylene-C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl, C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R7together with the atoms to which they are attached form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O and S, fused-C6-10aryl, or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S;wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0006] Another aspect of the disclosure provides a pharmaceutical composition comprising a compound disclosed herein (such a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, or Table B’, or a pharmaceutically acceptable salt of any of the foregoing), and a pharmaceutically acceptable excipient.

[0007] Yet another aspect of the disclosure provides a method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (such a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, or Table B’, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition described herein.

[0008] Still another aspect of the disclosure provides a compound described herein (such a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, or Table B’, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition described herein, for use as a medicament.

[0009] Another aspect of the disclosure provides a compound disclosed herein (such a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, or Table B’, or a pharmaceutically acceptable salt of any of the foregoing), or the pharmaceutical composition disclosed herein, for use in the treatment of cancer. Yet another aspect of the disclosure provides a compound disclosed herein (such a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, or Table B’, or a pharmaceutically acceptable salt of any of the foregoing), or the pharmaceutical composition disclosed herein, for the manufacture of a medicament for the treatment of cancer. In some cases, the cancer of any of the foregoing is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer,myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, a solid tumor, or any combination of the foregoing.

[0010] Still another aspect of the disclosure provides a compound listed in Table INT-A, INT-B, INT-D, INT-E, or INT, a nitrogen-protected analog thereof, a free base analog thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0011] Yet another aspect of the disclosure provides a method of preparing a compound or salt of a compound disclosed herein (such a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, or Table B’, or a pharmaceutically acceptable salt of any of the foregoing), comprising admixing a compound of Formula (nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, with a compound of Formulanitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the substituents are as defined herein.

[0012] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. The description hereafter includes specific cases, embodiments, and examples with the understanding that the disclosure is illustrative and is not intended to limit the embodiments of the present disclosure to the specific cases, embodiments, and examples described herein. DETAILED DESCRIPTION

[0013] Disclosed herein are compounds having activity as inhibitors of the G12C-mutant KRAS protein, pharmaceutical compositions comprising the compounds, and uses and methods of treating disorders, such as cancer, with the compounds and pharmaceutical composition described herein.COMPOUNDS OF THE DISCLOSURE

[0014] Provided herein are compounds of Formula (I):pharmaceutically acceptable salts thereof, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S, or heteroalkenylene having 3- 6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 3-5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2heteroatoms independently selected from N, O and S or fused-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; A is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; each of W1and W2independently is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C2-3alkenyl, C-C2-3alkynyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; Y’ is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; each of R1a, R1b, and R2independently is H, D, halo, C1-4alkyl, C1-4haloalkyl, C1-2alkylene- OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RN1)2, C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or R1band R2, together with the carbon atoms to which they are attached, formeach R3independently i3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, C1-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; R5is halo, C1-3haloalkyl, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3thioalkyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl; each R6independently is halo, CN, C1-3alkyl, C2-3alkenyl, C1-3haloalkyl, C0-3alkylene-OH, C0- 3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, C1-4alkylene-N(RN1)2, oxo, =CH2, C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4- 7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused- heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two non- neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl of each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN; each R7independently is halo, C0-3alkylene-CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, oxo, =CH2, C0-4alkylene- C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl, C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R7together with the atoms to which they are attached form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatomsindependently selected from N, O and S, fused-C6-10aryl, or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0015] In some cases, the compound of Formula (I) is a free base. In some cases, the compound of Formula (I) is a pharmaceutically acceptable salt.

[0016] In some cases, R1ais H or D. In some cases, R1ais H. In some cases, R1ais D. In some cases, R1bis H or D. In some cases, R1bis H. In some cases, R1bis D. In some cases, R2is H or D. In some cases, R2is H. In some cases, R2is D. In some cases, at least one of R1a, R1b, and R2is H or D. In some cases, at least one of R1a, R1b, and R2is H. In some cases, at least one of R1a, R1b, and R2is D. In some cases, at least two of R1a, R1b, and R2are each independently H or D. In some cases, at least two of R1a, R1b, and R2are H. In some cases, at least two of R1a, R1b, and R2are D. In some cases, each of R1a, R1b, and R2independently is H or D. In some cases, two of R1a, R1b, and R2are H and one of R1a, R1b, and R2is halo, C1-4alkyl, C1-4haloalkyl, C1-2alkylene-OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RN1)2, or C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S. In some cases, each of R1a, R1b, and R2is H. In some cases, each of R1a, R1b, and R2is D. In some cases, at least one of R1a, R1b, and R2is halo. In some cases, one of R1a, R1b, and R2is halo. In some cases, R1ais halo and each of R1band R2is H. In some cases, at least one of R1a, R1b, and R2is Br, Cl, or F. In some cases, one of R1a, R1b, and R2is Br, Cl, or F. In some cases, R1ais Br, Cl, or F and each of R1band R2is H. In some cases, at least one of R1a, R1b, and R2is Br or Cl. In some cases, one of R1a, R1b, and R2is Br or Cl. In some cases, R1ais Br or Cl and each of R1band R2is H. In some cases, at least one of R1a, R1b, and R2is C1-4alkyl or C1-4haloalkyl. In some cases, one of R1a, R1b, and R2is C1-4alkyl or C1-4haloalkyl. In some cases, at least one of R1a, R1b, and R2is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. In some cases, one of R1a, R1b, and R2is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2F, CHF2, or CF3. In some cases, at least one of R1a, R1b, and R2is CH3, CH2F, CHF2, or CF3. In some cases, one of R1a, R1b, and R2is CH3, CH2F, CHF2, or CF3. In some cases, at least one of R1a, R1b, and R2is C1-2alkylene-OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, or C0-2alkylene-N(RN1)2, and each RN1independently is H or C1-4alkyl. In some cases, each RN1independently is H or CH3. In some cases, each RN1independently is H. In some cases, at least one of R1a, R1b, and R2is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2. In some cases, one of R1a, R1b, and R2is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2. In some cases, at least one of R1a, R1b, and R2is C1-2alkylene-heterocycloalkyl wherein theterocycloalkyl contains 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S. In some cases, theterocycloalkyl is aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxathiolidinyl, isoxthiodinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, diazinyl, or morpholinyl. In some cases, theterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some cases, at least one of R1a, R1b, and R2is aziridin-1-yl-methyl, azetidin-1-yl- methyl, pyrrolidine-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl. In some cases, one of R1a, R1b, and R2is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidine-1-yl-methyl, piperidin-1- yl-methyl, or morpholin-1-yl-methyl. In some cases, one of R1a, R1b, and R2is Br, Cl, F, CH3, CH2F, CHF2, CF3, CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, CH2N(CH3)2, aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidine-1-yl-methyl, piperidin-1-yl- methyl, or morpholin-1-yl-methyl. In some cases, R1band R2, together with the carbon atoms to which they are attached, form. In some cases, R1ais H. In some cases, R1band R2together with t cs

[0017] In some cases,some cases, m is 1. In some cases, m is 2. In some cases, m is 3. In some cases, m is 4. In some cases,deuterated. In some cases,fully deuterated and has a structure:some cases, at least one R3is C1-3alkyl or C1-3haloalkyl. In some cases, at least one R3is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, at least one R3is CH3, CH2CH3, CF3, CHF2, or CH2F. In some cases, at least one R3is CH3. In some cases, m is 1 or 2 and each R3is CH3. In some cases, m is 1 and R3is CF3, CHF2, or CH2F. In some cases, at least oneeach of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl. In some cases, m is 1 and R3is or. In some cases, each of RA1and RA2independently is H, C es,3. In some cases, at least one R is C0-3alkyleneCN. In some cases, at least one R3is CN, CH2CN, or CH2CH2CN. In some cases, at least one R3is CN or CH2CN. In some cases, m is 1 and R3is CN or CH2CN. In some cases, at least one R3is C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy. In some cases, at least one R3is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, m is 1 and R3is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, at least one R3is oxo (=O). In some cases, at least one R3is spiro-C3-7cycloalkyl or spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, at least one R3is spiro-cyclopropyl, spiro- cyclobutyl, or spiro-cyclopentyl. In some cases, at least one R3is spiro-azetidinyl, spiro-oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, at least one R3is spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl, spiro-azetidinyl, spiro- oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, at least one R3is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro- tetrahydrofuranyl. In some cases, at least one R3is spiro-C4-7cycloalkenyl or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl or fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, fused-cyclopentyl, or fused-cyclohexyl. In some cases, two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused- cyclobutyl. In some cases, two vicinal R3, together with the atoms to which they are attached, form fused-C4-7cycloalkenyl or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, each R3independently is CH3,CH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro- oxetanyl, or spiro-tetrahydrofuranyl; or two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused-cyclobutyl. In some cases, each R3independently is CH3, CH2CH3, CH2F, CHF2, CF3, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl; or two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused-cyclobutyl. In some cases, m is 0; or m is 1 and R3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl. In some cases, m is 0; or m is 1 and R3is CH3. In some cases,

[0018] In some cases, A is N. In some cases, A is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy. In some cases, A is CH. In some cases, A is C-F, C- Cl, or C-CN. In some cases, A is C-halo or C-CN. In some cases, A is C-F or C-Cl. In some cases, A is C-F. In some cases, A is C-CN. In some cases, A is C-C1-3alkyl. In some cases, A is C-CH3, C- CH2CH3, C-CH2CH2CH3, or C-CH(CH3)2. In some cases, A is C-CH3. In some cases, A is C-C1-3haloalkyl. In some cases, A is C-CF3, C-CHF2, or C-CH2F. In some cases, A is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, A is C-CH3, C-CH2F, C- CHF2, or C-CF3. In some cases, A is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy. In some cases, A is C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C-CH2CH2OCH3. In some cases, A is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, A is CH, C-F, C-Cl, C-CN, C-CH3, C- CH2F, C-CHF2, C-CF3, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, A is N, CH, C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, C-CH2F, C-OH, C- CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C-CH2CH2OCH3. In some cases, A is N, CH, C-F, C-Cl, C-CN, C-CH3, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, A is N, CH, or C-CH3. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2. In some cases, at least one R4is C1-3alkyl or C1-3haloalkyl. In some cases, at least one R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, at least one R4is CH3. In some cases, one R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, n is 2 and each R4independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, n is 1 and R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, or CH2F. In some cases, n is 1 and R4is CH3. In some cases, at least one R4is C0-3alkyleneCN. In some cases, at least one R4is CN or CH2CN. In some cases, n is 1 and R4is CN or CH2CN. In some cases, at least one R4is C1-3alkyleneOH or C1-3alkylene-C1-3alkoxy. In some cases, at least one R4is CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, n is 1 and R4is CH2OH, CH2CH2OH, CH2OCH3, or CH2CH2OCH3. In some cases, at least one R4is oxo. In some cases, at least one R4is C3-7spiro- cycloalkyl. In some cases, the spiro-cycloalkyl is spiro-cyclopropyl, spiro-cyclobutyl, or spiro- cyclopentyl. In some cases, the spiro-cycloalkyl is spiro-cyclopropyl or spiro-cyclobutyl. In some cases, at least one R4is spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, the spiro-heterocycloalkyl is spiro-oxetanyl or spiro-tetrahydrofuranyl. In some cases, the spiro-heterocycloalkyl is spiro-oxetanyl. In some cases, at least one R4is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. In some cases, each R4independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. In some cases, each R4independently is CH3, CH2CH3, CH2CH2CH3, CH2F, CN, CH2CN, CH2OH,CH2CH2OH, CH2OCH3, or spiro-cyclopropyl. In some cases,I

[0019] In some cases, is unsubstituted. In some cases, is substituted with one or more substituents. In some cases, is substituted with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4 substituents). In some cases, is substituted with 1 substituent. In some cases, is substituted with 2 substituents. In some cases, is substituted with 3 substituents. In some cases,is substituted with 4 substituents. In some cases, each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 3-5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro- heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused- heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, or =CH2; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S. In some cases, each C1-3alkyl substituent independently is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, each C1-3alkyl substituent is CH3. In some cases, each C1-3haloalkyl substituent independently is CF3, CHF2, or CH2F. In some cases, each C2-3alkenyl substituent independently is CH=CH2, CH=CHCH3, or CH2CH=CH2. In some cases, each halo substituent independently is Cl or F. In some cases, each C0-3alkyleneOH substituent independently is OH, CH2OH, or CH2CH2OH. In some cases, each C0-3alkylene-C1-3alkoxy substituent independently is OCH3, OCH2CH3, CH2OCH3, or CH2OCH2CH3. Insome cases, each C3-5cycloalkyl substituent independently is cyclopropyl, cyclobutyl, or cyclopentyl. In some cases, each C4-5cycloalkenyl substituent independently is cyclobutenyl or cyclopentenyl. In some cases, each heterocycloalkyl substituent independently is oxetanyl, tetrahydrofuranyl, aziridinyl, or azetidinyl. In some cases, each spiro-cycloalkyl substituent independently is spiro-cyclopropyl or spiro-cyclobutyl. In some cases, each spiro-cycloalkenyl substituent is spiro-cyclobutenyl. In some cases, each spiro-heterocycloalkyl substituent independently is spiro-oxiranyl, spiro-oxetanyl, spiro- tetrahydrofuranyl, spiro-aziridinyl, or spiro-azetidinyl. In some cases, each fused-cycloalkyl substituent independently is fused-cyclopropyl or fused-cyclobutyl. In some cases, each fused- cycloalkenyl substituent is fused-cyclobutenyl. In some cases, each fused-heterocycloalkyl substituent independently is fused-oxiranyl, fused-oxetanyl, fused-tetrahydrofuranyl, fused-aziridinyl, or fused- azetidinyl. In some cases, each substituent of independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH=CH2, CH=CHCH3, CH2CH=CH2, Cl, F, OH, CH2OH, CH2CH2OH, OCH3, OCH2CH3, CH2OCH3, CH2OCH2CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, aziridinyl, azetidinyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxiranyl, spiro-oxetanyl, spiro- tetrahydrofuranyl, spiro-aziridinyl, or spiro-azetidinyl; or two vicinal substituents, together with the atoms to which they are attached form fused-cyclopropyl, fused-cyclobutyl, fused-oxiranyl, fused- oxetanyl, fused-tetrahydrofuranyl, fused-aziridinyl, or fused-azetidinyl. In some cases, each substituent of independently is CH3, =CH2, oxo, Cl, F, OH, OCH3,, or any combination of the foregoing. In some cases,is substituted with CH3, F, or a combination of the foregoing. In some cases,is C2-6alkylene, wherein the C2-6alkylene is unsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4 substituents). In some cases,is C2alkylene, wherein the C2alkylene is unsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4 swherein the C3alkylene is unsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4sunsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2substituents, 1 substituent, 2 substituents, 3 substituents, or 4 substituents). In some cases, isindependently is C1-3alkyl, halo, OH, OC1-3alkyl, oxo, =CH2; or two vicinal R8, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S. In some cases, each R8independently is CH3, Cl, F, OH, OCH3, oxo, or =CH2; or two vicinal R8, together with the atoms t6alkenylene is unsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4 substituents). In some cases, is C3alkenylene, wherein the C3alkenylene is unsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents,3 substituents, or 4 substituents). In some cases,. In some cases, is C4-6alkenylene, wherein the C4-6alkenylene is unsubstituted or substituted, such as with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 s0, 1, 2, or 3, and each R8independently is C1-3alkyl, halo, OH, OC1-3alkyl, oxo, =CH2; or two vicinal R8, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused- heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S. In some cases, each R8independently is CH3, Cl, F, OH, OCH3, oxo, or =CH2; or two vicinal R8, together with the atoms to which they are attached formis heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, theteroalkylene has 2-4 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S. In some cases,is heteroalkylene having 2 total atoms and 1 heteroatom selected from N, O, and S. In some cases,, or. In some cases, theteroalkylene has 3 total atoms and 1 heteroatom selected from N, O, and. In some cases, theteroalkylene has 4 total atoms and 1 heteroatom selected from N, O, and ,heteroalkenylene having 3-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S. s

[0020] In some cases,some cases, W1is CH and3C-CH3or C-CH2CH3. In some cases, W1is C-C2-3alkenyl or C-C2-3alkynyl, and each of the alkenyl and alkynyl is unsubstituted or substituted with 1 or more substituents. In some cases, each of the alkenyl and alkynyl is unsubstituted. In some cases, each of the alkenyl and alkynyl is substituted with1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, each of the alkenyl and alkynyl is substituted with 1 substituent. In some cases, each of the alkenyl and alkynyl is substituted with 2 substituents. In some cases, each of the alkenyl and alkynyl is substituted with 3 substituents. In some cases, each substituent of the alkenyl and alkynyl independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy. In some cases, W1is C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), or C-CCH. In some cases, W1is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy. In some cases, W1is C-OH, C-CH2OH, C-CH2CH2OH, C- OCH3, C-CH2OCH3, or C-CH2CH2OCH3. In some cases, W1is C-OH, C-CH2OH, C-OCH3, or C- CH2OCH3. In some cases, W1is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2CH2CH3, C- CH(CH3)2, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C- CH2CH2OCH3. In some cases, W1is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-OH, C-CH2OH, C- OCH3, or C-CH2OCH3. In some cases, W1is C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, CCl, or C-Br. In some cases, W2is C-F, C-Cl, or C-CN. In some cases, W2is C-C1-3alkyl or C-C1-3haloalkyl. In some cases, W2is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, W2is C-CH3,C-CH2CH3, C-CH2F, C-CHF2, or C-CF3. In some cases, W2is C-CH3or C-CH2CH3. In some cases, W2is C-C2-3alkenyl or C-C2-3alkynyl, and each of the alkenyl and alkynyl is unsubstituted or substituted with 1 or more substituents. In some cases, each of the alkenyl and alkynyl is unsubstituted. In some cases, each of the alkenyl and alkynyl is substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, each of the alkenyl and alkynyl is substituted with 1 substituent. In some cases, each of the alkenyl and alkynyl is substituted with 2 substituents. In some cases, each of the alkenyl and alkynyl is substituted with 3 substituents. In some cases, each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy. In some cases, W2is C-CH=CH2, C- C(OH)=CH2, C-CH=CH(OH), or C-CCH. In some cases, W2is C-C0-3alkyleneOH or C-C0-3alkylene- C1-4alkoxy. In some cases, W2is C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C- CH2CH2OCH3. In some cases, W2is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, W2is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, C-CH2F, C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C-CH2CH2OCH3. In some cases, W2is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, W2is C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, C- C(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, each of W1and W2independently is N, CH, or C-CH3. In some cases, W1is CH and W2is N, CH, or C-CH3. In some cases, W2is N and W1is N, CH, or C-CH3. In some cases, W1is CH and W2is N. In ssome cases, R5is halo. In some cases, R5is Br, Cl, or F. In some cases, R5is C1-3haloalkyl. In some cases, R5is CF3, CF2H, CFH2, or CF2CH3. In some cases, R5is CF3or CF2H. In some cases, R5is CF3. In some cases, R5is CF2H. In some cases, R5is CHF2. In some cases, R5is C1-3alkoxy or C1-3thioalkyl. In some cases, R5is OCH3, OCH2CH3, SCH3, or SCH2CH3. In some cases, R5is OCH3or SCH3. In some cases, R5is C1-6alkyl, C2-4alkenyl, or C2-4alkynyl, each of which is unsubstituted or substituted with 1 or more substituents. In some cases, the C1-6alkyl is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, the C2-4alkenyl is CH=CH2or CH=CHCH3, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, the C2-4alkynyl is, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, the C1-6alkyl, C2-4alkenyl, and C2-4alkynyl is unsubstituted. In some cases, R5is CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, the C1-6alkyl, C2-4alkenyl, and C2-4alkynyl is substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, each of the C1-6alkyl, C2-4alkenyl, and C2-4alkynyl issubstituted with 1 substituent. In some cases, each of the C1-6alkyl, C2-4alkenyl, and C2-4alkynyl is substituted with 2 substituents. In some cases, each of the C1-6alkyl, C2-4alkenyl, and C2-4alkynyl is substituted with 3 substituents. In some cases, each substituent of the alkyl, alkenyl, and alkynyl independently is C1-3haloalkyl, C0-6alkylene(OH), C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl. In some cases, each of the substituents independently is CH3, CF3, CF2H, CFH2, OH, OCH3, OCF3, CH2OH, CH2OCH3, cyclopropyl, cyclobutyl, or phenyl. In some cases, R5is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, ,7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl are each substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, each substituent of the cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is halo, C1-3alkyl, C1-3haloalkyl, C0-6alkylene(OH), or C0-6alkylene-C1-3alkoxy. In some cases, the C3-7cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, the C5-7cycloalkenyl is cyclopentenyl or cyclohexenyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, theterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothipyranyl, dithianyl, morpholinyl, or thiomorpholinyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, theterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents (e.g., 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, or 3 substituents). In some cases, R5is cyclopropyl, cyclobutyl, cyclopentenyl, oxetanyl, or tetrahydrofuranyl. In some cases, R5is CH3,, [css

[0022] In some cases, q is 0. In some cases, q is 1. In some cases, q is 2. In some cases, r is 0. In some cases, r is 1. In some cases, each of q and r is 0. In some cases, q is 0 and r is 1. In some cases, q is 1 and r is 0. In some cases, q is 1 and r is 1. In some cases, q is 2 and r is 0. In some cases, q is 2 asome cases, the compound of Formula (I) has a structure of Formula (IA):pharmaceutically acceptable salt of any of the foregoing. In some cases, the compound of Formula (I) has a Formula (IA), or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure of Formula (IB), or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure of Formula (IC), or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure of Formula (ID), or a pharmaceutically acceptable salt thereof.

[0023] In some cases, o is 0. In some cases, o is 1. In some cases, 0 is 2. In some cases, o is 3. In some cases, o is 4. In some cases, at least one R6is halo or CN. In some cases, at least one R6is Br, Cl, F, or CN. In some cases, at least one R6is F. In some cases, o is 1 or 2 and each R6independently is F. In some cases, at least one R6is C1-3alkyl or C1-3haloalkyl. In some cases, at least one R6is CH3, CH2F, CHF2, or CF3. In some cases, o is 1 or 2 and each R6independently is CH3. In some cases, at least one R6is C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, or C1-4alkylene-N(RN1)2, and each RN1independently is H or CH3. In some cases, each RN1independently isH. In some cases, at least one R6is OH, CH2OH, CH2CH2OH, OCH3, OCD3, CH2OCH3, or CH2CH2OCH3. In some cases, at least one R6is CH2N(CH3)2, CH2NH(CH3), or CH2NH2. In some cases, at least one R6is OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2. In some cases, o is 1 and R6is OH, CH2OH, OCH3, or CH2OCH3. In some cases, at least one R6is oxo or =CH2. In some cases, at least one R6is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R6is cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R6is cyclopropyl. In some cases, at least one R6is spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro- heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R6is spiro-C3-7cycloalkyl or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R6is spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R6is spiro-cyclopropyl that is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R6is spiro-cyclopropyl. In some cases, two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused- heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, the fused-C3-7cycloalkyl is fused-cyclopropyl, fused-cyclobutyl, or fused-cyclopentyl, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R6, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, fused-cyclopentyl, fused-oxetanyl, or fused-tetrahydrofuranyl, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R6, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, or fused-cyclopentyl, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro- cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused-cycloalkyl, fused-cycloalkenyl, fused-heterocycloalkyl, fused-heterocycloalkenyl of any of the foregoing is unsubstituted. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused-cycloalkyl, fused-cycloalkenyl, fused-heterocycloalkyl, fused-heterocycloalkenyl of any of the foregoing is substituted with 1 or more substituents. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused-cycloalkyl, fused-cycloalkenyl, fused-heterocycloalkyl, fused- heterocycloalkenyl of any of the foregoing is substituted with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4 substituents). In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused-cycloalkyl, fused- cycloalkenyl, fused-heterocycloalkyl, fused-heterocycloalkenyl of any of the foregoing is substituted with 1 or 2 substituents. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro- heterocycloalkenyl, fused-cycloalkyl, fused-cycloalkenyl, fused-heterocycloalkyl, fused- heterocycloalkenyl of any of the foregoing is substituted with 1 substituent. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused-cycloalkyl, fused-cycloalkenyl, fused- heterocycloalkyl, fused-heterocycloalkenyl of any of the foregoing is substituted with 2 substituents. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused-cycloalkyl, fused- cycloalkenyl, fused-heterocycloalkyl, fused-heterocycloalkenyl of any of the foregoing is substituted with 3 substituents. In some cases, the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-cycloalkyl, spiro-cycloalkenyl, spiro-heterocycloalkyl, spiro-heterocycloalkenyl, fused- cycloalkyl, fused-cycloalkenyl, fused-heterocycloalkyl, fused-heterocycloalkenyl of any of the foregoing is substituted with 4 substituents. In some cases, each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN. In some cases, each substituent independently is halo, OH, C1-3alkoxy, or CN. In some cases, each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN. In some cases, two non-neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge. In some cases, two non-neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, or a C1-3ether bridge. In some cases, two non-neighboring R6join together to form a C1-3alkylene bridge or a C2-3alkenylene bridge. In some cases, two non-neighboring R6join together to form a C1-3ether bridge or a C1-3thioether bridge. In some cases, two non-neighboring R6join together to form a C1alkylene bridge ( some cases, two non-neighboring R6join together to form a C2alkylene bridge ( In some cases, two non-neighboring R6join together to form a C3alkylene bridge (6n some cases, two non-neighboring R jointogether to form a C2alkenylene bridge ( n some cases, two non-neighboring R6join together to form a C3alkenylene bridge (some cases, two non-neighboring R6join together to form a C1-3ether bridge (e.g.,In some cases, two non- sCHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, or cyclopropyl, or two vicinal R6, together with the atoms to which they are attached, form fused-cyclopropyl, fused- cyclobutyl, or fused-cyclopentyl, or two non-neighboring R6join together to form —CH2—, — CH2CH2—, —CH2CH2CH2—, —CH2-CH=CH— or —CH2OCH2—; wherein each of the foregoing cycloalkyl groups is unsubstituted or substituted with 1-4 substituents, and each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN. In some cases, o is 0; or o is 1 and R6is H, ,.

[0024] In some cases, Y’ is C3-7cycloalkyl or C4-7cycloalkenyl. In some cases, Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl. In some cases, Y’ is cyclopropyl or cyclobutyl. In some cases, Y’ is heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, Y’ is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, dioxolanyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, or thiomorpholinyl. In some cases, Y’ is oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, or morpholinyl. In some cases, Y’ is tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl. In some cases, Y’ is heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, Y’ is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl. In some cases, Y’ is dihydrofuranyl or dihydropyranyl. In some cases, Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, dioxolanyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl. In some cases, Y’ is oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, dihydrofuranyl or dihydropyranyl. In some cases, Y’ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dihydrofuranyl or dihydropyranyl. In some cases, p is 0. In some cases, p is 1. In some cases, p is 2. In some cases, p is 3. In some cases, p is 4. In some cases, p is 5. In some cases, at least one R7is F, Cl, Br, CN, or CH2CN. In some cases, at least one R7is F, Cl, or Br. In some cases, at least one R7is CN or CH2CN. In some cases, at least one R7is F or CH2CN. In some cases, at least one R7is C1-3alkyl, C1-3haloalkyl, or C2-3alkenyl. In some cases, at least one some cases, at least one R7is CH3, CH2F, or CHF2. In some cases, at least one R is C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy. In some cases, at least one R7is OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, or CH2CH2OCH3. In some cases, at least one R7is OH or CH2OCH3. In some cases, atleast one R7is C(=O)OC1-3alkyl. In some cases, at least one R7is C(=O)OCH3. In some cases, at least one R7is oxo or =CH2. In some cases, at least one R7is C0-4alkylene-C3-7cycloalkyl; C0-4alkylene- heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl; or C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R7is C0-4alkylene-cyclopropyl, C0-4alkylene-cyclobutyl, C0-4alkylene-cyclopentyl, C0-4alkylene-oxetanyl, C0-4alkylene-pyrrolidinyl, C0-4alkylene-phenyl, or C0-4alkylene-oxadiazolyl; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R7is cyclopropyl. In some cases, at least one R7is spiro-C3-7cycloalkyl or a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R7is spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, or spiro-tetrahydropyranyl, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, at least one R7is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro- tetrahydrofuranyl, wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-C3-7cycloalkyl or fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, fused-oxetanyl, or fused-tetrahydrofuranyl. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused- cyclopropyl or fused-cyclobutyl. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-tetrahydrofuranyl. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-C6-10aryl or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused- pyridyl, fused-pyridazinyl, fused-pyrazinyl, or fused pyrimidinyl; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused- thiazolyl, fused-pyridyl, fused-pyridazinyl, or fused-pyrazinyl; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, two vicinal R7, together with the atoms to which they are attached, form fused-pyrazolyl, fused-pyridyl, or fused-pyridazinyl; wherein each of the foregoing is unsubstituted or substituted with 1 or more substituents. In some cases, each of the foregoing cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro-cycloalkyl, spiro- heterocycloalkyl, fused-cycloalkyl, fused-heterocycloalkyl, fused-aryl, and fused-heteroaryl isunsubstituted or substituted with 1-4 substituents. In some cases, each of the foregoing cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro-cycloalkyl, spiro-heterocycloalkyl, fused-cycloalkyl, fused- heterocycloalkyl, fused-aryl, and fused-heteroaryl is unsubstituted. In some cases, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro-cycloalkyl, spiro-heterocycloalkyl, fused-cycloalkyl, fused- heterocycloalkyl, fused-aryl, and fused-heteroaryl of any of the foregoing is substituted with 1-4 substituents (e.g., 1-4 substituents, 1-3 substituents, 1-2 substituents, 1 substituent, 2 substituents, 3 substituents, or 4 substituents). In some cases, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro- cycloalkyl, spiro-heterocycloalkyl, fused-cycloalkyl, fused-heterocycloalkyl, fused-aryl, and fused- heteroaryl of any of the foregoing is substituted with 1 or 2 substituents. In some cases, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro-cycloalkyl, spiro-heterocycloalkyl, fused- cycloalkyl, fused-heterocycloalkyl, fused-aryl, and fused-heteroaryl of any of the foregoing is substituted with 1 substituent. In some cases, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro- cycloalkyl, spiro-heterocycloalkyl, fused-cycloalkyl, fused-heterocycloalkyl, fused-aryl, and fused- heteroaryl of any of the foregoing is substituted with 2 substituents. In some cases, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro-cycloalkyl, spiro-heterocycloalkyl, fused-cycloalkyl, fused- heterocycloalkyl, fused-aryl, and fused-heteroaryl of any of the foregoing is substituted with 3 substituents. In some cases, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spiro-cycloalkyl, spiro- heterocycloalkyl, fused-cycloalkyl, fused-heterocycloalkyl, fused-aryl, and fused-heteroaryl of any of the foregoing is substituted with 4 substituents. In some cases, each substituent of the foregoing independently is halo, CN, oxo, or C1-3alkyl. In some cases, each substituent independently is F, Cl, Br, CN, oxo, or CH3. In some cases, each R7independently is F, Cl, Br, CN, CH2CN, CH3, CH2CH3, CH2F, CHF2, CF3, OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, CH2CH2OCH3, C(=O)OCH3, oxo, =CH2, cyclopropyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, spiro-tetrahydropyranyl; or two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, fused-oxetanyl, fused-tetrahydrofuranyl, fused-phenyl, fused- thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, fused-pyridazinyl, fused-pyrazinyl, or fused-pyrimidinyl; wherein each of the pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl is unsubstituted or substituted with CH3. In some cases, each substituent independently is F, Cl, Br, CN, oxo, or CH3. In some cases, each R7independently is F, Cl, Br, CN, CH2CN, CH3, CH2CH3, CH2F, CHF2, CF3, OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, CH2CH2OCH3, C(=O)OCH3, oxo, =CH2, cyclopropyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl; or two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused- cyclobutyl, fused-oxetanyl, fused-tetrahydrofuranyl, fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, fused-pyridazinyl, or fused-pyrazinyl; wherein each of the pyrazolyl, pyridyl, and pyridazinyl is substituted with CH3. In some cases, Y’ is substituted with F, CH2CN,any of the foregoing. In some cases, Y’ is substituted with F, CH2CN, CH3, CH2F, CHF2, OH,or; or a combination of any of the foregoing. In some cases,,,[ cor a pharmaceutically acceptable salt thereof, wherein:cycloalkyl.Ihe foregoing. In some cases, the compound of Formula (II) has a structure of Formula (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the compound of Formula (II) has a Formula (IIA), or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) has a structure of Formula (IIB), or a pharmaceutically acceptable saltthereof. In some cases, the compound of Formula (II) has a structure of Formula (IIC), or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (II) has a structureof Formula (IID), or a pharmaceutically acceptable salt thereof. In some cases, is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1 or 2 substituents, and each s

[0026] In some cases,exhibits the stereochemical configuration of Formula (

[0027] In some cases, the compound of Formula (I) is a compound as listed in Table A, or a pharmaceutically acceptable salt thereof: Table A

[0028] In some cases, the compound of Formula (I) has a structure of Formula (IA). Contemplated compounds of Formula (IA) include, for example,,

[0029] In some cases, the compound of Formula (I) has a structure of Formula (IB). Contemplated compounds of Formula (IB) include, for example,

[0030] In some cases, the compound of Formula (I) has a structure of Formula (IC). Contemplated cON

[0031] In some cases, the compound of Formula (I) is a compound as listed in Table B, or a pharmaceutically acceptable salt thereof: Table B

[0032] In some cases, the compound of Formula (I) has a structure:pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure:pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure:cases, the compound of Formula (I) has a structure:pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure: cpharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure: cpharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure:pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure:pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) has a structure:pharmaceutically acceptable salt thereof.

[0033] In some cases, the compound of Formula (I) is a compound listed in Table A’, below, or a pharmaceutically acceptable salt thereof. Table A’

[0034] In some cases, the compound of Formula (I) has a structure of Formula (IA). Contemplated compounds of Formula (IA) include, for example, compounds 1-036 to 1-038, 1-048, 1-049, 1-051, 1- 065 to 1-067, 1-084 to 1-089, and 1-103, and pharmaceutically acceptable salts thereof. In some cases, the compound of Formula (I) has a structure of Formula (IB). Contemplated compounds of Formula (IB) include, for example, compounds 1-079 to 1-083, and pharmaceutically acceptable salts thereof. In some cases, the compound of Formula (I) has a structure of Formula (IC). Contemplated compounds of Formula (IC) include, for example, compounds 1-001 to 1-035, 1-039 to 1-047, 1-050, 1-052 to 1-064, 1-068 to 1-078, 1-090 to 1-102, 1-104, and 1-105, and pharmaceutically acceptable salts thereof.

[0035] In some cases, the compound of Formula (I) is a compound listed in Table B’, below, or a pharmaceutically acceptable salt thereof.Table B’

[0036] In some cases, the compound of Formula (I) is compound 1-001, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-002, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1- 011, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-012, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-013, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-014, or a pharmaceutically acceptable salt thereof. In somecases, the compound of Formula (I) is compound 1-015, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-050, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-051, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1-089 or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) is compound 1- 104, or a pharmaceutically acceptable salt thereof.

[0037] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds.

[0038] Unless otherwise indicated, the depictions of partial structures do not represent any particular orientation of the partial structure. For example, compounds of Formula (I) havinginclude compounds of Formula (I) depicted asSimilarly, compounds of Formula (I)Stereoisomers

[0039] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.

[0040] If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of the structure. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted. Forexample, representsSimilarly, for example, the chemicalname (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4-methoxy-5- methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H- isoindole. A bond drawn with a wavy line may be used to indicate that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.

[0041] The term “stereoisomer” or “stereoisomerically pure” compound refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0042] This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). Tautomers

[0043] As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula.representsSimilarly, for example, the chemical name (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7- tetrahydro-1H-indazole and (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-indazole. Accordingly, the scope of the present disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Isotopically-Labeled Compounds

[0044] In some cases, the scope of the present disclosure includes pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labelled compounds of the compounds disclosed herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances. As such, the term “deuterated” refers to the substitution of one or more hydrogen atoms with one or more deuterium atoms on a particular structure or functional group. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically- labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying GENERAL SYNTHETIC PROCEDURES and EXAMPLES sections using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed. BIOLOGICAL ACTIVITY

[0045] In some cases, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), compounds listed in Table A, Table A’, Table B, and Table B’), and pharmaceutically acceptable salts of the foregoing, have an IC50value of less than 5 µM, or less than 4 µM, or less than 3 µM, or less than 2 µM, or less than 1 µM, or less than 0.9 µM, or less than 0.8 µM, or less than 0.7 µM, or less than 0.6 µM, or less than 0.5 µM, or less than 0.4 µM, or less than 0.3 µM, or less than 0.2 µM, or less than 0.1 µM, or less than 0.09 µM, or less than 0.08 µM, or less than 0.07 µM, or less than 0.06 µM, or less than 0.05 µM, or less than 0.04 µM, orless than 0.03 µM, or less than 0.02 µM, or less than 0.01 µM in the coupled exchange assay, which is described in “SECTION 3: Biochemical and Cellular Assays.” In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of less than 1 µM. In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of less than 0.5 µM. In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of less than 0.3 µM. In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of less than 0.1 µM. Also provided herein are compounds of the disclosure, and pharmaceutically acceptable salts of the foregoing, having an IC50of less than 5 µM in the 2h coupled exchange assay described herein. Further provided herein are compounds of the disclosure, and pharmaceutically acceptable salts of the foregoing, having an IC50 of less than 3 µM in the 2h coupled exchange assay described herein. Still further provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 1 µM in the 2h coupled exchange assay described herein. Still further provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.5 µM in the 2h coupled exchange assay described herein. Also provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.1 µM in the 2h coupled exchange assay described herein. Also provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.05 µM in the 2h coupled exchange assay described herein. Also provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.04 µM in the 2h coupled exchange assay described herein. Also provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.03 µM in the 2h coupled exchange assay described herein. Also provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.02 µM in the 2h coupled exchange assay described herein. Also provided herein are compounds of the disclosure, or pharmaceutically acceptable salts of the foregoing, having an IC50of less than 0.01 µM in the 2h coupled exchange assay described herein.

[0046] The foregoing merely summarizes certain aspect of this disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way. FORMULATION AND ROUTE OF ADMINISTRATION

[0047] While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a compound disclosed herein (such as a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula(IIB), Formula (IIC), Formula (IID), compounds listed in Table A, Table A’, Table B, and Table B’, or a pharmaceutically acceptable salt of any of the foregoing), in combination with one or more pharmaceutically acceptable excipients and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In some cases, the pharmaceutical composition described herein comprises a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0048] The compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended. The compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0049] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. In some cases, the pharmaceutical composition is made in the form of a dosage unit containing a particular amount of the active ingredient.

[0050] Thus, a further aspect of the disclosure is a pharmaceutical composition comprising one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, for use as a medicament. METHODS OF USE

[0051] The compounds described herein can covalently bind to cysteine-12 of the GDP-bound form of the G12C-mutant KRAS protein (“KRASG12C”). In some cases, the compounds described herein can act as potent inhibitors of KRASG12Cby, for example, permanently inactivating the protein. Without intending to be bound by any particular theory, the compounds of the disclosure can, in some cases, inhibit phosphorylation of extracellular signal-regulated (“ERK”), which is a key down-streameffector of KRAS, leading to tumor regression. Besides being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.

[0052] Another aspect of the disclosure provides methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions implicated by KRAS G12C mutation (e.g., cancer). See, e.g., U.S. Patent No.10,519,146 B2, issued December 31, 2019; specifically, the section from column 198, line 1, to column 201, line 36, which is herewith incorporated by reference.

[0053] Without wishing to be bound by any particular theory, the following is noted: sotorasib is a small molecule that—similarly to the compounds disclosed herein—specifically and irreversibly inhibits KRASG12C(see Hong et al., N. Engl. J. Med.2020, 383, 1207, at 1208). Hong et al. report that “[p]reclinical studies showed that [sotorasib] inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key down-stream effector of KRAS, leading to durable complete tumor regression in mice bearing KRAS p.G12C tumors.” (id., see also Section entitled “BIOLOGICAL EVALUATION” below, Canon et al., Nature 2019, 575(7781), 217; and Lanman et al., J. Med. Chem.2020, 63, 52).

[0054] Sotorasib was evaluated in a Phase 1 dose escalation and expansion trial with 129 subjects having histologically confirmed, locally advanced or metastatic cancer with the KRAS G12C mutation identified by local molecular testing on tumor tissues, including 59 subjects with non-small cell lung cancer, 42 subjects with colorectal cancer, and 28 subjects with other tumor types (Hong et al., 2020, at page 1208-1209). Hong et al. report a disease control rate (95% CI) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3). The cancer types showing either stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma (Hong et al., 2020, at page 1212 (Figure A), and Supplementary Appendix (page 59 (Figure S5) and page 63 (Figure S6)).

[0055] KRAS G12C mutations occur with the alteration frequencies shown in the table below (Cerami et al., Cancer Discov.2012, 2(5), 401; Gao et al., Science Signaling 2013, 6(269), p11). For example, the table shows that 11.6% of subjects with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C mutant protein. Accordingly, the compounds provided herein, which specifically and irreversibly bind to KRASG12C(see SECTION 3: Biochemical andCellular Assays), are useful for treatment of subjects having a cancer, including, but not limited to the cancers listed in the table below.

[0056] Another aspect of the disclosure provides a compound disclosed herein (such as a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), compounds listed in Table A, Table A’, Table B, and Table B’, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein, for use in treating cancer. Yet another aspect of the disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating cancer, wherein one or more cells express KRAS G12C mutant protein.

[0057] Another aspect of the disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in the preparation of a medicament for treating cancer. Yet another aspect of the disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12C mutant protein.

[0058] A further aspect provided by the disclosure is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. Another aspect of the disclosure is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, wherein one or more cells express KRAS G12C mutant protein. In some cases, the subject has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0059] In some cases, the cancer is metastatic. In some cases, the cancer is non-metastatic. In some cases, the cancer disclosed herein is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor. In some cases, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, melanoma, or a solid tumor. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer. In some cases, the cancer is solid tumor. Combination therapy

[0060] The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure (such as a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), compounds listed in Table A, Table A’, Table B, and Table B’, or a pharmaceutically acceptable salt of any of the foregoing). In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and / or radiation treatment, to provide a synergistic or additive therapeutic effect. See, e.g., U.S. Patent No.10,519,146 B2, issued December 31, 2019; specifically, the sections from column 201 (line 37) to column 212 (line 46) and column 219 (line 64) to column 220 (line 39), which are herewith incorporated by reference.

[0061] The compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound in any of the methods described herein. In some cases, the second compound is an ATR inhibitor, Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK2 inhibitor, CDK4 / 6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MAT2A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PARP inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, PRMT5 inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agents. In some cases, the second compound is administered as a pharmaceutically acceptable salt. In some cases, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0062] ATR inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an ATR inhibitor in any of the methods described herein. An ATR inhibitor is a compound that targets the ataxia telangiectasia mutated and Rad3-related kinase. Exemplary ATR inhibitors for use in the methods provided herein include, but are not limited to dactolisib, VE-821 (3-Amino-6-(4-(methylsulfonyl)phenyl)-N- phenylpyrazine-2-carboxamide, 3-Amino-6-[4-(methylsulfonyl)phenyl]-N-phenyl-2- pyrazinecarboxamide), Torin 2 (9-(6-amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]-benzo[h]-1,6- naphthyridin-2(1H)-one), ETP-46464 (α,α-dimethyl-4-[2-oxo-9-(3-quinolinyl)-2H- [1,3]oxazino[5,4101zetidinelin-1(4H)-yl]-benzeneacetonitrile), CGK 733 (α-Phenyl-N-[2,2,2- trichloro-1-[[[(4-fluoro-3-nitrophenyl)amino]thioxomethyl]amino]ethyl]benzeneacetamide), AZ20 (4- [4-[(3R)-3-Methyl-4-morpholinyl]-6-[1-(methylsulfonyl)cyclopropyl]-2-pyrimidinyl]-1H-indole), SKLB-197 ((R)-4-(2-(1H-indol-4-yl)-6-(1-methyl-1H-pyrazol-5-yl)quinazolin-4-yl)-3- methylmorpholine), elimusertib, gartisertib, elimusertib hydrochloride, ceralasertib, and schisandrin B.

[0063] Aurora Kinase A Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an Aurora kinase A inhibitor in any of the methods described herein. Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3- yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4- methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3- b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12- pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]morpholine), AMG 900 (N-[4- [3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine),MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2- yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5- (trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2- oxoethyl]acetamide), SNS-314 (1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4- ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4- yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0064] AKT Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an AKT inhibitor in any of the methods described herein. Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1- aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1- aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1- aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3- chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0065] Arginase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an arginase inhibitor in any of the methods described herein. Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.

[0066] CDK 2 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a CDK 2 inhibitor in any of the methods described herein. The term “CDK 2” as used herein refers to cyclin dependent kinases (“CDK”) 2, which is a member of the mammalian serine / threonine protein kinases. The term “CDK 2 inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 2. Exemplary CDK 2 inhibitors for use in the methods provided herein include, but are not limited to, flavopiridol, roscovitine, dinaciclib, milciclib, meriolin, variolin, AZD5438 (4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4- (methylsulfonyl)phenyl]-2-pyrimidinamine), roniciclib, SNS-032 (N-[5-[[[5-(1,1-Dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide).

[0067] CDK4 / 6 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a CDK4 / 6 inhibitor in any of the methods described herein. The term “CDK 4 / 6” as used herein refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine / threonine protein kinases. The term“CDK 4 / 6 inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and / or 6. Exemplary CDK 4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8- [(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfony1)-4-piperidinyl]amino]). In some cases, the CDK4 / 6 inhibitor is palbociclib.

[0068] ErbB Family Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an ErbB family inhibitor in any of the methods described herein. The term “ErbB family” as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The term “ErbB family inhibitor” as used herein refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family. The modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members. In some cases, the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti-EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In some cases, the anti-EGFR antibody is cetuximab. In some cases, the anti-EGFR antibody is panitumumab. In some cases, the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine. In some cases, the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience). In some cases, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody. In some cases, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1- yl]-6-quinazolinyl]-2-propenamide)), PF 6274484 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7- methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3- fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide). In some cases, the irreversible ErbB family inhibitor is afatinib. In some cases, the irreversible ErbB family inhibitor is dacomitinib. In some cases, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3- (trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3- fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2- methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine). In some cases, the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0069] ERK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an ERK inhibitor in any of the methods described herein. Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4- yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4- ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H- pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.

[0070] FAK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a FAK inhibitor in any of the methods described herein. Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3- yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo- 1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2- yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5- (trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449.

[0071] FGFR Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an FGFR inhibitor in any of the methods described herein. Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5- dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5- dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl- methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036.

[0072] Glutaminase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a glutaminaseinhibitor in any of the methods described herein. Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0073] IGF-1R Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of an IGF-1R inhibitor in any of the methods described herein. Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N- (6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2- hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene- 2-carboxamide), PL225B, AVE1642, and BIIB022.

[0001] KIF18A Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a KIF18A inhibitor in any of the methods described herein. Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653, each of which is herewith incorporated by reference in its entirety. In some cases, the KIF18A inhibitor is sovilnesib (AMG 650).

[0074] MAT2A inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a MAT2A inhibitor in any of the methods described herein. An MAT2A inhibitor is a compound that inhibits methionine adenosyltransferase II alpha. An exemplary MAT2A inhibitor for use in the methods provided herein is AG 270 (3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-105zetidindin-2- ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one).

[0075] MCL-1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a MCL-1 inhibitor in any of the methods described herein. Exemplary MCL-1 inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29- hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno- 10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-Chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4- pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467. In some cases, the MCL-1 inhibitor is murizatoclax. In some cases, the MCL-1 inhibitor is tapotoclax.

[0076] MEK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a MEK inhibitor in any of the methods described herein. Exemplary MEK inhibitors for use in the methods provided herein include,but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N- [(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2- fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2- yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)- 8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4- difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N- (cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxyphenyl)-4H- chromen-4-one), PD334581 (N-[5-[3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4- oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554. In some cases, the MEK inhibitor is trametinib.

[0077] mTOR Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a mTOR inhibitor in any of the methods described herein. Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (1-(4-(4- propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin- 2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2- rnorpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine). In some cases, the mTOR inhibitor is everolimus.

[0078] PARP inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PARP inhibitor in any of the methods described herein. A PARP inhibitor is a compound that targets poly(adenosine diphosphate)- ribose polymerase. The term PARP inhibitors encompass PARP1, PARP2, and PARP3 inhibitors. Exemplary PARP inhibitors for use in the methods provided herein include, but are not limited t106zetidinrib, rucaparib, rucaparib camsylate, niraparib, niraparib tosylate, talazoparib, AG-1461, A- 966492, PJ34 HCl, niraparib, UPF 1069, ME0328, venadaparib, AZD5305, DR2313, BYK204165, pamiparib, NMS-P118, and NU 1025.

[0079] PD-1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PD-1 inhibitor in any of the methods described herein. Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001),dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti- PD-1 antibody as described in US 10,640,504 B2 (the “Anti-PD-1 Antibody A,” column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference. In some cases, the PD-1 inhibitor is pembrolizumab. In some cases, the PD-1 inhibitor is the Anti-PD-1 Antibody A.

[0080] PD-L1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PD-L1 inhibitor in any of the methods described herein. Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR- 1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167. In some cases, the PD-L1 inhibitor is atezolizumab.

[0081] PI3K Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PI3K inhibitor in any of the methods described herein. Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acalisib, CUDC-907 (N- hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl- methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4- yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2- amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2- phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 ((2S)-2-[[(2S)-3- carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2- yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]- 3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4- methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3- thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H- purin-6-amine).

[0082] PRMT5 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a PRMT5 inhibitor in any of the methods described herein. A PRMT5 inhibitor in a compound that inhibits protein arginine methyltransferase 5. The term “PRMT5 inhibitor” includes MTA-cooperative PRMT5 inhibitors. Exemplary PRMT5 inhibitors for use in the methods provided herein include, but are not limited to, pemrametostat (6-[(1-acetylpiperidin-4-yl)amino]-N-[(2S)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2- hydroxypropyl]pyrimidine-4-carboxamide), GSK3203591 (2-(Cyclobutylamino)-N-[(2S)-3-(3,4- dihydro-2(1H)-isoquinolinyl)-2-hydropropyl]-4-pyridinecarboxamide dihydrochloride)), LLY-283 ((R)-5′-phenyl-7-deazaadenosine; 6-amino-9-[(R)-5′-phenyl(ribofuranosyl)]-7-deazapurine,(2R,3R,4S,5R)-2-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)- hydroxy(phenyl)methyl)tetrahydrofuran-3,4-diol), PRT 811, and MRTX1719 (2-(4-(4- (aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6- cyclopropoxy-3-fluorobenzonitrile).

[0083] Raf Kinase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a Raf kinase inhibitor in any of the methods described herein. The term “RAF kinase” as used herein refers to a member of a mammalian serine / threonine kinases composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C-Raf / B-Raf heterodimers. The term “Raf kinase inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity. In some cases, the Raf kinase inhibitor includes, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)- 3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1- sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6’-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'- bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3- dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6- yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3- (trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP- 32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2- yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3- oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4- methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl- sulfamide). In some cases, the Raf kinase inhibitor is encorafenib. In some cases, the Raf kinase inhibitor is sorafenib. In some cases, the Raf kinase inhibitor is lifirafenib.

[0084] SHP2 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a SHP2 inhibitor in any of the methods described herein. Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin- 2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8- yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2- amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine; vociprotafib (RMC-4630; 6-[(2-amino-3-chloro-4- pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol). In some cases, the SHP inhibitor for use in the methods provided herein is RMC- 4630 (vociprotafib, Revolution Medicine). In some cases, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8- azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3- [(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2- pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9). In some cases, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3- dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75- 1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1- amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4- yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3- chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3- dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3- chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl- pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4- pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6). In some cases, the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4). In some cases, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840- 56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840- 58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2- pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8- azaspiro[4.5]decan-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3- dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3- dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-64-5), 5-(4- amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5- [(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66- 7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3- dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840- 69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1- piperidinyl)-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino- 3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840- 72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)- 5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8), and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5- [(3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol. In some cases, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840- 56-5). In some cases, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020 / 017517 A1, US 2020 / 017511 A1, WO 2019 / 075265 A1, or WO 2021 / 142026, each of which is herewith incorporated by reference in its entirety.

[0085] SOS1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a SOS1 inhibitor in any of the methods described herein. Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2- methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine), BI 1701963, AST-NS2102, MRTX-0902 ((R)- 2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile), ERAS-9, RMC-5845, HM-99462, and GH-52.

[0086] Src Kinase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a Src kinase inhibitor in any of the methods described herein. The term “Src kinase” as used herein refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily. The term “Src kinase inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases. Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2- yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2- yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1- yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide). In some cases, the Src kinase inhibitor is dasatinib. In some cases, the Src kinase inhibitor is saracatinib. In some cases, the Src kinase inhibitor is ponatinib. In some cases, the Src kinase inhibitor is vandetanib. In some cases, the Src kinase inhibitor is KX-01.

[0087] Chemotherapeutic Agents. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of one or more chemotherapeutic agents in any of the methods described herein. Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate. DEFINITIONS AND GENERAL TERMINOLOGY

[0088] The following definitions are provided to assist in understanding the scope of this disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0089] The term “alkyl” refers to a saturated straight chain hydrocarbon or saturated branched chain hydrocarbon containing the indicated number of carbon atoms. For example, C3alkyl means an alkyl group that has 3 carbon atoms (e.g., n-propyl or isopropyl). For example, a C1-6alkyl refers to an alkyl group having 1 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C1-6alkyl includes alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges)). A “C1-4alkyl” includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

[0090] The term “alkenyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. For example, C3alkenyl means the alkenyl group has 3 carbon atoms (e.g., 1-propenyl or 2-propenyl). For example, a C2-6alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-6alkenyl includes alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). A C2-4alkenyl includes, for example,ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or 3-butenyl. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2- methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0091] The term “alkynyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. For example, C3alkynyl means the alkynyl group has 3 carbon atoms. For example, a C2-6alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-6alkynyl includes any alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). For illustration, C2-4alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl. Nonlimiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0092] The term “cycloalkyl” refers to a saturated, hydrocarbon monocyclic ring, or a saturated, hydrocarbon polycyclic ring system containing the indicated number of carbon atoms as ring members in the ring or ring system. No ring in a cycloalkyl ring or ring system has s double bond, a heteroatom, or is aromatic. When a cycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example, C5cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring or ring system. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C3-7cycloalkyl includes cycloalkyl groups having 3, 4, 5, 6, or 7 carbon atoms in the ring (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 3-4, 3-5, 3-6, 3-7, 4-5, 4-6, 4-7, 5-6, 5-7, or 6-7 carbon atom ring members, or any combination of the foregoing ranges). Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbornyl, decalinyl, and 7,7-dimethylbicyclo[2.2.1]heptanyl.

[0093] The term “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring or ring system containing the indicated number of carbon atoms as ring members and having one or more carbon-carbon double bonds in the ring or ring system. No ring in a cycloalkenyl ring or ring system contains a double bond or is aromatic. When a cycloalkenyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example, C5cycloalkenyl refers to a cycloalkenyl group that has 5 carbon atoms in the ring or ring system. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C5-7cycloalkenyl includes cycloalkenyl groups having 5, 6, or 7 carbon atoms in the ring or ring system (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 5-6, 5-7, or 6-7 carbon atom ring members in the ring or ring system, or combinations of the foregoing ranges). Nonlimiting examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and bicyclo[2.2.1]hept-2-enyl.

[0094] The term “aryl” refers to a monocyclic aromatic, hydrocarbon ring (i.e., phenyl,or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic hydrocarbon ring system containing the indicated number of carbon atoms. For example, C10aryl refers to an aryl group that has 10 carbon atoms in the ring system (e.g., naphthyl). When an aryl group is a polycyclic ring system, each ring in the ring system is aromatic, and no ring in the ring system contains a heteroatom. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C6-14aryl includes aryl groups having 6-14 (e.g., 6, 10, or 14) carbon atoms in the ring or ring system (or combinations of the foregoing), as well as all subgroups in the indicated range (e.g., 6-10 or 10-14 carbon atom ring members in the ring or ring system, or combinations of the foregoing). Nonlimiting examples of aryl groups include phenyl, naphthyl, and anthracenyl.

[0095] The term “heteroatom,” unless otherwise stated herein, refers to oxygen, sulfur, nitrogen, and phosphorus.

[0096] The term “heterocycloalkyl” refers to a saturated, monocyclic ring or saturated, polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring). When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. No ring in a heterocycloalkyl ring or ring system contains a double bond or is aromatic. For example, a heterocycloalkyl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S includes rings having 5, 6, or 7 total atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom independently is selected from N, O, and S. Thus, a heterocycloalkyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N,O, and S. Nonlimiting examples of heterocycloalkyl groups include but are not limited to aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene-yl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, azepanyl, and 1,4-diazepanyl.

[0097] The term “heterocycloalkenyl” refers to a monocyclic ring or a polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), wherein the ring or ring system has one or more double bonds. In a polycyclic ring system, the one or more heteroatoms may be located in any ring within the system, including in a ring lacking a double bond. When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion, and any ring in the ring system can contain a double bond. No ring in a heterocycloalkenyl ring or ring system is aromatic. For example, a heterocycloalkenyl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to a ring having at least one double bond, 3 carbon atoms, and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkenyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S includes rings having at least one double bond and 5, 6, or 7 total atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom independently is selected from N, O, and S. Thus, heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing at least one double bond and, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Nonlimiting examples of heterocycloalkenyl groups include but are not limited to dihydropyrrolyl, dihydrofuranyl, dihydrothiophene-yl, dihydroisoxazolyl, tetrahydropyridyl, dihydropyranyl, dihydrothiopyranyl, 3a,4,5,6,7,7a- hexahydrobenzofuranyl, 1,3a,3,4,7,7a-hexahydroisobenzofuranyl, and 3a,4,5,6,7,7a- hexahydroindolyl.

[0098] The term “heteroaryl” refers to a monocyclic aromatic ring comprising carbon and one or more heteroatoms and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic ring system having one or more heteroatoms and the indicated number of total ring atoms (the sum of carbonatoms and heteroatoms in the ring system). When a heteroaryl group is a polycyclic ring system, each ring in the ring system is aromatic. For example, a heteroaryl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S refers to an aromatic ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms, or any combination of the foregoing), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. A heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of monocyclic heteroaryl groups include: pyrrolyl, furanyl, thiophene-yl (or thienyl), pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (or pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Nonlimiting examples of bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzimidazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, furopyridinyl (e.g., furo[2,3-b]pyridinyl), imidazopyridinyl (imidazo[4,5-b]pyridinyl), imidazothiazolyl (e.g., imidazo[4,5-d]thiazolyl), indolizinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl (e.g., oxazolo[5,4-b]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (e.g., pyrrolo[2,3-b]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, cinnolinyl, isoquinolyl, pyrazolopyridinyl (e.g., pyrazolo[3,4-b]pyridinyl), and thiazolopyrindinyl (e.g., thiazolo[5,4-b]pyridinyl). Nonlimiting examples of tricyclic heteroaryl groups include carbazolyl, 4,5-benzindolyl, dibenzofuranyl, dibenzothiophene-yl, phenazinyl, and acridinyl.

[0099] The term “alkylene” refers to a divalent saturated, straight or branched hydrocarbon chain diradical containing the indicated number of carbon atoms. For example, C3alkylene means the alkylene group has 3 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, C1-6alkylene means an alkylene group having a 1, 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). When the number of carbon atoms in an alkylene group is indicated as “C0,” then the alkylene group is not present and the recited substituentis directly attached to the rest of the compound. For example, the term C0-6alkylene-OH indicates that the OH group can be directly attached to the compound or through a C1-6alkylene linker. Examples of alkylene groups include methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (— CH2CH2CH2—), isopropylene (—CH(CH3)CH2—), 1-butylene (—CH2CH2CH2CH2—), 1- methylbutylene (—CH(CH3)CH2CH2—), 2-methylbutylene (—CH2CH(CH3)CH2—), and 3- methylbutylene (—CH2CH2CH2(CH3)—).

[0100] The term “heteroalkylene” refers to an alkylene group containing one or more heteroatoms (e.g., one or more of N, O, and S) at one or more of theteroalkylene’s points of attachment (e.g., - OCH2CH2O- or -OCH2CH2-) or between two carbon atoms (e.g., ether), or a combination thereof. A heteroalkylene contains the indicated number of total atoms (i.e., the sum of the carbon atoms and heteroatoms in the chain). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroalkylene having 2-6 total atoms and 1, 2, or 3 heteroatoms independently selected from O and S includes heteroalkylene groups having 2, 3, 4, 5, or 6 total atoms in theteroalkylene chain (or any combination of the foregoing), as well as all subgroups of total atoms in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 total atoms, or any combination of the foregoing ranges), wherein 1, 2, or 3 (or any combination of the foregoing) of the total atoms in the chain are heteroatoms, as well as all subgroups in the indicated range (e.g., 1- 2, 1-3, or 2-3 heteroatoms, or any combination of the foregoing). Thus, a heteroalkylene having 5-7 total atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses moieties containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of heteroalkylene groups include - O(CH2)2O-.

[0101] The term “alkylene bridge” refers to an alkylene group that forms a bridge on a ring, wherein the bridge has the indicated number of carbon atoms. For example, a C1alkylene bridge ( ) on a cyclohexylene ring can be depicted as, for example,bridge ( ) on a cyclohexylene ring can be depicted as, for example,C3alkylene bridge () on a cyclohexylene ring can be depicted as, for example,.

[0102] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0103] The term “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen. The halogen is independently selected at each occurrence. The term includes, for example, monohaloalkyl (e.g., CH2F, CH(CH2F)CH3) dihaloalkyl (e.g., CHF2, CH(CHF2)CH3), trihaloalkyl (e.g., CF3, CH(CF3)CH3), and polyhaloalkyl (e.g., CF(CF3)CH3). A haloalkyl group may or may not be perhalogenated (e.g., perfluorinated, such as CF(CF3)CF3). For example, the term “C1-4haloalkyl” refers to a C1-4alkyl, wherein one or more hydrogen atoms is substituted with a halogen. For illustration, C1-4haloalkyl includes, for example, CH2F, CHF2, CF3, CHFCl, CH2CF3, CFHCF3, CF2CF3, CH(CF3)2, CF(CHF2)2, CH(CH2F)(CF3), CH2Cl, CHCl2, CCl3, CHFCl, CH2CCl3, CClHCCl3, CCl2CCl3, CH(CCl3)2, CCl(CHCl2)2, CH(CH2Cl)CCl3, and CH2CF(CH3)2.

[0104] The term “oxo” refers to a substituent oxygen atom connected to another atom by a double bond (e.g., =O). For example, an oxo substituent on a cyclopentyl ring can be depicted as:.

[0105] The terms “alkoxy” and “alkoxyl” are interchangeable and refer to an —O-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C3alkoxy group means the alkoxy group has 3 carbon atoms (e.g., OCH2CH2CH3). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C1-6alkoxy includes alkoxy groups having 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). Nonlimiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, 1-methylethyloxy (iso-propoxy), n-butoxy, isobutoxy, sec-butoxy, and tert- butoxy.

[0106] The term “thioalkyl” refers to an —S-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C3thioalkyl group means the thioalkyl group has 3 carbon atoms (e.g., SCH2CH2CH3). Where a range is indicated, all members of that range and all subgroups withinthat range are envisioned. For example, a C1-6thioalkyl includes thioalkyl groups having 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). Nonlimiting examples of thioalkyl groups include methylthiyl, ethylthiyl, n-propylthiyl, isopropylthiyl, n-butylthiyl, isobutylthiyl, sec-butylthiyl, and tert-butylthiyl.

[0107] The terms “haloalkoxy” and “haloalkoxyl” are interchangeable and refer to an alkoxy group in which one or more of the hydrogen atoms is replaced by a halogen. The halogen is independently selected at each occurrence. The term includes monohaloalkoxy (e.g., OCH2F, OCH(CH2F)CH3) dihaloalkoxy (e.g., OCHF2, OCH(CHF2)CH3), trihaloalkoxy (e.g., OCF3, OCH(CF3)CH3), and polyhaloalkoxy (e.g., OCF(CF3)CH3). A haloalkoxy group may or may not be perhalogenated (e.g., perfluorinated, such as OCF(CF3)CF3). For example, the term “C1-4haloalkoxy” refers to a C1-4alkoxy as defined herein, wherein one or more hydrogen atoms is substituted with a halogen. Representative examples of C1-4haloalkoxy include OCH2F, OCHF2, OCF3, OCHFCl, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, OCH(CH2F)(CF3), OCH2Cl, OCHCl2, OCF3, OCHFCl, OCH2CCl3, OCClHCCl3, OCCl2CCl3, OCH(CCl3)2, OCCl(CHCl2)2, OCH(CH2Cl)CCl3, and OCH2CF(CH3)2.

[0108] The term “ether” refers to an oxygen atom bonded to two alkyl or aryl groups (R-O-R). The term “ether bridge” refers to an ether group that forms a bridge on a ring, wherein the bridge has theindicated number of carbon atoms. For example, a C1 ethe cyclohexylenering cyclohexylene ring can be depicted as, for example,

[0109] The term “thioether” refers to a sulfur atom bonded to two alkyl or aryl groups (R-S-R). The term “thioether bridge” refers to a thioether group that forms a bridge on a ring, wherein thebridge has the indicated number of carbon atoms. For example, a C1 thioeta cyclohexylene ring cyclohexylene ring can be depicted as, for example,

[0110] The term “solvate” refers to a molecular aggregate comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non- stoichiometric amount of one or more pharmaceutically acceptable solvent molecules.

[0111] The term “geminal” refers to substituents that are attached to the same atom. Geminal R groups on a chain and ring can be depicted as:, respectively.

[0112] The term “vicinal” refers to substituents that are attached to adjacent atoms along a chain orwithin a ring. Vicinal R groups along a chain and within a ring can be depicted as and, respectively.

[0113] The term “non-neighboring” refers to substituents that are attached to atoms along a chain or within a ring that are not attached to adjacent atoms and that are not geminal. Non-neighboring R groups along a chain and within a ring can be depictedrespectively.

[0114] The term “protecting group” refers to a removable moiety that modifies a desired functional group to block the desired functional group from reacting in a subsequent chemical reaction. For example, the term “nitrogen protecting group” refers to a removable moiety that modifies a functional group having a nitrogen atom to block the functional group having a nitrogen atom from reacting in a subsequent chemical reaction (e.g., tert-butyloxycarbonyl). Examples of protecting groups are detailed in Greene, T. W., Wuts, P. G, “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book, such as Wuts, P.G.M. and Greene, T.W. “Greene’s Protective Groups in Organic Synthesis,” Fourth Edition, John Wiley & Sons, Hoboken: 2007).

[0115] As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0116] The term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure or functional group with the radical of a specified substituent. A substituted structure or functional group may have a substituent at any substitutable position of the structure or functionalgroup. When more than one position in a given structure can be substituted with more than one substituent, the substituent may be either the same or different at each position.

[0117] The term “pharmaceutically acceptable” refers to a species or component that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in a subject.

[0118] The term “pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N- methylglucamine, dicyclohexylamine). Additionally, the salts of the compounds described herein, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules.

[0119] The term “pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound, solvate, or salt disclosed herein to prepare a pharmaceutically acceptable composition or formulation. Excipients include, for example, vehicles (e.g., solvents, dispersion media), coatings, isotonic and absorption delaying agents, diluents, colorants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, and preservatives (e.g., antibacterial and antifungal agents).

[0120] The term “therapeutically effective amount” as used herein refers to that amount of a compound disclosed herein that elicits a desired biological or medical response in a cell, a tissue, a system, or a subject.

[0121] The term “patient” or “subject” refers to humans and other mammals. The term “mammal” as used herein includes, for example, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), and monkeys. Human subjects include neonates, infants, juveniles, adults, and geriatric subjects. GENERAL SYNTHETIC PROCEDURES

[0122] The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternativesynthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.

[0123] Generally, the compounds of Formula (I) can be synthesized according to the following schemes. Variables used in the following schemes are the variables as defined for Formula (I), unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ltd., Enamine Ltd, Combi-Blocks, Astech, Oakwood, Thermal Fisher, LabNetwork, PharmBlock, BLD Pharm, AstatTech, Inc., Apollo Scientific, AmBeed, Inc., eNovation Chemicals, and Aurum Pharmatech, or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting materials may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein. The abbreviation PG refers to a protecting group, as defined herein in the DEFINITIONS AND GENERAL TERMINOLOGY section. In the scheme below, each PG can be the same as or different from another PG in the compound, so long as each protecting group can be selectively removed.

[0124] In general, the compounds of Formula (I) can be synthesized according to Scheme 1.Scheme 1

[0125] A protected, piperazine linker portion of Formula (can be synthesized by reacting a desired alkene-substituted, protected, 4-membered ring, such as 3-azetidinone, with a desired, nitrogen-protected piperazine in the presence of an appropriate reducing reagent, such as a borohydride reagent, in a reductive amination reaction. Alternatively, the protected piperazine linker portion of Formula (can be synthesized via an SN2 reaction using a desired, nitrogen-protected piperazine with an azetidine functionalized with a leaving group (e.g., a mesylate or tosylate). A desired, alkene-substituted, halogenated aryl / heteroaryl core:can be synthesized by performing a palladium-catalyzed cross-coupling reaction with, wherein each of halo1and halo2is a halogen, and a desired, allyl boronic acid compound:. The nitrogen-protected linker portion of Formulacoupled to the alkene-substituted, halogenated, aryl / heteroaryl core:removing PG1and conducting a nucleophilic aromatic substitution reaction in the presence of anappropriate base to form a di-alkenyl portion of the compound of Formula (. The resulting compound can undergo an olefin metathesis reaction, using for example, Grubb’s catalyst, to form the middle portion of Formula (I) having an alkene tether:. The resulting alkene tether can optionally undergo modification to functionalize it with one or more desired substituents using common reactions know to one skilled in the art. For example, the double bond of the tether can be reduced to a saturated hydrocarbon using a reducing agent, such as Pd / C. Alternatively, the double bond of the tether can be reacted with an allylic oxidizing agent, such as SeO2, to result in an allylic alcohol. The allylic alcohol can be further oxidized to form an α,β- unsaturated carbonyl (e.g., under Dess-Martin oxidation conditions). The carbon of the α,β- unsaturated carbonyl can undergo difluorination to form an allylic geminal difluoride. The double bond of either the α,β-unsaturated carbonyl or the allylic geminal difluoride can be reduced via a suitable reducing agent to form a tether substituted with a ketone or geminal difluoride, respectively. An alcohol-substituted tether can be formed by subjecting the double bond of the tether to a halogenating agent and an alcohol (e.g., such as N-bromosuccinimide and AcOH) to form a vicinal alkoxyhalide, which can then be epoxidized using a suitable base (e.g., NaOMe), and then reduced (e.g,. using Pd / C) to form the alcohol. The alcohol-substituted tether can be oxidized (e.g., using Dess-Martins oxidation conditions) to a ketone, which can then be difluorinated using an organosulfur fluorinating agent, such as diethylaminosulfur trifluoride (DAST).

[0126] The spiro tail of Formula (can be synthesized, for example, according to Scheme 1.1 or Scheme 1.2. Scheme 1.1Scheme 1.2In Scheme 1.1, a desired, optionally substituted, N-protected, piperidin-4-one compound: nd a desired Z-Y-Z’ compound can undergo a nucleophilic addition reaction to form, wherein Z is a functional group capable of nucleophilic addition to the carbonyl on the piperidin-4-one (e.g., an alkyne in an alkynylation reaction, or a halogen in a nucleophilic aromatic substitution reaction), Y is the precursor to the desired Y’ spiro group, and Z’ is a nucleophilic group (e.g., OH) that acts in a subsequent cyclization reaction. In a next step,can be subjected to a cyclization and deprotection reaction to form the spiro tail:

[0127] In Scheme 1.2, a boronic ester or acid derived from a substituted, N-protected, piperidin-4- one compound (e.g., a pinacolborane-derived, N-protected, piperidin-4-one compound) and a desired Z-Y-Z’ can undergo a Suzuki coupling reaction, wherein Z is a halogen or leaving group, Y is the precursor to the desired Y’ spiro group, and Z’ is a nucleophilic group (e.g., OH) that acts in a subsequent cyclization reaction to formnext step,can undergo iodine-mediated cyclization, reduction, and deprotection to form compound (Alternatively, compound B can be prepared by reacting a desired aryl group functionalized with a boronic ester or acid (e.g., BPin-Ar-Y-Z’) with a desired dihydropyridine in which the olefin is functionalized with a leaving group, such as triflate:which then can undergo iodine-mediated cyclization, reduction, and deprotection, as previously described. Further reactions can be performed, as necessary, to add desired substituents to the spiro Y’ group. The piperidine tail can be added to the core by, e.g., performing a nucleophilic aromatic substitution reaction in the presence of a base (e.g., DIPEA). Alternatively, the C-N bond can be formed by, e.g., a palladium-catalyzed amination reaction.

[0128] If the double bond of the tether that resulted from the olefin-metathesis reaction is present, it can be functionalized, as previously described, to form compounds of Formula (I) e.g., via reduction, oxidation and the like.

[0129] The Michael acceptor can be installed on the compound by deprotecting the nitrogen atom of the piperazine ring using an appropriate reagent (e.g., acid or Pd / C), and reacting the deprotected piperazine ring with a desired halogenated α,β-unsaturated ketone, such as acryloyl chloride to form the compound of Formula (II) having an alkene tether.

[0130] Compounds of Formula (I) having a tether substituted with a methylene group (=CH2) can be synthesized similarly to the general procedure described herein for compounds having an alkene tether, except that the tether can be formed via a palladium catalyzed cross-coupling of the nitrogen- protected linker portion of Formula (the aryl halide of the core halogenated (e.g., a Heck Reaction), aryl / heteroaryl core:, as shown in Scheme 2, below. Scheme 2

[0131] Compounds of Formula (I) having an ether tether can be synthesized similarly to the general procedure described herein for compounds having an alkene tether, except that the tether can be formed by installing an alkylene-OMe group on the azetidine of the nitrogen-protected, linker portion of Formula (I), and coupling the resulting intermediate to a desired core:. The alkylene can then be demethylated, coupled to chloroacetic acid, and cyclized to the core to form an ether linker, as shown in Scheme 3.Scheme 3

[0132] As can be appreciated by the skilled artisan, the above synthetic scheme and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.

[0133] Purification methods for the compounds described herein are known in the art and include, for example, crystallization, chromatography (for example, liquid, gas phase, and supercritical fluid), extraction, distillation, trituration, and reverse phase HPLC. INTERMEDIATES

[0134] The disclosure further encompasses intermediate compounds, including structures produced from the synthetic procedures described, whether isolated or generated in-situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure.

[0135] Further provided herein are intermediates useful in preparing the spiro tale of the compounds of Formula (I), such as the compounds depicted in Table INT-A, protected analogs thereof, and pharmaceutically acceptable salts of any of the foregoing.Table INT-A

[0136] Further provided herein are intermediates of Formula, nitrogen- protected analogs thereof, and pharmaceutically acceptable salts of any of the foregoing, wherein o, p, q, r, Y’, R6, and R7are each as defined herein in the COMPOUNDS OF FORMULA (I) section. In some cases, the compound of Formula (Int-B) is the free base:pharmaceutically acceptable salt thereof. In some cases, the nitrogen of the compound of Formula (Int-B), or pharmaceutically acceptable salt thereof, is protected with a protecting group (PG3):described in the “DEFINITIONS AND GENERAL TERMINOLOGY” section.

[0137] Contemplated examples of intermediates of Formula (Int-B) include the compounds listed in Table INT-B, nitrogen-protected analogs thereof, and pharmaceutically acceptable salts of any of the foregoing. In some cases, the compound of Formula (Int-B), such as a compound listed in Table INT-B, is a TFA salt.Table INT-B

[0138] Further provided herein are intermediates of Formula (, nitrogen- protected analogs thereof (e.g., a BOC-protected or benzyl carbamate-protected analogs, such aspharmaceutically acceptable salts of any of the foregoing(e.g., TFA salt), wherein m, n, R3, and R4are each as defined herein in the COMPOUNDS OF FORMULA (I) section, and B is C1-3alkylene-CH=CH2or C1-3alkyleneOH. In some cases, m is 0 or 1; R3is CH3. In some cases, B is CH2CH=CH2or CH2CH2OH. Contemplated examples of intermediates of Formula (Int-D) are listed in Table INT-D and include pharmaceutically acceptable salts thereof. Table INT-D

[0139] Further provided herein are intermediates of Formulanitrogen-protected analogs thereof, and pharmaceutically acceptable salts of any of the foregoing, wherein halo2is F, Cl, Br, or I, and m, n, , R3, R4, and R5are as defined herein in the COMPOUNDS OF FORMULA (I) section. Contemplated examples of intermediates of Formula (Int- E) include the compound listed in Table INT-E, nitrogen-protected analogs of the depicted free bases, free base analogs of the depicted nitrogen-protected analogs, and pharmaceutically acceptable salts of any of the foregoing.Table INT-E

[0140] Also provided herein are intermediates listed in Table INT, protected analogs thereof (such as nitrogen-protected analogs), and pharmaceutically acceptable salts of any of the foregoing. Table INTF

[0141] Another aspect of the disclosure is a process for preparing a compound or salt described herein (such as a compound of Formula (I), Formula (I’), Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (II), Formula (II’), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), a compound listed in Table A, Table A’, Table B, and Table B’, or a pharmaceutically acceptable salt of any of the foregoing), comprising converting an intermediate described herein, such as an intermediate of Formula (Int-B), Formula (Int-D), Formula (Int-E), an intermediate listed in Table INT-A, INT-B, INT-D, INT-E, INT, a protected analog of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, into a compound disclosed herein. In some cases, the intermediate is a compound listed in Table INT-A, a protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound of Formula (Int-B), a protected analog thereof (such as a nitrogen-protected analog), or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table INT-B, a protected analog thereof (such as a nitrogen-protected analog), or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound of Formula (Int-D), a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table INT-D, a protected analog thereof (such as a nitrogen-protected analog), or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound of Formula (Int-E), a protected analog thereof (such as a nitrogen-protected analog), or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table INT-E, a protected analog thereof (such as a nitrogen-protected analog), or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the intermediate is a compound listed in Table INT, a protected analog thereof (such as a nitrogen-protected analog), or a pharmaceutically acceptable salt of any of the foregoing.ADDITIONAL EMBODIMENTS

[0142] Provided herein as Embodiment 1 is a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S, or heteroalkenylene having 3- 6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 3-5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; A is N, CH, C-halo, C- 3alkylene-C1-4each of W1and W2independently is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C2-3alkenyl, C-C2-3alkynyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; Y’ is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; each of R1a, R1b, and R2independently is H, D, halo, C1-4alkyl, C1-4haloalkyl, C1-2alkylene- OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RN1)2, C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or R1band R2, together with the carbon atoms to which they are attached, form; each R3independently is C1-3alkyl, C1-3haloalkyl,, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or fused- heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, C1-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; R5is halo, C1-3haloalkyl, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3thioalkyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl; each R6independently is halo, CN, C1-3alkyl, C2-3alkenyl, C1-3haloalkyl, C0-3alkylene-OH, C0- 3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, C1-4alkylene-N(RN1)2, oxo, =CH2, C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused- heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two non- neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl of each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN; each R7independently is halo, C0-3alkylene-CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, oxo, =CH2, C0-4alkylene-C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl, C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R7together with the atoms to which they are attached form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatomsindependently selected from N, O and S, fused-C6-10aryl, or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0143] Provided herein as Embodiment 2 is the compound or salt of Embodiment 1, wherein at least one of R1a, R1b, and R2is H or D.

[0144] Provided herein as Embodiment 3 is the compound or salt of Embodiment 2, wherein each of R1a, R1b, and R2independently is H or D.

[0145] Provided herein as Embodiment 4 is the compound or salt of Embodiment 3, wherein each of R1a, R1b, and R2is H.

[0146] Provided herein as Embodiment 5 is the compound or salt of Embodiment 3, wherein each of R1a, R1b, and R2is D.

[0147] Provided herein as Embodiment 6 is the compound or salt of Embodiment 1 or 2, wherein at least one of R1a, R1b, and R2is halo.

[0148] Provided herein as Embodiment 7 is the compound or salt of Embodiment 6, wherein R1ais halo and each of R1band R2is H.

[0149] Provided herein as Embodiment 8 is the compound or salt of Embodiment 6 or 7, wherein each halo independently is Br, Cl, or F.

[0150] Provided herein as Embodiment 9 is the compound or salt of Embodiment 1 or 2, wherein at least one of R1a, R1b, and R2is C1-4alkyl or C1-4haloalkyl.

[0151] Provided herein as Embodiment 10 is the compound or salt of Embodiment 9, wherein at least one of R1a, R1b, and R2is CH3, CH2F, CHF2, or CF3.

[0152] Provided herein as Embodiment 11 is the compound or salt of Embodiment 1 or 2, wherein at least one of R1a, R1b, and R2is C1-2alkylene-OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, or C0-2alkylene-N(RN1)2.

[0153] Provided herein as Embodiment 12 is the compound or salt of Embodiment 11, wherein each RN1independently is H or CH3.

[0154] Provided herein as Embodiment 13 is the compound or salt of Embodiment 12, wherein each RN1is H.

[0155] Provided herein as Embodiment 14 is the compound or salt of Embodiment 11 or 12, wherein at least one of R1a, R1b, and R2is CH2OH, OCH3, CH2OCH3, OCF3, CH2OCF3, CN, CH2CN, NH2, N(CH3)2, CH2NH2, or CH2N(CH3)2.

[0156] Provided herein as Embodiment 15 is the compound or salt of Embodiment 1 or 2, wherein at least one of R1a, R1b, and R2is C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0157] Provided herein as Embodiment 16 is the compound or salt of Embodiment 15, wherein theterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.

[0158] Provided herein as Embodiment 17 is the compound or salt of Embodiment 15 or 16, wherein at least one of R1a, R1b, and R2is aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidine-1-yl- methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl.

[0159] Provided herein as Embodiment 18 is the compound or salt of Embodiment 1 or 2, wherein R1band R2, together with the carbon atoms to which they are attached, form .

[0160] Provided herein as Embodiment 19 is the compound or salt of Embodiment 1 or 2, wherein

[0161] Provided herein as Embodiment 20 is the compound or salt of Embodiment 19, wherein .

[0162] Provided herein as Embodiment 21 is the compound or salt of Embodiment 20, wherein.

[0163] Provided herein as Embodiment 22 is the compound or salt of any one of Embodiments 1- 21, wherein m is 0.

[0164] Provided herein as Embodiment 23 is the compound or salt of any one of Embodiments 1- 21, wherein m is 1.

[0165] Provided herein as Embodiment 24 is the compound or salt of any one of Embodiments 1- 21, wherein m is 2.

[0166] Provided herein as Embodiment 25 is the compound or salt of any one of Embodiments 1- 21, wherein m is 3.

[0167] Provided herein as Embodiment 26 is the compound or salt of any one of Embodiments 1- 21, wherein m is 4.

[0168] Provided herein as Embodiment 27 is the compound or salt of any one of Embodiments 1- 21, whereindeuterated.

[0169] Provided herein as Embodiment 28 is the compound or salt of Embodiment 27, wherein.

[0170] Provided herein as Embodiment 29 is the compound or salt of any one of Embodiments 23- 26, wherein at least one R3is C1-3alkyl or C1-3haloalkyl.

[0171] Provided herein as Embodiment 30 is the compound or salt of Embodiment 29, wherein at least one R3is CH3, CH2CH3, CF3, CHF2, or CH2F.

[0172] Provided herein as Embodiment 31 is the compound or salt of Embodiment 30, wherein at least one R3is CH3.

[0173] Provided herein as Embodiment 32 is the compound or salt of any one of Embodiments 23- 26, wherein at least one.

[0174] Provided herein as Embodiment 33 is the compound or salt of Embodiment 32, wherein each of RA1and RA2independently is H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl.

[0175] Provided herein as Embodiment 34 is the compound or salt of Embodiment 32 or 33,

[0176] Provided herein as Embodiment 35 is the compound or salt of any one of Embodiments 23- 26, wherein at least one R3is C0-3alkyleneCN.

[0177] Provided herein as Embodiment 36 is the compound or salt of Embodiment 35, wherein at least one R3is CN or CH2CN.

[0178] Provided herein as Embodiment 37 is the compound or salt of any one of Embodiments 23- 26, wherein at least one R3is C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy.

[0179] Provided herein as Embodiment 38 is the compound or salt of Embodiment 37, wherein at least one R3is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3.

[0180] Provided herein as Embodiment 39 is the compound or salt of any one of Embodiments 23- 26, wherein at least one R3is oxo.

[0181] Provided herein as Embodiment 40 is the compound or salt of any one of Embodiments 23- 26, wherein at least one R3is spiro-C3-7cycloalkyl or spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

[0182] Provided herein as Embodiment 41 is the compound or salt of Embodiment 40, wherein at least one R3is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl.

[0183] Provided herein as Embodiment 42 is the compound or salt of any one of Embodiments 23- 26, wherein at least one R3is spiro-C4-7cycloalkenyl or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

[0184] Provided herein as Embodiment 43 is the compound or salt of any one of Embodiments 24- 26, wherein two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl or fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

[0185] Provided herein as Embodiment 44 is the compound or salt of Embodiment 43, wherein two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused- cyclobutyl.

[0186] Provided herein as Embodiment 45 is the compound or salt of any one of Embodiment 24- 26, wherein two vicinal R3, together with the atoms to which they are attached, form fused-C4-7cycloalkenyl or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

[0187] Provided herein as Embodiment 46 is the compound or salt of any one of Embodiments 23-spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl; or two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused-cyclobutyl.

[0188] Provided herein as Embodiment 47 is the compound or salt of any one of Embodiments 1- 21, wherein m is 0; or m is 1 and R3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

[0189] Provided herein as Embodiment 48 is the compound or salt of Embodiment 47, wherein m is 0; or m is 1 and R3is CH3.

[0190] Provided herein as Embodiment 49 is the compound or salt of any one of Embodiments 1- 2

[0191] Provided herein as Embodiment 50 is the compound or salt of Embodiment 49, wherein

[0192] Provided herein as Embodiment 51 is the compound or salt of Embodiment 50, wherein

[0193] Provided herein as Embodiment 52 is the rovided herein as Embodiment 2 is the compound or salt of any one of Embodiments 1-51, wherein A is N.

[0194] Provided herein as Embodiment 53 is the compound or salt of any one of Embodiments 1- 51, wherein A is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy.

[0195] Provided herein as Embodiment 54 is the compound or salt of Embodiment 53, wherein A is CH.

[0196] Provided herein as Embodiment 55 is the compound or salt of Embodiment 53, wherein A is C-F, C-Cl, or C-CN.

[0197] Provided herein as Embodiment 56 is the compound or salt of Embodiment 53, wherein A is C-C1-3alkyl.

[0198] Provided herein as Embodiment 57 is the compound or salt of Embodiment 56, wherein A is C-CH3.

[0199] Provided herein as Embodiment 58 is the compound or salt of Embodiment 53, wherein A is C-C1-3haloalkyl.

[0200] Provided herein as Embodiment 59 is the compound or salt of Embodiment 58, wherein A is C-CH2F, C-CHF2, or C-CF3.

[0201] Provided herein as Embodiment 60 is the compound or salt of Embodiment 53, wherein A is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy.

[0202] Provided herein as Embodiment 61 is the compound or salt of Embodiment 60, wherein A is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0203] Provided herein as Embodiment 62 is the compound or salt of Embodiment 53, wherein A is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2F, C-CHF2, C-CF3, C-OH, C-CH2OH, C-OCH3, or C- CH2OCH3.

[0204] Provided herein as Embodiment 63 is the compound or salt of any one of Embodiments 1- 62, wherein n is 0.

[0205] Provided herein as Embodiment 64 is the compound or salt of any one of Embodiments 1- 62, wherein n is 1.

[0206] Provided herein as Embodiment 65 is the compound or salt of any one of Embodiments 1- 62, wherein n is 2.

[0207] Provided herein as Embodiment 66 is the compound or salt of Embodiment 64 or 65, wherein at least one R4is C1-3alkyl or C1-3haloalkyl.

[0208] Provided herein as Embodiment 67 is the compound or salt of Embodiment 66, wherein at least one R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, or CF3.

[0209] Provided herein as Embodiment 68 is the compound or salt of Embodiment 67, wherein at least one R4is CH3.

[0210] Provided herein as Embodiment 69 is the compound or salt of Embodiment 64 or 65, wherein at least one R4is C0-3alkyleneCN.

[0211] Provided herein as Embodiment 70 is the compound or salt of Embodiment 69, wherein at least one R4is CN or CH2CN.

[0212] Provided herein as Embodiment 71 is the compound or salt of Embodiment 64 or 65, wherein at least one R4is C1-3alkyleneOH or C1-3alkylene-C1-3alkoxy.

[0213] Provided herein as Embodiment 72 is the compound or salt of Embodiment 71, wherein at least one R4is CH2OH, CH2CH2OH, CH2OCH3, or CH2CH2OCH3.

[0214] Provided herein as Embodiment 73 is the compound or salt of Embodiment 64 or 65, wherein at least one R4is oxo.

[0215] Provided herein as Embodiment 74 is the compound or salt of Embodiment 64 or 65, wherein at least one R4is spiro-C3-7cycloalkyl or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

[0216] Provided herein as Embodiment 75 is the compound or salt of Embodiment 74, wherein at least one R4is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

[0217] Provided herein as Embodiment 76 is the compound or salt of Embodiment 64 or 65, wherein each R4independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

[0218] Provided herein as Embodiment 77 is the compound or salt of any one of Embodiments 1- 6

[0219] Provided herein as Embodiment 78 is the compound or salt of Embodiment 77, wherein . [ n as Embodiment 79 is the compound or salt of any one of Embodiments 1- 78, wherein is unsubstituted.

[0221] Provided herein as Embodiment 80 is the compound or salt of any one of Embodiments 1- 78, whereinis substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro- C4-5cycloalkenyl, spiro-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatomsindependently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused- heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

[0222] Provided herein as Embodiment 81 is the compound or salt of Embodiment 80, wherein each substituent independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH=CH2, CH=CHCH3, CH2CH=CH2, Cl, F, OH, CH2OH, CH2CH2OH, OCH3, OCH2CH3, CH2OCH3, CH2OCH2CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, aziridinyl, azetidinyl, spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxiranyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, spiro-aziridinyl, or spiro-azetidinyl; or two vicinal substituents, together with the atoms to which they are attached form fused-cyclopropyl, fused-cyclobutyl, fused-oxiranyl, fused-oxetanyl, fused-tetrahydrofuranyl, fused-aziridinyl, or fused-azetidinyl.

[0223] Provided herein as Embodiment 82 is the compound or salt of Embodiment 81, whereincombination of the foregoing.

[0224] Provided herein as Embodiment 83 is the compound or salt of Embodiment 82, wherein is substituted with CH3, F, or a combination of the foregoing.

[0225] Provided herein as Embodiment 84 is the compound or salt of any one of Embodiments 1- 83, wherein is C2-6alkylene.

[0226] Provided herein as Embodiment 85 is the compound or salt of Embodiment 84, wherein

[0227] Provided herein as Embodiment 86 is the compound or salt of any one of Embodiments 1-

[0228] Provided herein as Embodiment 87 is the compound or salt of Embodiment 86, wherein

[0229] Provided herein as Embodiment 88 is the compound or salt of Embodiment 84, wherein is C3alkylene.

[0230] Provided herein as Embodiment 89 is the compound or salt of any one of Embodiments 1-

[0231] Provided herein as Embodiment 90 is the compound or salt of Embodiment 89, wherein

[0232] Provided herein as Embodiment 91 is the compound or salt of Embodiment 84, wherein is C4-6alkylene.

[0233] Provided herein as Embodiment 92 is the compound or salt of any one of Embodiments 1- 78, wherein, wherein t is 0, 1, 2, or 3; and each R8independently is C1-3alkyl, halo, OH, OC1-3alkyl, oxo, =CH2; or two vicinal R8, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0234] Provided herein as Embodiment 93 is the compound or salt of Embodiment 92, wherein each R8independently is CH3, Cl, F, OH, OCH3, oxo, or =CH2; or two vicinal R8, together with the atoms to which they are attached form.

[0235] Provided herein as Embodiment 94 is the compound or salt of any one of Embodiments 1- 83, wherein is C3-6alkenylene.

[0236] Provided herein as Embodiment 95 is the compound or salt of Embodiment 94, wherein is C3alkenylene.

[0237] Provided herein as Embodiment 96 is the compound or salt of any one of Embodiments 1-.

[0238] Provided herein as Embodiment 97 is the compound or salt of Embodiment 94, wherein is C4-6alkenylene.

[0239] Provided herein as Embodiment 98 is the compound or salt of any one of Embodiments 1-OH, OC1-3alkyl, oxo, =CH2; or two vicinal R8, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0240] Provided herein as Embodiment 99 is the compound or salt of Embodiment 98, wherein each R8independently is CH3, Cl, F, OH, OCH3, oxo, or =CH2; or two vicinal R8, together with the atoms to which they are attached form.

[0241] Provided herein as Embodiment 100 is the compound or salt of any one of Embodiments 1-83, wherein is heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0242] Provided herein as Embodiment 101 is the compound or salt of Embodiment 100, wherein the heteroalkylene has 2-4 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0243] Provided herein as Embodiment 102 is the compound or salt of any one of Embodiments 1-

[0245] Provided herein as Embodiment 104 is the compound or salt of Embodiment 103, wherein

[0246] Provided herein as Embodiment 105 is the compound or salt of any one of Embodiments 1- 83, wherein is heteroalkenylene having 3-6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

[0247] Provided herein as Embodiment 106 is the compound or salt of any one of Embodiments 1-

[0248] Provided herein as Embodiment 107 is the compound or salt of Embodiment 106, wherein.

[0249] Provided herein as Embodiment 108 is the compound or salt of Embodiment 107, wherein [ as Embodiment 109 is the compound or salt of Embodiment 108, wherein

[0251] Provided herein as Embodiment 110 is the compound or salt of any one of Embodiments 1- 109, wherein

[0252] Provided herein as Embodiment 111 is the compound or salt of any one of Embodiments 1- 109, wherein

[0253] Provided herein as Embodiment 112 is the compound or salt of any one of Embodiments 1- 109, wherein W1is C-F, C-Cl, or C-CN.

[0254] Provided herein as Embodiment 113 is the compound or salt of any one of Embodiments 1- 109, wherein W1is C-C1-3alkyl or C-C1-3haloalkyl.

[0255] Provided herein as Embodiment 114 is the compound or salt of Embodiment 113, wherein W1is C-CH3,C-CH2CH3, C-CH2F, C-CHF2, or C-CF3.

[0256] Provided herein as Embodiment 115 is the compound or salt of any one of Embodiments 1- 109, wherein W1is C-C2-3alkenyl or C-C2-3alkynyl, and each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy.

[0257] Provided herein as Embodiment 116 is the compound or salt of Embodiment 115, wherein W1is C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), or C-CCH.

[0258] Provided herein as Embodiment 117 is the compound or salt of any one of Embodiments 1- 109, wherein W1is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy.

[0259] Provided herein as Embodiment 118 is the compound or salt of Embodiment 117, wherein W1is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0260] Provided herein as Embodiment 119 is the compound or salt of any one of Embodiments 1- 109, wherein W1is C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, C- C(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0261] Provided herein as Embodiment 120 is the compound or salt of any one of Embodiments 1- 119, wherein

[0262] Provided herein as Embodiment 121 is the compound or salt of any one of Embodiments 1- 119, wherein

[0263] Provided herein as Embodiment 122 is the compound or salt of any one of Embodiments 1- 119, wherein W2is C-F, C-Cl, or C-CN.

[0264] Provided herein as Embodiment 123 is the compound or salt of any one of Embodiments 1- 119, wherein W2is C-C1-3alkyl or C-C1-3haloalkyl.

[0265] Provided herein as Embodiment 124 is the compound or salt of Embodiment 123, wherein W2is C-CH3,C-CH2CH3, C-CH2F, C-CHF2, or C-CF3.

[0266] Provided herein as Embodiment 125 is the compound or salt of any one of Embodiments 1- 119, wherein W2is C-C2-3alkenyl or C-C2-3alkynyl, and each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy.

[0267] Provided herein as Embodiment 126 is the compound or salt of Embodiment 125, wherein W2is C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), or C-CCH.

[0268] Provided herein as Embodiment 127 is the compound or salt of any one of Embodiments 1- 119, wherein W2is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy.

[0269] Provided herein as Embodiment 128 is the compound or salt of Embodiment 127, wherein W2is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0270] Provided herein as Embodiment 129 is the compound or salt of any one of Embodiments 1- 119, wherein W2is C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, C- C(OH)=CH2, C-CH=CH(OH), C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0271] Provided herein as Embodiment 130 is the compound or salt of any one of Embodiments 1- 109, wherein each of W1and W2independently is N, CH, or C-CH3.

[0272] Provided herein as Embodiment 131 is the compound or salt of Embodiment 130, wherein W1is CH and W2is N, CH, or C-CH3.

[0273] Provided herein as Embodiment 132 is the compound or salt of Embodiment 130, wherein W2is N and W1is N, CH, or C-CH3.

[0274] Provided herein as Embodiment 133 is the compound or salt of Embodiment 130, wherein.

[0275] Provided herein as Embodiment 134 is the compound or salt of any one of Embodiments 1- 133, wherein R5is Br, Cl, or F.

[0276] Provided herein as Embodiment 135 is the compound or salt of any one of Embodiments 1- 133, wherein R5is C1-3haloalkyl.

[0277] Provided herein as Embodiment 136 is the compound or salt of Embodiment 135, wherein R5is CF3, CF2H, CFH2, or CF2CH3.

[0278] Provided herein as Embodiment 137 is the compound or salt of Embodiment 136, wherein R5is CF3or CF2H.

[0279] Provided herein as Embodiment 138 is the compound or salt of Embodiment 137, wherein R5is CF2H.

[0280] Provided herein as Embodiment 139 is the compound or salt of any one of Embodiments 1- 133, wherein R5is C1-3alkoxy or C1-3thioalkyl.

[0281] Provided herein as Embodiment 140 is the compound or salt of Embodiment 139, wherein R5is OCH3or SCH3.

[0282] Provided herein as Embodiment 141 is the compound or salt of any one of Embodiments 1- 133, wherein R5is C1-6alkyl, C2-4alkenyl, or C2-4alkynyl, and each of the foregoing independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl.

[0283] Provided herein as Embodiment 142 is the compound or salt of Embodiment 141, whereinand each of the foregoing independently is unsubstituted or substituted with 1-3 substituents, and eachsubstituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl.

[0284] Provided herein as Embodiment 143 is the compound or salt of Embodiment 142, wherein each substituent independently is CH3, CF3, CF2H, CFH2, OH, OCH3, OCF3, CH2OH, CH2OCH3, cyclopropyl, cyclobutyl, or phenyl.

[0285] Provided herein as Embodiment 144 is the compound or salt of Embodiments 143, wherein

[0286] Provided herein as Embodiment 145 is the compound or salt of any one of Embodiments 1- 133, wherein R5is C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl.

[0287] Provided herein as Embodiment 146 is the compound or salt of any one of Embodiments 1- 109, wherein W1is CH, W2is N, and R5is CF3, CF2H, or CFH2.

[0288] Provided herein as Embodiment 147 is the compound or salt of Embodiment 146, wherein R5is CF2H.

[0289] Provided herein as Embodiment 148 is the compound or salt of any one of Embodiments 1-109, wherein

[0290] Provided herein as Embodiment 149 is the compound or salt of Embodiment 148, wherein

[0291] Provided herein as Embodiment 150 is the compound or salt of Embodiment 149, wherein

[0292] Provided herein as Embodiment 151 is the compound or salt of Embodiment 150, wherein.

[0293] Provided herein as Embodiment 152 is the compound or salt of any one of Embodiments 1- 151, wherein q is 0.

[0294] Provided herein as Embodiment 153 is the compound or salt of any one of Embodiments 1- 151, wherein q is 1.

[0295] Provided herein as Embodiment 154 is the compound or salt of any one of Embodiments 1- 151, wherein q is 2.

[0296] Provided herein as Embodiment 155 is the compound or salt of any one of Embodiments 1- 151, wherein r is 0.

[0297] Provided herein as Embodiment 156 is the compound or salt of any one of Embodiments 1- 151, wherein r is 1.

[0298] Provided herein as Embodiment 157 is the compound or salt of any one of Embodiment 1- 1

[0299] Provided herein as Embodiment 158 is the compound of any one of Embodiments 1-157, wherein o is 0.

[0300] Provided herein as Embodiment 159 is the compound of any one of Embodiments 1-157 wherein o is 1.

[0301] Provided herein as Embodiment 160 is the compound of any one of Embodiments 1-157, wherein o is 2.

[0302] Provided herein as Embodiment 161 is the compound of any one of Embodiments 1-157, wherein o is 3.

[0303] Provided herein as Embodiment 162 is the compound of any one of Embodiments 1-157, wherein o is 4.

[0304] Provided herein as Embodiment 163 is the compound of any one of Embodiments 159-162, wherein at least one R6is Br, Cl, F, or CN.

[0305] Provided herein as Embodiment 164 is the compound or salt of Embodiment 163, wherein at least one R6is F.

[0306] Provided herein as Embodiment 165 is the compound or salt of any one of Embodiments 159-162, wherein at least one R6is C1-3alkyl or C1-3haloalkyl.

[0307] Provided herein as Embodiment 166 is the compound or salt of Embodiment 165, wherein at least one R6is CH3, CH2F, CHF2, or CF3.

[0308] Provided herein as Embodiment 167 is the compound or salt of any one of Embodiments 159-162, wherein at least one R6is C0-3alkylene-OH, C0-3alkylene-C1-3alkoxy, deuterated C0-3alkylene- C1-3alkoxy, or C1-4alkylene-N(RN1)2, and each RN1independently is H or CH3.

[0309] Provided herein as Embodiment 168 is the compound or salt of Embodiment 167, wherein at least one R6is OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2.

[0310] Provided herein as Embodiment 169 is the compound or salt of any one of Embodiments 159-162, wherein at least one R6is oxo or =CH2.

[0311] Provided herein as Embodiment 170 is the compound or salt of any one of Embodiments 159-162, wherein at least one R6is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0312] Provided herein as Embodiment 171 is the compound or salt of Embodiment 170, wherein at least one R6is cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl; wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0313] Provided herein as Embodiment 172 is the compound or salt of Embodiment 171, wherein at least one R6is cyclopropyl.

[0314] Provided herein as Embodiment 173 is the compound or salt of any one of Embodiments 159-162, wherein at least one R6is spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro- heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0315] Provided herein as Embodiment 174 is the compound or salt of Embodiment 173, wherein at least one R6is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl, wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0316] Provided herein as Embodiment 175 is the compound or salt of any one of Embodiments 160-162, wherein two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 4-7 total ring atoms and 1-3heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0317] Provided herein as Embodiment 176 is the compound or salt of Embodiment 175, wherein two vicinal R6, together with the atoms to which they are attached, form fused-cyclopropyl, fused- cyclobutyl, or fused-cyclopentyl; wherein each of the foregoing is unsubstituted or substituted with 1- 4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0318] Provided herein as Embodiment 177 is the compound or salt of any one of Embodiments 170-171 and 173-176, wherein each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

[0319] Provided herein as Embodiment 178 is the compound or salt of any one of Embodiments 160-162, wherein two non-neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge.

[0320] Provided herein as Embodiment 179 is the compound or salt of Embodiment 178, wherein two non-neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2- CH=CH— or —CH2OCH2—.

[0321] Provided herein as Embodiment 180 is the compound or salt of any one of Embodiments 1- 157, wherein at least one R6is Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, or cyclopropyl, or two vicinal R6, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, or fused-cyclopentyl, or two non- neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2-CH=CH— or —CH2OCH2—; wherein each of the foregoing cycloalkyl groups is unsubstituted or substituted with 1-4 substituents, and each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

[0322] Provided herein as Embodiment 181 is the compound or salt of any one of Embodiments 1- 157, wherein o is 0; or o is 1 and R6is H, CH3, or cyclopropyl.

[0323] Provided herein as Embodiment 182 is the compound or salt of any one of Embodiments 1- 157, wherein

[0324] Provided herein as Embodiment 183 is the compound or salt of Embodiment 182, wherein.

[0325] Provided herein as Embodiment 184 is the compound or salt of Embodiment 183, wherein

[0326] Provided herein as Embodiment 185 is the compound or salt of any one of Embodiments 1- 184, wherein Y’ is C3-7cycloalkyl or C4-7cycloalkenyl.

[0327] Provided herein as Embodiment 186 is the compound or salt of Embodiment 185 wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl.

[0328] Provided herein as Embodiment 187 is the compound or salt of Embodiment 186, wherein Y’ is cyclopropyl or cyclobutyl.

[0329] Provided herein as Embodiment 188 is the compound or salt of any one of Embodiments 1- 184, wherein Y’ is heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0330] Provided herein as Embodiment 189 is the compound or salt of Embodiment 188, wherein Y’ is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, dioxolanyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, or thiomorpholinyl.

[0331] Provided herein as Embodiment 190 is the compound or salt of Embodiment 189, wherein Y’ is oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, or morpholinyl.

[0332] Provided herein as Embodiment 191 is the compound or salt of Embodiment 190, wherein Y’ is tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.

[0333] Provided herein as Embodiment 192 is the compound or salt of any one of Embodiments 1- 184, wherein Y’ is heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0334] Provided herein as Embodiment 193 is the compound or salt of Embodiment 192, wherein Y’ is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl.

[0335] Provided herein as Embodiment 194 is the compound or salt of Embodiment 193, wherein Y’ is dihydrofuranyl or dihydropyranyl.

[0336] Provided herein as Embodiment 195 is the compound or salt of any one of Embodiments 1- 184, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, dioxolanyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl.

[0337] Provided herein as Embodiment 186 is the compound or salt of Embodiment 195, wherein Y’ is oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, dihydrofuranyl or dihydropyranyl.

[0338] Provided herein as Embodiment 197 is the compound or salt of Embodiment 196, wherein Y’ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dihydrofuranyl or dihydropyranyl.

[0339] Provided herein as Embodiment 198 is the compound or salt of any one of Embodiments 1- 197, wherein p is 0.

[0340] Provided herein as Embodiment 199 is the compound or salt of any one of Embodiments 1- 197, wherein p is 1.

[0341] Provided herein as Embodiment 200 is the compound or salt of any one of Embodiments 1- 197, wherein p is 2.

[0342] Provided herein as Embodiment 201 is the compound or salt of any one of Embodiments 1- 197, wherein p is 3.

[0343] Provided herein as Embodiment 202 is the compound or salt of any one of Embodiments 1- 197, wherein p is 4.

[0344] Provided herein as Embodiment 203 is the compound or salt of any one of Embodiments 1- 197, wherein p is 5.

[0345] Provided herein as Embodiment 204 is the compound or salt of any one of Embodiment 199-203, wherein at least one R7is F, Cl, Br, CN, or CH2CN.

[0346] Provided herein as Embodiment 205 is the compound or salt of Embodiment 204, wherein at least one R7is F or CH2CN.

[0347] Provided herein as Embodiment 206 is the compound or salt of any one of Embodiments 199-203, wherein at least one R7is C1-3alkyl, C1-3haloalkyl, or C2-3alkenyl.

[0348] Provided herein as Embodiment 207 is the compound or salt of Embodiment 206, wherein at least one R7is CH3, CH2CH3, CH2F, CHF2, or CF3.

[0349] Provided herein as Embodiment 208 is the compound or salt of Embodiment 207, wherein at least one R7is CH3, CH2F, or CHF2.

[0350] Provided herein as Embodiment 209 is the compound or salt of any one of Embodiments 199-203, wherein at least one R7is C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy.

[0351] Provided herein as Embodiment 210 is the compound or salt of Embodiment 209, wherein at least one R7is OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, or CH2CH2OCH3.

[0352] Provided herein as Embodiment 211 is the compound or salt of Embodiment 210, wherein at least one R7is OH or CH2OCH3.

[0353] Provided herein as Embodiment 212 is the compound or salt of any one of Embodiments 199-203, wherein at least one R7is C(=O)OCH3.

[0354] Provided herein as Embodiment 213 is the compound or salt of any one of Embodiments 199-203, wherein at least one R7is oxo or =CH2.

[0355] Provided herein as Embodiment 214 is the compound or salt of any one of Embodiments 199-203, wherein at least one R7is C0-4alkylene-C3-7cycloalkyl; C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl; or C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0356] Provided herein as Embodiment 215 is the compound or salt of Embodiment 214, wherein at least one R7is C0-4alkylene-cyclopropyl, C0-4alkylene-cyclobutyl, C0-4alkylene-cyclopentyl, C0-4alkylene-oxetanyl, C0-4alkylene-pyrrolidinyl, C0-4alkylene-phenyl, or C0-4alkylene-oxadiazolyl.

[0357] Provided herein as Embodiment 216 is the compound or salt of Embodiment 215, wherein at least one R7is cyclopropyl.

[0358] Provided herein as Embodiment 217 is the compound or salt of any one of Embodiments 199-203, wherein at least one R7is spiro-C3-7cycloalkyl or a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; wherein each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0359] Provided herein as Embodiment 218 is the compound or salt of Embodiment 217, wherein at least one R7is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, or spiro-tetrahydropyranyl.

[0360] Provided herein as Embodiment 219 is the compound or salt of any one of Embodiments 200-203, wherein two vicinal R7, together with the atoms to which they are attached, form fused-C3-7cycloalkyl or fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0361] Provided herein as Embodiment 220 is the compound or salt of Embodiment 219, wherein two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused- cyclobutyl, fused-oxetanyl, fused-tetrahydrofuranyl, or fused-tetrahydropyranyl.

[0362] Provided herein as Embodiment 221 is the compound or salt of Embodiment 220, wherein two vicinal R7, together with the atoms to which they are attached, form fused-tetrahydrofuranyl.

[0363] Provided herein as Embodiment 222 is the compound or salt of any one of Embodiments 200-203, wherein two vicinal R7, together with the atoms to which they are attached, form fused-C6-10aryl or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0364] Provided herein as Embodiment 223 is the compound or salt of Embodiment 222, wherein two vicinal R7, together with the atoms to which they are attached, form fused-phenyl, fused- thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, fused-pyridazinyl, or fused-pyrazinyl; wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0365] Provided herein as Embodiment 224 is the compound or salt of Embodiment 223, wherein two vicinal R7, together with the atoms to which they are attached, form fused-pyrazolyl, fused- pyridyl, fused-pyridazinyl, or fused-pyrimidinyl; wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0366] Provided herein as Embodiment 225 is the compound or salt of any one of Embodiments 214, 217, 219, 222, and 223, wherein each substituent independently is F, Cl, Br, CN, oxo, or CH3.

[0367] Provided herein as Embodiment 226 is the compound or salt of any one of Embodiments 1- 197, wherein each R7independently is F, Cl, Br, CN, CH2CN, CH3, CH2CH3, CH2F, CHF2, CF3, OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, CH2CH2OCH3, C(=O)OCH3, oxo, =CH2, cyclopropyl, spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, spiro-tetrahydropyranyl; or two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused- cyclobutyl, fused-oxetanyl, fused-tetrahydrofuranyl, fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, fused-pyridazinyl, fused-pyrazinyl, fused-pyrimidinyl; wherein each of the pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl is unsubstituted or substituted with CH3.

[0368] Provided herein as Embodiment 227 is the compound or salt of Embodiment 226, wherein

[0369] Provided herein as Embodiment 228 is the compound or salt of any one of Embodiments 1- 1,,

[0370] Provided herein as Embodiment 229 is the compound or salt of Embodiment 228, wherein

[0371] Provided herein as Embodiment 230 is the compound or salt of Embodiment 229, wherein

[0372] Provided herein as Embodiment 231 is the compound or salt of Embodiment 229, wherein

[0373] Provided herein as Embodiment 232 is the compound or salt of Embodiment 229, wherein

[0374] Provided herein as Embodiment 233 is the compound or salt of any one of Embodiments 1- 232, wherein Formula (I) exhibits a stereochemical configuration of Formula (I’):pharmaceutically acceptable salt thereof.

[0375] Provided herein as Embodiment 234 is the compound or salt of Embodiment 1, wherein the compound of Formula (I) has a structure of Formula (II):o is 0 or 1; R5is CHF2or CF3; and R6is C1-3alkyl or C3-7cycloalkyl.

[0376] Provided herein as Embodiment 235 is the compound or salt of Embodiment 234, wherein the compound of Formula (II) has a Formula (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt of any of the foregoing:

[0377] Provided herein as Embodiment 236 is the compound or salt of Embodiment 235, wherein is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1 or 2 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, halo, or CN.

[0378] Provided herein as Embodiment 237 is the compound or salt of any one of Embodiments 2

[0379] Provided herein as Embodiment 238 is the compound or salt of Embodiment 237, wherein .

[0380] Provided herein as Embodiment 239 is the compound or salt of any one of Embodiments 2

[0381] Provided herein as Embodiment 240 is the compound of Embodiment 1, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt thereof.

[0382] Provided herein as Embodiment 241 is the compound of Embodiment 240, wherein the compound is a compound listed in Table A’, or a pharmaceutically acceptable salt thereof.

[0383] Provided herein as Embodiment 242 is the compound of Embodiment 240, wherein the compound is a compound listed in Table B, or a pharmaceutically acceptable salt thereof.

[0384] Provided herein as Embodiment 243 is the compound of Embodiment 242, wherein the compound is a compound listed in Table B’, or a pharmaceutically acceptable salt thereof.

[0385] Provided herein as Embodiment 244 is a pharmaceutical composition comprising the compound or salt of any one of Embodiments 1- 243 and a pharmaceutically acceptable excipient.

[0386] Provided herein as Embodiment 245 is a method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of Embodiments 1-243, or the composition of Embodiment 244.

[0387] Provided herein as Embodiment 246 is the method of Embodiment 245, wherein one or more cancer cells express KRAS G12C mutant protein.

[0388] Provided herein as Embodiment 247 is the method of Embodiment 245 or 246, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, a solid tumor, or any combination of the foregoing.

[0389] Provided herein as Embodiment 248 is the method of Embodiment 247, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

[0390] Provided herein as Embodiment 249 is the method according to any one of Embodiments 245-248, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of the compound, salt, or pharmaceutical composition.

[0391] Provided herein as Embodiment 250 is the method according to any one of Embodiments 245-249, further comprising simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ATR inhibitor, Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK2 inhibitor, CDK4 / 6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MAT2A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PARP inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, PRMT5 inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agents.

[0392] Provided herein as Embodiment 251 is the compound or salt of any one of Embodiments 1- 243, or the composition of Embodiment 244 for use as a medicament.

[0393] Provided herein as Embodiment 252 is the compound or salt of any one of Embodiments 1- 243, or the composition of Embodiment 244 for use in treating cancer.

[0394] Provided herein as Embodiment 253 is the compound or salt of any one of Embodiments 1- 243 or the pharmaceutical composition of Embodiment 244 for use in treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

[0395] Provided herein as Embodiment 254 is the compound or salt of Embodiment 252 or 253, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor.

[0396] Provided herein as Embodiment 255 is the compound or salt of Embodiment 254, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

[0397] Provided herein as Embodiment 256 is the use of a compound or salt of any one of Embodiments 1-243 or the pharmaceutical composition of Embodiment 244 for the manufacture of a medicament for the treatment of cancer.

[0398] Provided herein as Embodiment 257 is the use of a compound or salt of any one of Embodiments 1-243 or the pharmaceutical composition of Embodiment 244 in the preparation of a medicament for treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

[0399] Provided herein as Embodiment 258 is the use of Embodiment 256 or 257, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, a solid tumor, or any combination of the foregoing.

[0400] Provided herein as Embodiment 259 is the use of Embodiment 258, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

[0401] Provided herein as Embodiment 260 is a compound listed in Table INT-A, INT-B, INT-D, INT-E, or INT, a nitrogen-protected analog thereof, a free base analog thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0402] Provided herein as Embodiment 261 is a method of preparing the compound or salt of any one of Embodiments 1-243, comprising admixing a compound of Formulaa nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing,with a compound of Formula (nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; halo2is F, Cl, Br, or I; is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S, or heteroalkenylene having 3- 6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S; whereinis unsubstituted or substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; A is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy;each of W1and W2independently is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C2-3alkenyl, C-C2-3alkynyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; Y’ is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; each R3independently is C1-3alkyl, C1-3haloalkyl,, , C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, C1-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; R5is halo, C1-3haloalkyl, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3thioalkyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl;each R6independently is halo, CN, C1-3alkyl, C2-3alkenyl, C1-3haloalkyl, C0-3alkylene-OH, C0-3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, C1-4alkylene-N(RN1)2, oxo, =CH2, C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4- 7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused- heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two non- neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl of each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN; each R7independently is halo, C0-3alkylene-CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, oxo, =CH2, C0-4alkylene- C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl, C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R7together with the atoms to which they are attached form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O and S, fused-C6-10aryl, or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.EXAMPLES

[0403] This section provides specific examples of compounds of Formula (I) and methods of making the same. List of Abbreviations

[0404] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.

[0405] Chromatography: Unless otherwise indicated, product-containing residues were purified by passing the material or concentrate through either a Biotage or ISCO brand silica gel column pre- packed with flash silica and eluting the product off the column with a solvent gradient as indicated.

[0406] Preparative HPLC Method: Where indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18,150 × 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 × 30 mm). A typical run through the instrument included: eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% CH3CN (0.1% v / v formic acid) in H2O (0.1% formic acid) over 10 min. Conditions can be varied to achieve improved separations.

[0407] Proton NMR Spectra: Unless otherwise indicated, all1H NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. All observed protons are reported as parts-per- million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some1H signals may be missing due to exchange with D from CD3OD, or due to signal suppression.

[0408] Fluorine-19 NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 300 or 400 MHz.

[0409] Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary compounds are reported as mass / charge (m / z), having an [M+H]+ molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity, Shimadzu, or Agilent UPLC / MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art. SECTION 1: Synthesis of Intermediates

[0410] Provided in this section is the synthesis of various intermediates used to prepare compounds of Formula (I). All starting materials are either commercially available from Combi-Blocks, Inc.; Strem Chemicals, Inc.; Sigma-Aldrich, Inc.; Thermo Fisher; Aurum Pharmatech LLC; Ambeed, Inc.; AA BLOCKS, Inc.; Chempure; J&W Pharmlab; Oakwood Products; eNovation Chemicals LLC; AstaTech, Inc; AOBChem USA; TCI America;, or similar vendors, unless otherwise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill. Intermediate A1 - 3-(3-Chloro-4-methylpyridin-2-yl)oxetan-3-ol

[0411] To a mixture of 2-bromo-3-chloro-4-picoline (9.45 g, 45.8 mmol, AA BLOCKS, Inc.) and toluene (120 mL), n-BuLi, 2.5 M solution in hexanes (19 mL, 47.5 mmol, Sigma-Aldrich, Inc.) was slowly added at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h. Then, 3-oxetanone (3.1 mL, 48.4 mmol, Combi-Blocks, Inc.) was added at -78 °C, and the reaction mixture was stirred for 1 h. The reaction was warmed to rt and quenched by adding sat. aq. NH4Cl solution (150 mL). Thecrude material was extracted with EtOAc (150 mL × 3), washed with brine, dried through Na2SO4, and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 10-50% acetone in heptane to provide Intermediate A1 (6.8 g, 34.1 mmol, 74% yield). m / z (ESI): 200.1 (M+H)+.1H NMR (DMSO-d6, 400 MHz): δ 8.37 (d, J=4.8 Hz, 1H), 7.40 (d, J=4.8 Hz, 1H), 6.45 (s, 1H), 5.15 (dd, J=6.9, 0.9 Hz, 2H), 4.68 (dd, J=6.9, 1.0 Hz, 2H), 2.38 (s, 3H).

[0412] Intermediates in Table 1-1 were prepared following the procedure described for Intermediate A1, using appropriate starting materials. All starting materials are commercially available or are described above. Table 1-1Intermediate A4 - 5-Bromo-4-methyl-1-(oxetan-3-yl)-1H-pyrazole

[0413] Step 1: 4-Methyl-1-(oxetan-3-yl)-1H-pyrazole. To a mixture of 4-methyl-1H-pyrazole (50.0 g, 609 mmol, Combi-Blocks, Inc.) and Cs2CO3(397 g, 1218 mmol, Chempure) in DMF (750 mL) was added 3-iodooxetane (168 g, 913 mmol, Oakwood) and the mixture was heated at 80 °C for 16 h. The mixture was cooled to rt, quenched with H2O (3000 mL), and extracted with EtOAc (1000 mL). The organic extract was washed with brine, concentrated, and then purified by chromatography (0 to 20% EtOAc:hexanes) to give methyl 4-methyl-1-(oxetan-3-yl)-1H-pyrazole (52.1 g, 377.6 mmol, 62% yield). m / z (ESI): 139.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.37 (s, 1H), 5.4-5.5 (m, 1H), 4.7-4.9 (m, 4H), 2.02 (s, 3H).

[0414] Step 2: 5-Bromo-4-methyl-1-(oxetan-3-yl)-1H-pyrazole, Intermediate A4. LDA (2 M solution in THF, 326 mL, 651 mmol, Sigma-Aldrich, Inc.) was added to a solution of 4-methyl-1- (oxetan-3-yl)-1H-pyrazole (60 g, 434 mmol) in THF (750 mL) at -78 °C, and the mixture was stirred for 30 min. Carbon tetrabromide (216 g, 651 mmol, TCI) in THF (500 mL) was added dropwise over 1 h at -78 °C, and the mixture was stirred for another 1 h. The reaction mixture was quenched with satd. aq. NH4Cl (1500 mL) and extracted with EtOAc (600 mL). The organic extract was dried over Na2SO4, concentrated, and then purified by chromatography (silica, 0 to 15% EtOAc:hexanes) to give Intermediate A4 (72 g, 332 mmol, 51% yield). m / z (ESI): 215.1 and 217.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 5.61 (p, 1H, J=6.9 Hz), 4.90 (d, 4H, J=6.9 Hz), 1.97 (s, 3H). Intermediate A5 - (1-(4-Methyl-1H-pyrazol-1-yl)cyclopropyl)methanol

[0415] Step 1: tert-Butyl 1-(4-methyl-1Hpyrazol-1-yl)cyclopropane-1-carboxylate. To a suspension of sodium hydride (60% dispersion in mineral oil) (2.91 g, 72.8 mmol, Oakwood Products, Inc.) in THF (20 mL) at 0 °C was added a solution of 4-methyl-1H-pyrazole (2.72 g, 33.1 mmol, Ambeed, Inc.) in THF (10 mL) dropwise, and the reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added tert-butyl 2,4-dibromobutanoate (10 g, 33.1 mmol, Aurum Pharmatech LLC), and the reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was carefully quenched by the slow addition of H2O and was extracted with EtOAc. The organic extract was washed with brine, run through a plug of silica, and concentrated in vacuo to give the crude tert-butyl 1-(4-methyl-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (7.36 g, 33.1 mmol). The material was used in the next step without further purification. m / z (ESI): 223.2 (M+H)+.

[0416] Step 2: (1-(4-Methyl-1H-pyrazol-1-yl)cyclopropyl)methanol, Intermediate A5. To a solution of tert-butyl 1-(4-methyl-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (7.36 g, 33.1 mmol) in THF (30 mL) 0 °C was added LAH, 1.0 M in THF (33.1 mL, 33.1 mmol, Sigma-Aldrich, Inc.) dropwise and the reaction mixture was stirred for 1 h. The reaction mixture was quenched at 0 °C via the slow addition of H2O until bubbling stopped. The reaction mixture was diluted with NaOH (1 M aq. sol.), stirred at rt for 15 min, and filtered through celite. The organic phase was separated, and the aq. phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, then filtered through a plug of silica, eluting with EtOAc to give Intermediate A5 (5.04 g, 33.1 mmol) which was used without further purification. m / z (ESI): 153.2 (M+H)+.Intermediate A6 - 1-(5-Bromo-4-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0417] A mixture of 3-bromo-4-methyl-1h-pyrazole (4.0 g, 24.84 mmol, Ambeed, Inc.), 1,1- dimethyloxirane (2.15 g, 29.8 mmol, Combi-Blocks, Inc.) and K2CO3(8.58 g, 62.1 mmol, Sigma- Aldrich, Inc.) in DMF (80 mL) was heated at 100 °C for 18 h. The reaction mixture was cooled to rt, diluted with H2O, and extracted with EtOAc. The combined organics extracts were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with a gradient of 0-20% EtOAc in heptane to afford Intermediate A6 as the 1steluting isomer and 1-(3-bromo-4-methyl-1H- pyrazol-1-yl)-2-methylpropan-2-ol as the 2ndeluting isomer. Peak 1: (1.24 g, 5.32 mmol, 21% yield); m / z (ESI): 233.0 and 235.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1 H), 4.65 (s, 1 H), 4.01 (s, 2 H), 1.97 (s, 3 H), 1.10 (s, 6 H). Peak 2: (3.80 g, 16.30 mmol, 66% yield). m / z (ESI): 233.0 and 235.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=0.6 Hz, 1 H), 4.63 (s, 1 H), 3.92 (s, 2 H), 1.94 (d, J=0.6 Hz, 3 H), 1.05 (s, 6 H).

[0418] Intermediates in Table 1-2 were prepared following the procedure described for Intermediate A6, using appropriate starting materials. All starting materials are commercially available or are described above. Table 1-2Intermediate A12 - 1-(3-Chloro-4-methylpyridin-2-yl)ethan-1-ol

[0419] To a solution of 3-chloro-2-formyl-4-methylpyridine (3.0 g, 19.28 mmol, AOBChem USA) in THF (70 mL) at 0 °C was added dropwise methylmagnesium bromide (3 M in diethylether) (9.64 mL, 28.9 mmol, Sigma-Aldrich, Inc.), and the resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with sat. NH4Cl, diluted with H2O, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using 0-60% (3:1) EtOAc / EtOH in heptane to provide Intermediate A12 (1.43 g, 8.33 mmol, yield: 43.2%). m / z (ESI): 172.2 (M+H)+.Intermediate A13 - 3-Bromo-4-methyl-2-(oxiran-2-yl)pyridine

[0420] Step 1: 3-Bromo-4-methyl-2-vinylpyridine. To a stirred solution of 2,3-dibromo-4- methylpyridine (7.5 g, 29.9 mmol) in a mixture of EtOH (150 mL) and H2O (0.12 mL) was added trifluoro(vinyl)-l4-borane, potassium salt (8.01 g, 59.8 mmol) followed Pd(dppf)Cl2(1.094 g, 1.494 mmol) and TEA (8.33 mL, 59.8 mmol) at rt. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated, diluted with H2O, extracted with EtOAc (2 × 100 mL), dried over Na2SO4, filtered, and concentrated to afford crude material. The crude material was purified by silica gel chromatography, eluting with a mobile phase of 0-20% EtOAc in hexanes to provide 3-bromo-4- methyl-2-vinylpyridine (5 g, 25.2 mmol, 84% yield). m / z (ESI): 198.1 and 200.1 (M+H)+.1H NMR (DMSO-d6, 400 MHz): δ 8.40 (d, J=4.7 Hz, 1H), 7.34 – 7.22 (m, 2H), 6.38 (dd, J=16.9, 2.4 Hz, 1H), 5.59 (dd, J=10.6, 2.4 Hz, 1H), 2.39 (d, J=0.7 Hz, 3H).

[0421] Step 2: 3-Bromo-4-methyl-2-(oxiran-2-yl)pyridine, Intermediate A13. To a solution of 3- bromo-4-methyl-2-vinylpyridine (12 g, 60.6 mmol) in a mixture of tert-butanol (300 mL) and H2O (60 mL) was added 1-bromopyrrolidine-2,5-dione (12.94 g, 72.7 mmol) at rt. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was quenched with NaOH (7.27 g, 182 mmol) solution in H2O (30 mL) at rt and stirred at rt for 3h. The reaction mixture was diluted with H2O and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography using a mobile phase of 0- 10% EtOAc in hexanes to afford Intermediate A13 (7 g, 32.7 mmol, 54% yield). m / z (ESI): 214.1 and 216.0 (M+H)+.1H NMR (DMSO-d6, 400 MHz): δ 8.38 (d, J=4.7 Hz, 1H), 7.38 (dd, J=4.8, 0.9 Hz, 1H), 4.36 (dd, J=4.0, 2.5 Hz, 1H), 3.21 – 3.10 (m, 2H), 2.41 (d, J=0.7 Hz, 3H). Intermediate A14 - 3-bromo-4-methyl-2-(oxetan-3-yl)pyridine

[0422] To nickel(ii) iodide hydrate (0.838 g, 1.99 mmol, Combi-Blocks, Inc.), 2,2'-bipyridine (0.311 g, 1.993 mmol, Ambeed, Inc.), sodium iodide (0.747 g, 4.98 mmol, Sigma-Aldrich Corporation), 3-bromooxetane (2.73 g, 19.93 mmol, Combi-Blocks, Inc.), 2,3-dibromo-4- methylpyridine (5.0 g, 19.93 mmol, ChemScene LLC), and zinc dust (2.61 g, 39.9 mmol, Sigma-Aldrich Corporation) under nitrogen, were added pyridine (0.161 mL, 1.993 mmol, Sigma-Aldrich Corporation) and DMPU (30 mL). After stirring at rt for 5 min, the mixture was heated at 60 °C for 17 h. The reaction was diluted with EtOAc and filtered through celite. The filtrate was washed with H2O, and the organic phase was dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using 0-30% EtOAc in heptane to afford 3-bromo-4-methyl-2-(oxetan-3-yl)pyridine (0.434 g, 1.903 mmol, 9.6 % yield). m / z (ESI): 228.0 and 230.0 (M+H)+. Intermediate B1 - 4'-Methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine-5',4''-piperidine]

[0423] Step 1: tert-Butyl 2-(3-hydroxyoxetan-3-yl)-4-methyl-3',6'-dihydro-[3,4'-bipyridine]- 1'(2'H)-carboxylate. To a solution of 3,6-dihydro-2H-pyridine-1-N-boc-4-boronic acid pinacol ester (1704 mg, 5.51 mmol, Combi-Blocks, Inc.) and Intermediate A1 (1000 mg, 5.01 mmol) in 1,4- dioxane (12 mL) and H2O (1.2 mL) was added K2CO3 (2077 mg, 15.03 mmol, Sigma-Aldrich, Inc.) and P(Cy3) Pd G3 DCM adduct (326 mg, 0.501 mmol, Strem Chemicals, Inc.). The reaction mixture was bubbled with N2for 15 min, then stirred at 100 °C for 20 h. The reaction was quenched with sat. aq. NH4Cl solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 10%–60% acetone in heptane to provide tert- butyl 2-(3-hydroxyoxetan-3-yl)-4-methyl-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1250 mg, 3.61 mmol, 72% yield). m / z (ESI): 347.0 (M+H)+.

[0424] Step 2: tert-Butyl 3''-iodo-4'-methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine-5',4''- piperidine]-1''-carboxylate. To a solution of tert-butyl 2-(3-hydroxyoxetan-3-yl)-4-methyl-3',6'- dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1.8 g, 5.20 mmol) in 1,4-dioxane (80 mL) and H2O (16 mL), was added iodine (4.72 g, 18.60 mmol, Sigma-Aldrich, Inc.), and the reaction mixture was stirred at rt for 30 min before silver oxide (4.82 g, 20.78 mmol, Sigma-Aldrich, Inc.) was added. The reaction was stirred for 72 h. The reaction was filtered, concentrated, and the crude mixture waspurified by silica gel chromatography with a gradient of 0-60% acetone in heptane to provide tert- butyl 3''-iodo-4'-methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine-5',4''-piperidine]-1''-carboxylate (1.84 g, 3.9 mmol, 75% yield). m / z (ESI): 472.8 (M+H)+.

[0425] Step 3: tert-Butyl 4'-methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine-5',4''-piperidine]-1''- carboxylate. To a solution of tert-butyl 3''-iodo-4'-methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine- 5',4''-piperidine]-1''-carboxylate (1.84 g, 3.90 mmol) and TEA (2.2 mL, 15.65 mmol, Thermo Fisher) in EtOAc (39 mL) was added 10 wt% Pd / C (1.4 g, 1.32 mmol, Sigma-Aldrich, Inc.), and the reaction was purged with N2. Then, the reaction was charged with H2and stirred at rt for 48 h. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography with a gradient of 3- 40% acetone in heptane to provide tert-butyl 4'-methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine-5',4''- piperidine]-1''-carboxylate (1.0 g, 2.89 mmol, 74% yield). m / z (ESI): 347.0 (M+H)+.

[0426] Step 4: 4’-Methyldispiro[oxetane-3,7’-furo[3,4-b]pyridine-5’,4’’-piperidine], Intermediate B1. To a solution of tert-butyl 4'-methyldispiro[oxetane-3,7'-furo[3,4-b]pyridine-5',4''-piperidine]-1''- carboxylate (280 mg, 0.808 mmol) in DCM (6 mL), was added TFA (0.52 mL, 6.74 mmol, Oakwood Products, Inc.) at rt, and stirred for 3 h, then concentrated to provide Intermediate B1, as a TFA salt. m / z (ESI): 247.2 (M+H)+.Intermediate B2 - 4,7-Dimethyl-7H-spiro[furo[3,4-c]pyridazine-5,4'-piperidine]

[0427] Step 1: 4-Chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one. A mixture of 4,5-dichloro-2-(tetrahydro-pyran-2-yl)-2h-pyridazin-3-one (5 g, 20.07 mmol, eNovation Chemicals LLC), Pd(dppf)Cl2(0.881 g, 1.204 mmol, Sigma-Aldrich, Inc.), methylboronic acid (1.38 g, 23.08 mmol, Oakwood Products, Inc.), and K2CO3(8.32 g, 60.2 mmol, Thermo Scientific) was purged with N2. To the reaction mixture was then added 1,4-dioxane (60 mL) and H2O (10 mL) and, was stirred at 95 °C for 17 h. The reaction mixture was cooled to rt, diluted with H2O, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and chromatographed using 0-70% EtOAc in heptane to afford 4-chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (1.65 g, 7.22 mmol, 36% yield). m / z (ESI): 229.1 (M+H)+.

[0428] Step 2: Benzyl 4-(5-methyl-3-oxo-2-(tetrahydro-2H-pyran-2-yl)-2,3-dihydropyridazin-4- yl)-3,6-dihydropyridine-1(2H)-carboxylate. To a glass vial equipped with a stirring bar was added K2CO3(2.42 g, 17.49 mmol, Sigma-Aldrich, Inc.), SPhos Pd G3 (0.303 g, 0.350 mmol, Sigma- Aldrich, Inc.), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)- carboxylate (2.88 g, 8.40 mmol, Combi-Blocks, Inc.), and 4-chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.6 g, 7.00 mmol) in 1,4-dioxane (16 mL) and H2O (1.6 mL). The reaction mixture was bubbled with N2for 15 min before being heated at 95 °C for 2 h. The reaction was quenched by the addition of 5 mL sat. aq. NH4Cl solution and extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine, dried through Na2SO4, and concentrated. The crude material was purified by silica gel chromatography eluting with acetone in heptane (0-50%) to afford benzyl 4-(5-methyl-3-oxo-2-(tetrahydro-2H-pyran-2-yl)-2,3-dihydropyridazin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (2.1 g, 5.13 mmol, 73% yield). m / z (ESI): 410.2 (M+H)+.

[0429] Step 3: Benzyl 4-(3-chloro-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate. To a glass vial equipped with a stirring bar was added phosphorus oxychloride (5.69 mL, 61.1 mmol, Sigma-Aldrich, Inc.) and benzyl 4-(5-methyl-3-oxo-2-(tetrahydro-2H-pyran-2-yl)-2,3- dihydropyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5 g, 12.21 mmol). The reaction mixture was heated to 80 °C for 1 h, and the reaction was quenched by Na2CO3(2 M in H2O) (122 mL, 244 mmol, Sigma-Aldrich, Inc.) at 0 °C. The reaction mixture was extracted by DCM (70 mL x 3), and the combined organic extracts were dried over Na2SO4and concentrated. The crude material was purified by silica gel chromatography using 0-80% EtOAc in heptane to afford benzyl 4-(3- chloro-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.2 g, 9.31 mmol, 76% yield). m / z (ESI): 344.2 (M+H)+.

[0430] Step 4: Benzyl 4-(3-(1-ethoxyvinyl)-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate. To a mixture of Pd(dppf)Cl2(0.106 g, 0.145 mmol, Sigma-Aldrich, Inc.), benzyl 4-(3- chloro-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.91 mmol), and toluene (15 mL) was added tributyl(1-ethoxyvinyl)tin (1.179 mL, 3.49 mmol, AstaTech, Inc). The reaction mixture was degassed with N2for 10 min and stirred at 110 °C for 12 h. The reaction mixture was directly subjected to chromatography with 0-100% EtOAc in heptane as the eluant to afford benzyl 4- (3-(1-ethoxyvinyl)-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (820 mg, 2.161 mmol, 74% yield). m / z (ESI): 379.9 (M+H)+.

[0431] Step 5: Benzyl 4-(3-acetyl-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate. Benzyl 4-(3-(1-ethoxyvinyl)-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 1.713 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL) at 0 °C. A solution of HCl (4.0 M in dioxane) (0.63 mL, 17.13 mmol, Sigma-Aldrich, Inc.) was added, and the reaction was stirred for 12 h. The reaction was quenched by adding K2CO3aq. solution (2 M, 10 mL), diluted with H2O, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated to afford benzyl 4-(3-acetyl-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate to be used directly. m / z (ESI): 352.2 (M+H)+.

[0432] Step 6: Benzyl 4-(3-(1-hydroxyethyl)-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)- carboxylate. Benzyl 4-(3-acetyl-5-methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate wasdissolved in MeOH (15 mL) and DCM (5 mL). Sodium borohydride (97 mg, 2.57 mmol, Sigma- Aldrich, Inc.) was added portion-wise and after 15 min, the reaction mixture was quenched with acetone. The mixture was diluted with H2O and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated. The crude mixture was subjected to a chromatography with 0-100% EtOAc in heptane as the eluant to afford benzyl 4-(3-(1-hydroxyethyl)-5- methylpyridazin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (350 mg, 0.99 mmol, 58% yield). m / z (ESI): 354.0 (M+H)+.

[0433] Step 7: Benzyl 3'-iodo-4,7-dimethyl-7H-spiro[furo[3,4-c]pyridazine-5,4'-piperidine]-1'- carboxylate. To a solution of benzyl 4-(3-(1-hydroxyethyl)-5-methylpyridazin-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (1 g, 2.83 mmol) in dioxane (18 mL) and H2O (3 mL) was added iodine (2.15 g, 8.49 mmol, Sigma-Aldrich, Inc.) at rt. The mixture was stirred for 45 min, then silver oxide (1.97 g, 8.49 mmol, Combi-Blocks, Inc.) was added portion wise and the mixture was stirred at rt for 3 days. The reaction mixture was filtered through celite, concentrated, and chromatographed with 0-50% EtOAc in heptane to afford benzyl 3'-iodo-4,7-dimethyl-7H-spiro[furo[3,4-c]pyridazine- 5,4'-piperidine]-1'-carboxylate (670 mg, 1.40 mmol, 49% yield). m / z (ESI): 480.0 (M+H)+.

[0434] Step 8: Benzyl 4,7-dimethyl-7H-spiro[furo[3,4-c]pyridazine-5,4'-piperidine]-1'-carboxylate. To a hydrogenation vessel equipped with a stirring bar was added 10 wt% Pd / C (0.888 g, 0.835 mmol, Sigma-Aldrich, Inc.), benzyl 3'-iodo-4,7-dimethyl-7H-spiro[furo[3,4-c]pyridazine-5,4'-piperidine]-1'- carboxylate (2 g , 4.17 mmol), TEA (1.173 mL, 8.35 mmol, Sigma-Aldrich, Inc.), and EtOAc (60 mL). The reaction vessel was sealed and purged with H23 times. The reaction vessel was then placed under 40 psi of H2and stirred at rt for 24 h. The mixture was filtered over celite, eluting with EtOH, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to afford benzyl 4,7-dimethyl-7H-spiro[furo[3,4- c]pyridazine-5,4'-piperidine]-1'-carboxylate (750 mg, 2.12 mmol, 51% yield). m / z (ESI): 354.2 (M+H)+.

[0435] Step 9: 4,7-Dimethyl-7H-spiro[furo[3,4-c]pyridazine-5,4'-piperidine], Intermediate B2. To a glass vessel equipped with a stirring bar was added benzyl 4,7-dimethyl-7H-spiro[furo[3,4- c]pyridazine-5,4'-piperidine]-1'-carboxylate (750 mg, 2.122 mmol) and IPA (20 mL). The reaction vessel was charged with N2followed by purging with H2, and the reaction was hydrogenated at 35 psi for 2 h. The reaction mixture was filtered through a pad of celite. The pad was washed with EtOH, and the solvent was removed under vacuum to afford Intermediate B2 (400 mg, 1.82 mmol). m / z (ESI): 220.2 (M+H)+.Intermediate B3 - (R)-4,7-Dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4'-piperidine]

[0436] Step 1: tert-Butyl 2-(1-hydroxyethyl)-4-methyl-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)- carboxylate. A mixture of Intermediate A12 (1.43 g, 8.33 mmol), K2CO3(3.45 g, 25.00 mmol, Sigma- Aldrich, Inc.), (1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (5.15 g, 16.66 mmol, Combi-Blocks, Inc.), and SPhos Pd G3 (1.30 g, 1.67 mmol, Ambeed, Inc.) was purged with N2followed by the addition of 1,4-dioxane (20 mL) and H2O (2.0 mL). The reaction mixture was heated to 100 °C and stirred for 18 h. The reaction was brought to rt, diluted with H2O, and extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, concentrated, and chromatographed using a gradient of 0- 40% (3:1) EtOAc / EtOH in heptane to afford tert-butyl 2-(1-hydroxyethyl)-4- methyl-3',6'-dihydro-[3,4'-bipyridine]- 1'(2'H)-carboxylate (2.10 g, 6.60 mmol, 79% yield). m / z (ESI): 319.2 (M+H)+.

[0437] Step 2: tert-Butyl 3'-iodo-4,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4'-piperidine]-1'- carboxylate. To a solution of tert-butyl 2-(1-hydroxyethyl)-4-methyl-3',6'-dihydro-[3,4'-bipyridine]- 1'(2'H)-carboxylate (2.10 g, 6.60 mmol) in dioxane / H2O (60 mL / 10 mL) was added iodine (6.70 g, 26.4 mmol, Sigma-Aldrich, Inc.) at rt, and the mixture was stirred for 1 h. Then, silver oxide (6.11 g, 26.4 mmol, Sigma-Aldrich, Inc.) was added, and the mixture was stirred 18 h at rt. Additional iodine (6.70 g, 26.4 mmol, Sigma-Aldrich, Inc.) was added, and the reaction was stirred for 1 h. Additional silver oxide (6.11 g, 26.4 mmol, Sigma-Aldrich, Inc.) was added, and the stirring continued for 15 h. The reaction was filtered through celite, concentrated, and chromatographed with a gradient of 0- 40% (3:1) EtOAc / EtOH in heptane to afford tert-butyl 3'-iodo-4,7-dimethyl-7H-spiro[furo[3,4- b]pyridine-5,4'-piperidine]-1'-carboxylate (1.805 g, 4.06 mmol, 62% yield). m / z (ESI): 444.9 (M+H)+.

[0438] Step 3: tert-Butyl 4,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4'-piperidine]-1'- carboxylate. To a solution of tert-butyl 3'-iodo-4,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4'- piperidine]-1'-carboxylate (1.80 g, 4.05 mmol) and TEA (0.847 mL, 6.08 mmol, Sigma-Aldrich, Inc.)in EtOAc (20 mL) under N2atmosphere was added 10 wt% Pd / C (2.16 g, 2.03 mmol, Sigma-Aldrich, Inc.) and the reaction was stirred under 35 psi of H2for 24 h. The mixture was filtered through a pad of celite, concentrated, and chromatographed on silica gel using 0-30% EtOAc in heptane to afford tert-butyl 4,7-dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4'-piperidine]-1'-carboxylate. m / z (ESI): 319.2 (M+H)+. The sample was purified via SFC using a Lux Cellulose-2, 2 x 25 cm 5 µm column with a mobile phase of 10% MeOH using a flowrate of 100 mL / min.1steluting isomer was used in the next step.

[0439] Step 4: (R)-4,7-Dimethyl-7H-spiro[furo[3,4-b]pyridine-5,4'-piperidine], Intermediate B3. To a solution of the product from step 3 (0.124 g, 0.389 mmol) in DCM (5 mL) was added TFA (3.0 mL, 38.9 mmol, Oakwood) and the resulting mixture was stirred at rt for 15 min. The reaction mixture was concentrated to provide Intermediate B3 as a TFA salt which was used directly in the next step. m / z (ESI): 219.2 (M+H)+.

[0440] Intermediates in Table 1-3, or TFA salts thereof, were prepared following the procedure described for Intermediate B3, using appropriate starting materials. All starting materials are commercially available or are described above. Table 1-3Intermediate B13 - 3'-Methyl-6'H-dispiro[cyclopropane-1,7'-pyrazolo[5,1-c][1,4]oxazine-4',4''- piperidine]

[0441] Step 1: (1-(1-(Hydroxymethyl)cyclopropyl)-4-methyl-1H-pyrazol-5-yl)boronic acid. To a solution of Intermediate A5 (1.73 g, 11.37 mmol) in THF (20 mL) at -78 °C was added a solution of LDA (2.0 M in THF / heptane / ethylbenzene) (14.21 mL, 28.4 mmol, Sigma-Aldrich, Inc.), and the reaction mixture was stirred for 30 min. To the reaction mixture was added triisopropyl borate (6.60 mL, 28.4 mmol, Sigma-Aldrich, Inc.), and the reaction mixture was stirred for 30 min and then allowed to warm to rt. The reaction mixture was quenched by the addition of MeOH, and concentrated in vacuo. The crude residue was redissolved in EtOAc, filtered, and concentrated in vacuo to give (1-(1-(hydroxymethyl)cyclopropyl)-4-methyl-1H-pyrazol-5-yl)boronic acid which was directly used in the next step without further purification. m / z (ESI): 197.0 (M+H)+.

[0442] Step 2: tert-Butyl 4-(1-(1-(hydroxymethyl)cyclopropyl)-4-methyl-1H-pyrazol-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate. A mixture of K2CO3(3.14 g, 22.74 mmol, Sigma-Aldrich, Inc.), 4- trifluoromethanesulfonyloxy-3,6-dihydro-2h-pyridine-1-carboxylic acid tert-butyl ester (3.77 g, 11.37 mmol, J&W Pharmlab), Pd(dppf)Cl2(0.416 g, 0.569 mmol, Sigma-Aldrich, Inc.), and (1-(1- (hydroxymethyl)cyclopropyl)-4-methyl-1H-pyrazol-5-yl)boronic acid (2.23 g, 11.37 mmol) was evacuated and backfilled with N2. Then, 1,4-dioxane (10 mL) and H2O (1 mL) were added, and thereaction mixture was heated to 100 °C and stirred for 30 min. The reaction mixture was filtered over a plug of silica, eluted with EtOAc, and concentrated in vacuo. The material was redissolved in DCM, and the solids were filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in heptane to provide tert-butyl 4-(1- (1-(hydroxymethyl)cyclopropyl)-4-methyl-1H-pyrazol-5-yl)- 3,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 5.40 mmol, 47.5% yield). m / z (ESI): 334.0 (M+H)+.

[0443] Step 3: tert-Butyl 3''-iodo-3'-methyl-6'H-dispiro[cyclopropane-1,7'-pyrazolo[5,1- c][1,4]oxazine-4',4''-piperidine]-1''-carboxylate. To a solution of tert-Butyl 4-(1-(1- (hydroxymethyl)cyclopropyl)-4-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 5.40 mmol) in ACN (15 mL), was added NaHCO3(1.360 g, 16.20 mmol, Sigma-Aldrich, Inc.), iodine (4.11 g, 16.20 mmol, Sigma-Aldrich, Inc.), and the reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched by the addition of sat. aq. Na2S2O8, extracted with EtOAc, washed with sat. NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in heptane, to provide tert-butyl 3''-iodo-3'-methyl-6'H-dispiro[cyclopropane-1,7'-pyrazolo[5,1-c][1,4]oxazine-4',4''- piperidine]-1''-carboxylate (0.856 g, 1.86 mmol, 35% yield). m / z (ESI): 459.8 (M+H)+.

[0444] Step 4: tert-Butyl 3'-methyl-6'H-dispiro[cyclopropane-1,7'-pyrazolo[5,1-c][1,4]oxazine- 4',4''-piperidine]-1''-carboxylate. To a solution of tert-butyl 3''-iodo-3'-methyl-6'H- dispiro[cyclopropane-1,7'-pyrazolo[5,1-c][1,4]oxazine-4',4''-piperidine]-1''-carboxylate (0.856 g, 1.863 mmol), TEA (0.524 mL, 3.73 mmol, Sigma-Aldrich, Inc.) and EtOAc (8 mL), was added 10 wt% Pd / C (0.396 g, 0.373 mmol, Sigma-Aldrich, Inc.), and the vial was sealed and purged with H2(3 times). The reaction was then placed under 40 psi of H2and stirred at rt for 16 h. The mixture was filtered through a plug of silica, eluting with EtOAc, and concentrated in vacuo to give tert-butyl 3'- methyl-6'H-dispiro[cyclopropane-1,7'-pyrazolo[5,1-c][1,4]oxazine-4',4''-piperidine]-1''-carboxylate (0.611 g, 1.83 mmol, 98% yield) which was used without further purification. m / z (ESI): 334.0 (M+H)+.

[0445] Step 5: 3'-Methyl-6'H-dispiro[cyclopropane-1,7'-pyrazolo[5,1-c][1,4]oxazine-4',4''- piperidine], Intermediate B13. To a solution of tert-butyl 3'-methyl-6'H-dispiro[cyclopropane-1,7'- pyrazolo[5,1-c][1,4]oxazine-4',4''-piperidine]-1''-carboxylate (211 mg, 0.632 mmol) in DCM (2 mL) was added TFA (1 mL, 13.42 mmol, Thermo Fisher Scientific), and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to provide Intermediate B13 as a TFA salt (0.214 g, 0.318 mmol, 50.4% yield). m / z (ESI): 234.2 (M+H)+.

[0446] Intermediates in Table 1-4 as TFA salts were prepared following the procedure described for Intermediate B13, using appropriate starting materials. All starting materials are commercially available or are described above.Table 1-4Intermediate B17-1 - (S)-7'-(Methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine] Intermediate B17-2 - (R)-7'-(Methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]

[0447] Step 1: tert-Butyl 7'-(hydroxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate. A mixture of Intermediate A4 (5.0 g, 23.03 mmol) andTHF was cooled to -78 °C and n-BuLi (2.5 M in hexanes) (11 mL, 27.6 mmol, Sigma-Aldrich, Inc.) was added dropwise. The mixture was stirred for 10 min, then tert-butyl 4-oxopiperidine-1- carboxylate (5.05 g, 25.3 mmol, Oakwood) in THF (8 mL) was added. The mixture was warmed to rt over 2 h. The reaction was quenched with brine, extracted with EtOAc, concentrated, and chromatographed with 0-20% MeOH in DCM to give tert-butyl 7'-(hydroxymethyl)-3'-methyl-6',7'- dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (6.26 g, 18.55 mmol, 81% yield). m / z (ESI): 338.2 (M+H)+.

[0448] Step 2: tert-Butyl-7'-(methoxymethyl)-3'-methyl- 6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate. To a mixture of tert-butyl 7'-(hydroxymethyl)-3'-methyl- 6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (1.0 g, 2.96 mmol) and THF (10 mL) at 0 °C was added NaH (0.213 g, 8.89 mmol, 60% in mineral oil, TCI America). The mixture was allowed to slowly warm up to rt over 20 min, then MeI (2.10 g, 14.82 mmol, Sigma- Aldrich, Inc.) was added and stirred for 18 h. The reaction was quenched with H2O, extracted with EtOAc, and chromatographed with 0-10% MeOH in DCM to give tert-butyl-7'-(methoxymethyl)-3'- methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (706 mg, 2.01 mmol, 68% yield).

[0449] tert-Butyl 7'-(methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxylate was purified via SFC using a (S,S)-Whelk-O1, 2 x 25 cm, 5 µm column with a mobile phase of 15% IPA in liquid CO2, using a flowrate of 120 mL / min. to generate a 1steluting isomer and a 2ndeluting isomer. The 1steluting isomer was arbitrarily assigned as tert-butyl (S)-7'-(methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1- carboxylate. m / z (ESI): 352.2 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 7.23 (s, 1H), 4.23-4.21 (m, 1H), 4.06-3.97 (m, 2H), 3.85-3.83 (m, 2H), 3.68-3.60 (m, 2H), 3.29 (s, 3H), 3.02-2.99 (m, 2H), 1.98- 1.87 (m, 5H), 1.78-1.72 (m, 2H), 1.42 (s, 9H). The 2nd-eluting isomer was arbitrarily assigned as tert- butyl (R)-7'-(methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxylate. m / z (ESI): 352.4 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ7.23 (s, 1H), 4.23-4.21 (m, 1H), 4.06-3.97 (m, 2H), 3.85-3.83 (m, 2H), 3.65-3.62 (m, 2H), 3.29 (s, 3H), 3.04- 2.99 (m, 2H), 1.98-1.87 (m, 5H), 1.78-1.72 (m, 2H), 1.42 (s, 9H).

[0450] Step 3: (S)-7'-(Methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine], Intermediate B17-1; (R)-7'-(Methoxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine- 4,4'-pyrazolo[5,1-c][1,4]oxazine], Intermediate B17-2. To a solution of the 1steluting isomer (371 mg, 1.06 mmol) in DCM (5.0 mL) was added TFA (0.39 mL, 5.28 mmol, Thermo Fisher Scientific), and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated to give Intermediate B17-1 as a TFA salt. m / z (ESI): 252.2 (M+H)+. A similar reaction was made with the 2ndeluting isomer to provide Intermediate B17-2 as a TFA salt. m / z (ESI): 252.2 (M+H)+.

[0451] Intermediates in Table 1-5 were prepared as TFA salts following the procedure described for Intermediates B17-1 and B17-2, using appropriate starting materials. All starting materials are commercially available or are described above. Table 1-5Intermediate B28-1 - (S)-3',7'-Dimethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]Intermediate B28-2 - (R)-3',7'-Dimethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]

[0452] Step 1: tert-Butyl 3'-methyl-7'-((((trifluoromethyl)sulfonyl)oxy)methyl)-6',7'- dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate. To a solution of tert-butyl 7'-(hydroxymethyl)-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1- carboxylate (Intermediate B17, step 1) (200 mg, 0.593 mmol) in DCM (10 mL) at -78 °C was added DIPEA (0.31 mL, 1.778 mmol, Sigma-Aldrich, Inc.), followed by OTf2(1 M in DCM) (0.71 mL, 0.711 mmol, Sigma-Aldrich, Inc.). The mixture was warmed to rt and stirred for 15 min. The mixture was quenched with satd. NH4Cl aq. sol., extracted with DCM, dried with NaSO4, and concentrated to give tert-butyl 3'-methyl-7'-((((trifluoromethyl)sulfonyl)oxy)methyl)-6',7'-dihydrospiro[piperidine- 4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (278 mg, 0.592 mmol) that was used in the following step. m / z (ESI): 470.1 (M+H)+.

[0453] Step 2: tert-Butyl 3'-methyl-7'-methylene-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxylate. To a solution of tert-butyl 3'-methyl-7'- ((((trifluoromethyl)sulfonyl)oxy)methyl)-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxylate (2.78 g, 5.92 mmol) in THF (60 mL) at 0 °C was added lithium triethylborohydride, (1.0 M in THF) (12.00 mL, 12.00 mmol, Sigma-Aldrich, Inc.), and the reaction was stirred for 15 h at 0 °C. The reaction was quenched with satd. aq. NaHCO3, extracted with EtOAc, and purified by chromatography eluting with 0-10% MeOH in DCM to give tert-butyl 3'-methyl-7'-methylene-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (1.89 g, 5.92 mmol, 100% yield). m / z (ESI): 320.2 (M+H)+.

[0454] Step 3: tert-Butyl 3',7'-dimethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxylate. To a solution of tert-butyl 3'-methyl-7'-methylene-6',7'- dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (1.89 g, 5.92 mmol), and EtOH (60 mL), was added Pd(OH)2on carbon (20 wt%, 1.25 g, 1.775 mmol, Combi Blocks, Inc.), Pd / C (10 wt%, 1.89 g, 1.775 mmol, Oakwood), and ammonium formate (7.46 g, 118 mmol, Sigma- Aldrich, Inc.). The reaction was placed in a preheated aluminum block and kept at 50 °C for 2 h. The mixture was cooled to rt, filtered over celite, and the solvent was removed under vacuum. The residue was purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane to give tert- butyl 3',7'-dimethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (1.29 g, 4.01 mmol, 68% yield). m / z (ESI): 322.2 (M+H)+.

[0455] tert-Butyl 3',7'-dimethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1- carboxylate was purified via SFC using a Chiralcel OX 2 × 25 cm, 5 µm column with a mobile phase of 10% IPA using a flowrate of 120 mL / min to generate tert-butyl (S)-3',7'-dimethyl-6',7'- dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate, 1steluting isomer (m / z (ESI): 321.6 (M+H)+) and tert-butyl (R)-3',7'-dimethyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate, 2ndeluting isomer (m / z (ESI): 321.6 (M+H)+). The stereochemistry was arbitrarily assigned.

[0456] Step 4: (S)-3',7'-Dimethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine], Intermediate B28-1. To a solution of the 1steluting isomer from step 3, (280 mg, 0.871 mmol) in DCM (5.0 mL) was added TFA (0.325 mL, 4.36 mmol, Thermo Fisher Scientific) and the reaction mixture was stirred at rt for 30 min. The reaction was then concentrated to dryness to give Intermediate B28-1 as a TFA salt. m / z (ESI): 222.2 (M+H)+. The same step was performed with the 2ndeluting isomer to provide Intermediate B28-2 as a TFA salt. m / z (ESI): 222.2 (M+H)+.Intermediate B29 - 3'-Methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]

[0457] Step 1: tert-Butyl 4-(1-(2-hydroxyethyl)-4-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine- 1(2H)-carboxylate. To a solution of Intermediate A11 (3 g, 14.63 mmol) in 1,4-dioxane (60 mL) and H2O (12 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (5.43 g, 17.56 mmol), K2CO3(6.07 g, 43.9 mmol), and Pd(dppf)Cl2(0.535 g, 0.732 mmol) in sequence. The mixture was stirred at 90 °C for 3 h and allowed to cool to rt. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. Purification was employed by silica gel chromatography eluting with a gradient of 0 % to 60% EtOAc in heptane to give tert-butyl 4-(1-(2-hydroxyethyl)-4-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine- 1(2H)-carboxylate (4.3 g, 14.0 mmol, 96% yield). m / z (ESI): 308.3 (M+H)+.

[0458] Step 2: tert-Butyl 3-iodo-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxylate. To a solution of tert-butyl 4-(1-(2-hydroxyethyl)-4-methyl-1H- pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.51 mmol) in DCM (50 mL) was added I2(8.26 g, 32.5 mmol) and CF3CO2Ag (2.87 g, 13.01 mmol). The mixture was stirred at 20 °C for 3 h. The reaction mixture was filtered with EtOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, pet. ether / EtOAc = 5 / 1 to 3 / 1), and triturated with pet. ether (10 mL) at 20 ℃ for 60 min to give tert-butyl 3-iodo-3'-methyl-6',7'- dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (450 mg, 1.04 mmol, 16% yield). m / z (ESI): 434.1 (M+H)+.

[0459] Step 3: tert-Butyl 3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1- carboxylate. To a suspension of tert-butyl 3-iodo-3'-methyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (450 mg, 1.04 mmol) in EtOAc (40 mL) was added Pd / C(10 wt%, 900 mg, 1.039 mmol) and TEA (430 µL, 3.12 mmol), under argon atmosphere. The suspension was degassed and purged 3 times with H2. The mixture was stirred under H2(50 Psi) at 20 °C for 12 h. The reaction mixture was filtered with EtOAc, concentrated, and purified by column chromatography on silica eluting with 0-80 % of EtOAc in heptane to give tert-butyl 3'-methyl-6',7'- dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate. m / z (ESI): 308.2 (M+H)+.

[0460] Step 4: 3'-methyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine], Intermediate B29. To a solution of tert-butyl 3'-methyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate (250 mg, 0.813 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at 20 °C for 1 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to provide Intermediate B29 as a TFA salt. m / z (ESI): 208.2 (M+H)+.

[0461] Intermediates in Table 1-6, or TFA salts thereof, were prepared following the procedure described for Intermediate B29, using appropriate starting materials. All starting materials are commercially available or are described above. Table 1-6Intermediate B32 - 4-Methyl-1-oxa-8-azaspiro[4.5]dec-3-ene

[0462] Step 1: tert-Butyl 4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-8-azaspiro[4.5]dec-3-ene-8- carboxylate. To tert-butyl 4-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (8 g, 31.3 mmol) in dry tetrahydrofuran (80 mL) at -78 °C added 1 M LiHMDS in THF (41 mL, 41 mmol) dropwise at -78 °C, and the reaction was stirred at -78 °C for 1 h. To the reaction mixture, N-(5-chloropyridin-2-yl)- 1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (16 g, 41 mmol) in THF (25 mL) was added, and the reaction mixture was allowed to rt and stirred for 1h. The reaction mixture was quenched with H2O (80 mL) and extracted with EtOAc (2 x 250 mL). The overall organic extracts were washed with brine (100 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using 5-10% EtOAc in pet. ether as an eluent to give tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-8- azaspiro[4.5]dec-3-ene-8-carboxylate (8.5 g, 70% yield).

[0463] Step 2: tert-Butyl 4-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. To a solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (1.0 g, 2.58 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) under N2 atm, was added Cs2CO3 (2.52 g, 7.74 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50% in THF) (2.59 g, 10.33 mmol) at rt. The reaction mixture was purged by N2for 5 min, then PdCl2(dppf) (211 mg, 0.26 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica, eluting with a gradient of 0% to 10% EtOAc in pet. ether to provide tert- butyl 4-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (484 mg, 1.9 mmol, 74% yield). m / z (ESI): 198.3 (M-tBu+H)+.

[0464] Step 3: 4-Methyl-1-oxa-8-azaspiro[4.5]dec-3-ene, Intermediate B32. To a solution of tert- butyl 4-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (0.700 g, 2.76 mmol) in DCM (7 mL) at 0 °C was added TFA (3.19 mL, 41.4 mmol) dropwise, and the reaction mixture was slowly warmed to rt, stirred for 3 h, and concentrated under reduced pressure. The crude product was co-distilled withdiethyl ether (5 mL × 2) and dried under reduced pressure to provide Intermediate B32 as a TFA salt. m / z (ESI): 154.1 (M+H)+. Intermediate B33 - (7R)-4,7-Dimethyl-1-oxa-8-azaspiro[4.5]dec-3-ene

[0465] Step-1: tert-Butyl (2R)-4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)-2-methylpiperidine-1- carboxylate. To a stirred solution of propargyl alcohol (28.9 g, 516 mmol) in dry THF (300 mL) at -78 °C under N2atm, was added 2.5 M n-BuLi in hexanes (248 mL, 619 mmol) and stirred for 40 min at - 78 °C, then 20 min at 0 °C. The reaction mixture was again cooled to -78 °C, and a pre-stirred solution of tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (30 g, 141 mmol) and cerium (III) chloride (6.93 g, 28.1 mmol) in THF (150 mL) was added and stirred at -78 °C for 30 min. Then, the reaction was warmed to rt and stirred for 4 h. The reaction mixture was quenched with 1 M aq. HCl solution (200 mL) and extracted with EtOAc (2 × 250 mL). The combined organic extracts were washed with brine solution (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0-50% (3:1) EtOAc / EtOH in hexanes to give tert-butyl (2R)-4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)-2- methylpiperidine-1-carboxylate. m / z (ESI): 170.1 (M-Boc+H)+.1H NMR (400 MHz, DMSO-d6): δ 5.76 (s, 1H), 5.12 (t, J = 5.9 Hz, 1H), 4.11 – 4.20 (m, 1H), 4.07 (d, J = 5.9 Hz, 2H), 3.69 (ddd, J = 13.3, 4.7, 2.3 Hz, 1H), 3.06 (td, J = 13.1, 2.6 Hz, 1H), 1.74 – 1.82 (m, 3H), 1.57 (td, J = 13.1, 4.7 Hz, 1H), 1.39 (s, 9H), 1.14 – 1.23 (m, 3H).

[0466] Step-2: tert-Butyl (2R)-4-(3-acetoxyprop-1-yn-1-yl)-4-hydroxy-2-methylpiperidine-1- carboxylate. To a stirred solution of tert-butyl (2R)-4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)-2- methylpiperidine-1-carboxylate (22.0 g, 82 mmol) and pyridine (19.8 mL, 245 mmol) in DCM (220 mL) at 0 °C was added acetic anhydride (10.8 mL, 114 mmol)and stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, redissolved in EtOAc (2 × 150 mL), and washed with satd. aq. NaHCO3solution (80 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatographyeluting with 0-40% EtOAc in hexanes to afford tert-butyl (2R)-4-(3-acetoxyprop-1-yn-1-yl)-4- hydroxy-2-methylpiperidine-1-carboxylate. m / z (ESI): 212.1 (M-Boc+H)+.1H NMR (400 MHz, DMSO-d6): δ 5.55 (s, 1H), 4.70 (s, 2H), 4.16 (tt, J = 7.6, 5.7 Hz, 1H), 3.69 (dq, J = 13.4, 2.2 Hz, 1H), 3.05 (td, J = 13.1, 2.5 Hz, 1H), 2.04 (s, 3H), 1.67 – 1.86 (m, 3H), 1.58 (td, J = 12.9, 4.5 Hz, 1H), 1.39 (s, 9H), 1.19 (d, J = 7.0 Hz, 3H).

[0467] Step-3: tert-Butyl (7R)-4-acetoxy-7-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. To a stirred solution of tert-butyl (2R)-4-(3-acetoxyprop-1-yn-1-yl)-4-hydroxy-2-methylpiperidine-1- carboxylate (18 g, 57.8 mmol) in toluene (200 mL) under N2was added silver perchlorate (6.0 g, 28.9 mmol). The reaction vessel was covered with aluminum foil and stirred at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography on silica, eluting with a gradient of 0-10% EtOAc in hexanes to afford tert- butyl (7R)-4-acetoxy-7-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. m / z (ESI): 212.3 (M- Boc+H)+.1H NMR (400 MHz, DMSO-d6): δ 5.72 – 5.81 (m, 1H), 4.57 (t, J = 1.8 Hz, 2H), 4.30 (s, 1H), 3.83 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 1.79 (dd, J = 13.9, 6.7 Hz, 1H), 1.45 – 1.67 (m, 4H), 1.51 (s, 9H), 1.12 – 1.33 (m, 3H).

[0468] Step-4: tert-Butyl (7R)-4-hydroxy-7-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. To a stirred solution of tert-butyl (7R)-4-acetoxy-7-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8- carboxylate (11 g, 35.3 mmol) in THF (75 mL) and H2O (25 mL) was added LiOH monohydrate (2.17 g, 53.0 mmol). The reaction mixture was stirred for 16 h at rt. The reaction mixture was quenched with brine solution (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 0-50% EtOAc in hexanes to afford tert-butyl (7R)-4-hydroxy-7-methyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. m / z (ESI): 170.1 (M- Boc+H)+.1H NMR (400 MHz, DMSO-d6) δ 4.23 – 4.36 (m, 1H), 3.99 – 4.17 (m, 2H), 3.81 (ddd, J = 13.5, 5.1, 2.3 Hz, 1H), 2.99 (t, J = 13.3 Hz, 1H), 2.54 – 2.60 (m, 2H), 1.63 (dq, J = 13.8, 2.5 Hz, 1H), 1.48 – 1.57 (m, 2H), 1.40 (s, 9H), 1.08 – 1.33 (m, 4H).

[0469] Step-5: tert-Butyl (7R)-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-8- azaspiro[4.5]dec-3-ene-8-carboxylate. To a stirred solution of tert-butyl (7R)-4-hydroxy-7-methyl-1- oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (6 g, 22.28 mmol) in dry THF (60 mL) at -78 °C was added LiHMDS (1 M in THF) (29.0 mL, 29.0 mmol) dropwise, and the reaction was stirred for 1 h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoro methyl)sulfonyl)methanesulfonamide (11.4 g, 29.0 mmol) in THF (30 mL) was added at -78 °C, and the reaction was stirred for another 3 h. The reaction mixture was quenched with satd. aq. NH4Cl solution (150 mL) and extracted with EtOAc (2 × 250 mL). The combined organic extracts were washed with brine solution (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 0-10% EtOAc inhexanes to afford tert-butyl (7R)-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-8- azaspiro[4.5]dec-3-ene-8-carboxylate. m / z (ESI): 302.1 (M-Boc+H)+.1H NMR (400 MHz, DMSO- d6): δ 6.17 (t, J = 1.9 Hz, 1H), 4.64 (t, J = 1.7 Hz, 2H), 4.20 – 4.30 (m, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.05 (s, 1H), 1.73 (dd, J = 13.9, 6.6 Hz, 1H), 1.47 – 1.67 (m, 3H), 1.40 (s, 9H), 1.21 (d, J = 7.0 Hz, 3H).

[0470] Step-6: tert-Butyl (7R)-4,7-dimethyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. To a solution of tert-butyl (7R)-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1-oxa-8-azaspiro[4.5]dec-3- ene-8-carboxylate (5.5 g, 13.70 mmol) in 1,4-dioxane (50 mL) and H2O (25 mL) under N2were added Cs2CO3(13.4 g, 41.1 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50% solution in THF, 27.5 mL, 54.8 mmol). The reaction mixture was degassed and purged with N2gas for 5 min. To this mixture was added Pd(dppf)Cl2DCM adduct (1.12 g, 1.37 mmol), and the reaction was stirred at 100 °C for 16 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 0-5% EtOAc in hexanes to afford tert-butyl (7R)-4,7-dimethyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate. m / z (ESI): 168.1 (M-Boc+H)+.1H NMR (400 MHz, DMSO-d6) δ 5.56 (s, 1H), 4.42 (s, 2H), 4.29 (br s, 1H), 3.82 (s, 1H), 3.06 (m, 1H), 1.79 (dd, J = 13.6, 6.7 Hz, 1H), 1.80 – 1.60 (m, 4H), 1.40 (m, 11H), 1.22 (d, J = 7.0 Hz, 3H).

[0471] Step-7: (7R)-4,7-Dimethyl-1-oxa-8-azaspiro[4.5]dec-3-ene, Intermediate B33. To a solution of tert-butyl (7R)-4,7-dimethyl-1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (1.5 g, 5.61 mmol) in DCM (16 mL) under N2was added TFA (2.2 mL, 28.1 mmol) at 0 °C and stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford Intermediate B33 as a TFA salt. m / z (ESI): 168.1 (M +H)+.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.45 (s, 1H), 5.64 (s, 1H), 4.43 (s, 2H), 3.71 – 3.54 (m, 1H), 3.33 – 3.04 (m, 2H), 2.06 – 1.86 (m, 2H), 1.72 (q, J = 2.1 Hz, 3H), 1.64 – 1.45 (m, 2H), 1.38 (d, J = 6.9 Hz, 3H).Intermediate D1 - Benzyl 4-((2S,3R)-2-allylazetidin-3-yl)piperazine-1-carboxylate

[0472] Step 1: tert-Butyl (S)-3-((2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1-carboxylate. To tert-butyl 3-oxoazetidine-1-carboxylate (248 g, 1448 mmol), (S)-2-(methoxymethyl)pyrrolidin-1- amine (200 g, 1383 mmol) was added dropwise, and the mixture was stirred at 70 °C for 16 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica, eluting with a gradient of 0-50% EtOAc in pet. ether to give tert- butyl (S)-3-((2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1-carboxylate (350 g, 81% yield). m / z (ESI): 284.3 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 4.78 – 4.68 (m, 1H), 4.63 – 4.39 (m, 3H), 3.45 (dd, J = 8.8, 3.5 Hz, 1H), 3.35 – 3.16 (m, 6H), 2.77 (q, J = 8.3 Hz, 1H), 1.89 – 1.72 (m, 3H), 1.58 (dtd, J = 10.9, 5.8, 1.2 Hz, 1H), 1.40 (s, 9H).

[0473] Step 2: tert-Butyl (S, E)-2-allyl-3-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1- carboxylate. To a mixture of tert-butyl (S)-3-((2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1- carboxylate (30 g, 106 mmol) and allyl bromide (17.38 mL, 201 mmol) in THF (800 mL) was added 2.5 M n-BuLi in THF (80 mL, 201 mmol) dropwise at -78 °C under N2atmosphere, and the reaction was stirred for 1 h. The reaction mixture was quenched with satd. aq. NH4Cl sol. (250 mL) at -78 °C. The reaction mixture was warmed to rt and extracted with EtOAc (2 × 500 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give tert-butyl (S, E)-2-allyl-3-(((S)-2-(methoxymethyl)pyrrolidin-1- yl)imino)azetidine-1-carboxylate. m / z (ESI): 324.3 (M+ H)+

[0474] Step 3: tert-Butyl (S)-2-allyl-3-oxoazetidine-1-carboxylate. To a solution of tert-butyl (S, E)- 2-allyl-3-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1-carboxylate (56 g, 173 mmol) in diethyl ether (700 mL) was added a solution of oxalic acid (78 g, 866 mmol) in H2O (350 mL) at 0 °C, and the reaction was stirred at rt for 16 h. The reaction mixture was quenched with H2O (500 mL) and extracted with EtOAc (2 × 500 mL). The combined organic extracts were washed with brine (100mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica, eluting with a gradient of 0-5% EtOAc in pet. ether to afford tert-butyl (S)-2-allyl-3-oxoazetidine-1-carboxylate. m / z (ESI): 112.1 (M-Boc+H)+.1H NMR (400 MHz, Chloroform-d): δ 5.83 (ddt, J = 17.3, 10.2, 7.1 Hz, 1H), 5.24 – 5.14 (m, 2H), 4.96 (dt, J = 6.5, 4.7 Hz, 1H), 4.68 (d, J = 16.6 Hz, 1H), 4.49 (dd, J = 16.6, 4.7 Hz, 1H), 2.71 – 2.60 (m, 1H), 2.61 – 2.50 (m, 1H), 1.51 (s, 9H).

[0475] Step 4: tert-Butyl benzyl 4-((2S,3R)-2-allyl-1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine- 1-carboxylate. To a solution of tert-butyl (S)-2-allyl-3-oxoazetidine-1-carboxylate (20.0 g, 95 mmol) in DCE (500 mL) was added benzyl piperazine-1-carboxylate (41.7 g, 189 mmol,) followed by AcOH (0.55 mL, 9.47 mmol) at rt under N2atmosphere, and the reaction was stirred for 16 h. Sodium cyanoborohydride (8.9 g, 142 mmol) was added to the reaction mixture, and the reaction was stirred for another 5 h. The reaction mixture was quenched with H2O (150 mL) and extracted with DCM (2 × 150 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica, eluting with a gradient of 0-25% EtOAc in hexanes to afford tert-butyl benzyl 4-((2S,3R)-2-allyl-1-(tert- butoxycarbonyl)azetidin-3-yl)piperazine-1-carboxylate. m / z (ESI): 416.3 (M+ H)+.1H NMR (400 MHz, DMSO-d6): δ 7.47 – 7.24 (m, 5H), 5.87 – 5.78 (m, 1H), 5.17 – 5.06 (m, 4H), 3.96 (dt, J = 8.8, 4.4 Hz, 1H), 3.84 – 3.66 (m, 1H), 3.52 (dd, J = 8.7, 4.8 Hz, 1H), 3.39 (br s, 4H), 2.81 – 2.61 (m, 1H), 2.46 – 2.37 (m, 2H), 2.25 (dd, J = 11.0, 5.9 Hz, 4H), 1.38 (s, 9H).

[0476] Step 5: Benzyl 4-((2S,3R)-2-allylazetidin-3-yl)piperazine-1-carboxylate, Intermediate D1. To a solution of tert-butyl benzyl 4-((2S,3R)-2-allyl-1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine-1- carboxylate (3 g, 7.22 mmol) in DCM (30 mL) was added TFA (5.6 mL, 72.2 mmol) dropwise at 0 °C under N2atmosphere. The reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The crude material was co-distilled with MTBE (2 × 30 mL) and dried under reduced pressure to afford Intermediate D1 as a TFA salt. m / z (ESI): 316.2 (M+H)+.Intermediate D2 - Benzyl 4-((2S,3R)-2-(2-hydroxyethyl)azetidin-3-yl)piperazine-1-carboxylate

[0477] Step 1: Benzyl 4-((2S,3R)-1-(tert-butoxycarbonyl)-2-(2-oxoethyl)azetidin-3-yl)piperazine-1- carboxylate. A solution of benzyl 4-((2S,3R)-2-allyl-1-(tert-butoxycarbonyl)azetidin-3-yl)piperazine- 1-carboxylate (1 g, 2.41 mmol) in DCM (10 mL) was purged with ozone for 1 min. After that, it was quenched with BH3-DMS (0.5 mL) at 0 °C. The reaction mixture was diluted with H2O (25 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was carried to next step without further purification. Step 2: Benzyl 4-((2S,3R)-1-(tert-butoxycarbonyl)-2-(2-hydroxyethyl)azetidin-3-yl)piperazine-1- carboxylate. To a solution of benzyl 4-((2S,3R)-1-(tert-butoxycarbonyl)-2-(2-oxoethyl)azetidin-3- yl)piperazine-1-carboxylate (1 g, 2.39 mmol) in MeOH (20 mL) at 0 °C was added NaBH4(0.28 g, 6.0 mmol). The reaction mixture was stirred at rt for 2 h and cooled to 0 °C. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give benzyl 4-((2S,3R)-1-(tert-butoxycarbonyl)-2-(2-hydroxyethyl)azetidin-3-yl)piperazine-1-carboxylate (900 mg, 2.14 mmol, 90% yield). m / z (ESI): 420.1 (M+ H)+.1H NMR (400 MHz, DMSO-d6) δ 7.43 – 7.28 (m, 5H), 5.08 (s, 2H), 4.45 (t, J = 4.9 Hz, 1H), 3.99 (q, J = 6.5, 5.9 Hz, 1H), 3.76 (s, 1H), 3.50 (h, J = 6.9, 6.0 Hz, 3H), 3.33 (s, 4H), 2.70 – 2.63 (m, 1H), 2.28 (tq, J = 11.7, 6.4, 5.8 Hz, 4H), 1.92 (dq, J = 13.3, 6.9 Hz, 1H), 1.70 (dq, J = 13.2, 6.4 Hz, 1H), 1.38 (s, 9H).

[0478] Step 3: Benzyl 4-((2S,3R)-2-(2-hydroxyethyl)azetidin-3-yl)piperazine-1-carboxylate, Intermediate D2. To a solution of benzyl 4-((2S,3R)-1-(tert-butoxycarbonyl)-2-(2- hydroxyethyl)azetidin-3-yl)piperazine-1-carboxylate (683 mg, 2.14 mmol) in DCM (10 mL) was added TFA (2 mL) dropwise at 0 °C under N2atmosphere. The reaction mixture was warmed to rt andstirred for 3 h. The reaction mixture was concentrated under reduced pressure. The crude material was co-distilled with MTBE (2 × 10 mL) and dried under reduced pressure to afford Intermediate D2 as a TFA salt. m / z (ESI): 320.1 (M+H)+. Intermediate E1 - Benzyl 4-((7aS,8R)-2-chloro-4-(difluoromethyl)-7,7a,8,9-tetrahydroazeto[1,2- a]pyrido[3,4-f]azepin-8-yl)piperazine-1-carboxylate

[0479] Step 1: 4,6-Dichloro-2-(difluoromethyl)-3-vinylpyridine. To a stirred solution of 3-bromo- 4,6-dichloro-2-(difluoromethyl)pyridine (150 g, 542 mmol) in THF (2400 mL) and H2O (600 mL) were added potassium trifluoro(vinyl)borate (102 g, 758 mmol) and K3PO4(345 g, 1625 mmol), and the solution was degassed and purged with N2for 5 min. PEPPSI-IPr catalyst (36.8 g, 54.2 mmol) was added, and the reaction system was purged with N2for 5 min and stirred at 85 °C for 16 h. The reaction mixture was cooled to rt, filtered, diluted with H2O (500 mL), and extracted with MTBE (3 × 500 mL). The combined organic extracts were washed with brine solution (500 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0-100% EtOAc in hexanes to give 4,6-dichloro-2-(difluoromethyl)-3-vinylpyridine (74 g, 330 mmol, 61% yield).1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.04 (t, J = 53.1 Hz, 1H), 6.78 (ddt, J = 17.8, 11.6, 1.8 Hz, 1H), 5.87 (dd, J = 11.6, 1.1 Hz, 1H), 5.59 (dd, J = 17.8, 1.0 Hz, 1H). No ionization observed in MS.

[0480] Step 2: Benzyl 4-((2S,3R)-2-allyl-1-(6-chloro-2-(difluoromethyl)-3-vinylpyridin-4- yl)azetidin-3-yl)piperazine-1-carboxylate. To a stirred solution of 4,6-dichloro-2-(difluoromethyl)-3- vinylpyridine (370.0 g, 895 mmol) in DMA (1500 mL) was added K2CO3(866 g, 6264 mmol) and Intermediate D1 as a TFA salt (200 g, 895 mmol) at 0 °C. The reaction mixture was stirred at 80 °Cfor 16 h. The reaction mixture was cooled to rt, quenched with ice cold H2O (6000 mL), and extracted with EtOAc (2 × 4000 mL). The combined organic extracts were washed with H2O (2 × 4000 mL) followed by brine (3 × 2000 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography, eluting with a gradient of 0 to 25% EtOAc:hexanes to give benzyl 4-((2S,3R)-2-allyl-1-(6-chloro-2-(difluoromethyl)-3-vinylpyridin-4- yl)azetidin-3-yl)piperazine-1-carboxylate (304 g, 604 mmol, 68% yield). m / z (ESI): 503.3 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 7.42 – 7.29 (m, 5H), 6.99 – 6.64 (m, 3H), 5.83 (ddt, J = 17.2, 10.0, 7.2 Hz, 1H), 5.68 (dd, J = 11.4, 1.6 Hz, 1H), 5.32 (dd, J = 17.6, 1.7 Hz, 1H), 5.21 – 5.04 (m, 4H), 4.33 – 4.19 (m, 2H), 3.63 (dd, J = 9.1, 4.4 Hz, 1H), 3.48 – 3.39 (m, 4H), 2.86 (dt, J = 7.3, 4.1 Hz, 1H), 2.49 – 2.36 (m, 2H), 2.31 (d, J = 5.4 Hz, 2H), 2.24 (d, J = 11.5 Hz, 2H).

[0481] Step 3: Benzyl 4-((7aS,8R)-2-chloro-4-(difluoromethyl)-7,7a,8,9-tetrahydroazeto[1,2- a]pyrido[3,4-f]azepin-8-yl)piperazine-1-carboxylate, Intermediate E1. To a stirred solution of benzyl 4-((2S,3R)-2-allyl-1-(6-chloro-2-(difluoromethyl)-3-vinylpyridin-4-yl)azetidin-3-yl)piperazine-1- carboxylate (120.5 g, 240 mmol) in DCM (3600 mL) was added Grubbs catalyst 2ndgeneration (30.5 g, 35.9 mmol) at rt. The reaction mixture was stirred for 48 h and was quenched with H2O (1500 mL) and extracted with DCM (2 × 1000 mL). The combined organic extracts were washed with H2O (2 × 2000 mL), followed by brine (2 × 1000 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography, eluting with a gradient of 0 to 25% EtOAc in hexanes to give Intermediate E1 (86 g, 181 mmol, 76% yield). m / z (ESI): 475.1 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 7.42 – 7.29 (m, 5H), 6.99 (t, J = 53.8 Hz, 1H), 6.76 – 6.68 (m, 1H), 6.55 (s, 1H), 6.09 (ddd, J = 12.5, 7.4, 3.3 Hz, 1H), 5.08 (s, 2H), 4.01 (t, J = 7.9 Hz, 2H), 3.84 (t, J = 7.6 Hz, 1H), 3.48 – 3.38 (m, 4H).3.08 (q, J = 6.6 Hz, 1H), 2.75 (ddd, J = 17.0, 7.5, 2.7 Hz, 1H), 2.65 (dd, J = 16.2, 13.0 Hz, 1H), 2.44 – 2.26 (m, 4H). Intermediate E2 - Benzyl 4-((7aS,8R)-2-chloro-4-(difluoromethyl)-6,6-difluoro-5,6,7,7a,8,9- hexahydroazeto[1,2-a]pyrido[3,4- f]azepin-8-yl)piperazine-1-carboxylateIntermediate E3 -Benzyl 4-((7aS,8R)-2-chloro-4-(difluoromethyl)-6-fluoro-7,7a,8,9- tetrahydroazeto[1,2-a]pyrido[3,4-f]azepin-8-yl)piperazine-1-carboxylate

[0482] Step 1: Benzyl 4-((7aS,8R)-5-acetoxy-6-bromo-2-chloro-4-(difluoromethyl)-5,6,7,7a,8,9- hexahydroazeto[1,2- a]pyrido[3,4-f]azepin-8-yl)piperazine-1-carboxylate. A solution of Intermediate E1 (400 mg, 0.842 mmol), lithium acetate (222 mg, 3.37 mmol, TCI America), and NBS (157 mg, 0.884 mmol, Sigma-Aldrich, Inc.) in AcOH (3 mL) was stirred at rt for 3 h. The reaction was concentrated, and the crude material was diluted using EtOAc (2 mL) and 10 wt% NaCO3aq solution (1 mL). The crude material was extracted with EtOAc (6 mL × 3), washed with brine, dried through Na2SO4, and concentrated. The crude material was purified using chromatography, eluting with a gradient of 3-40% acetone in heptane to give benzyl 4-((7aS,8R)-5-acetoxy-6-bromo-2-chloro-4- (difluoromethyl)-5,6,7,7a,8,9-hexahydroazeto[1,2- a]pyrido[3,4-f]azepin-8-yl)piperazine-1- carboxylate (505 mg, 0.823 mmol, 98% yield). m / z (ESI): 612.8 and 614.8 (M+H)+.

[0483] Step 2: Benzyl 4-((7aS,8R)-5-acetoxy-6-bromo-2-chloro-4-(difluoromethyl)-5,6,7,7a,8,9- hexahydroazeto[1,2-a]pyrido[3,4-f]azepin-8-yl)piperazine-1-carboxylate. To a solution of benzyl 4- ((7aS,8R)-5-acetoxy-6-bromo-2-chloro-4-(difluoromethyl)- 5,6,7,7a,8,9-hexahydroazeto[1,2- a]pyrido[3,4-f]azepin-8-yl)piperazine-1-carboxylate (505 mg, 0.823 mmol) in THF (4.5 mL) was added sodium methoxide (222 mg, 4.11 mmol, Sigma-Aldrich, Inc.). The reaction mixture was stirred at rt for 3 h. The ...

Claims

What is claimed is:

1. A compound of Formula (I):pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S, or heteroalkenylene having 3- 6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 3-5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; A is N, CH, C-halo, C- 3alkylene-C1-4each of W1and W2independently is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C2-3alkenyl, C-C2-3alkynyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; Y’ is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; each of R1a, R1b, and R2independently is H, D, halo, C1-4alkyl, C1-4haloalkyl, C1-2alkylene- OH, C0-2alkylene-C1-4alkoxy, C0-2alkylene-C1-4haloalkoxy, C0-2alkylene-CN, C0-2alkylene-N(RN1)2, C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or R1band R2, together with the carbon atoms to which they are attached, form; each R3independently is C1-3alkyl, C1-3haloalkyl,, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or fused- heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, C1-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; R5is halo, C1-3haloalkyl, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3thioalkyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl; each R6independently is halo, CN, C1-3alkyl, C2-3alkenyl, C1-3haloalkyl, C0-3alkylene-OH, C0- 3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, C1-4alkylene-N(RN1)2, oxo, =CH2, C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused- heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two non- neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl of each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN; each R7independently is halo, C0-3alkylene-CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, oxo, =CH2, C0-4alkylene-C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl, C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R7together with the atoms to which they are attached form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatomsindependently selected from N, O and S, fused-C6-10aryl, or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

2. The compound or salt of claim 1, wherein at least one of R1a, R1b, and R2is H or D.

3. The compound or salt of claim 2, wherein each of R1a, R1b, and R2independently is H or D.

4. The compound or salt of claim 3, wherein each of R1a, R1b, and R2is H.7 The compound or salt of claim 6, wherein8. The compound or salt of any one of claims 1-7, wherein m is 0.

9. The compound or salt of any one of claims 1-7, wherein m is 1.

10. The compound or salt of any one of claims 1-7, wherein at least one R3is CH3, CH2CH3, CF3, CHF2, or CH2F.

11. The compound or salt of any one of claims 1-7, wherein each R3independently isCH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro- oxetanyl, or spiro-tetrahydrofuranyl; or two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused-cyclobutyl.

12. The compound or salt of any one of claims 1-7, wherein m is 0; or m is 1 and R3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

13. The compound or salt of claim 12, wherein m is 0; or m is 1 and R3is CH3.The compound or salt of claim 14, wherein. The compound or salt of claim 15, wherein17. The compound or salt of any one of claims 1-16, wherein A is N.

18. The compound or salt of any one of claims 1-16, wherein A is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2F, C-CHF2, C-CF3, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

19. The compound or salt of any one of claims 1-18, wherein n is 0.

20. The compound or salt of any one of claims 1-18, wherein n is 1 or 2.

21. The compound or salt of any one of claims 1-18, wherein each R4independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

22. The compound or salt of any one of claims 1-16, wherein. 2 The compound or salt of claim 22, wherein.

24. The compound or salt of any one of claims 1-23, wherein is unsubstituted.

25. The compound or salt of any one of claims 1-23, wherein is substituted with 1- 4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro- heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S or fused- heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S.

26. The compound or salt of claim 25, wherein each substituent independently is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CHF2, CH2F, CH=CH2, CH=CHCH3, CH2CH=CH2, Cl, F, OH, CH2OH, CH2CH2OH, OCH3, OCH2CH3, CH2OCH3, CH2OCH2CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, aziridinyl, azetidinyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxiranyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, spiro-aziridinyl, or spiro-azetidinyl; or two vicinal substituents, together with the atoms to which they are attached form fused-cyclopropyl, fused-cyclobutyl, fused-oxiranyl, fused-oxetanyl, fused-tetrahydrofuranyl, fused-aziridinyl, or fused- azetidinyl.

27. The compound or salt of claim 26, wherein is substituted with CH3, =CH2,, or a combination of the foregoing.

28. The compound or salt of claim 27, wherein is substituted with CH3, F, or a combination of the foregoing.

29. The compound or salt of any one of claims 1-28, whereinis C2alkylene. The compound or salt of any one of claims 1-27, wherein,. 3 . The compound or salt of claim 30, wherein.

32. The compound or salt of any one of claims 1-28, wherein is C3alkylene.

33. The compound or salt of any one of claims 1-27, whereinalt of any one of claims 1-28, wherein, wherein t is 0, 1, 2, or 3; and each R8independently is C1-3alkyl, halo, OH, OC1-3alkyl, oxo, =CH2; or two vicinal R8, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

36. The compound or salt of claim 35, wherein each R8independently is CH3, Cl, F, OH, OCH3, oxo, or =CH2; or two vicinal R8, together with the atoms to which they are attached form37. The compound or salt of any one of claims 1-28, wherein is C3alkenylene.0, 1, 2, or 3, and each R8independently is C1-3alkyl, halo, OH, OC1-3alkyl, oxo, =CH2; or two vicinal R8, together with the atoms to which they are attached, form fused-C3-5cycloalkyl or fused- heterocycloalkyl having 3-5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S.

40. The compound or salt of claim 39, wherein each R8independently is CH3, Cl, F, OH, OCH3, oxo, or =CH2; or two vicinal R8, together with the atoms to which they are attached form41. The compound or salt of any one of claims 1-28, wherein is heteroalkylene having 2-4 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S.,4 The compound or salt of claim 43, wherein. 4 The compound or salt of any one of claims 1-28, wherein,46. The compound or salt of claim 45, wherein is, , , .of claim 46, wherein. 4 The compound or salt of claim 47, wherein.

49. The compound or salt of any one of claims 1-48, wherein W1is CH and50. The compound or salt of any one of claims 1-48, wherein W1is C-F, C-Cl, C-CN, C- CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), C-CCH, C- OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

51. The compound or salt of any one of claims 1-50, whereini52. The compound or salt of any one of claims 1-50, wherein W2is C-F, C-Cl, C-CN, C- CH3, C-CH2CH3, C-CH2F, C-CHF2, C-CF3, C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), C-CCH, C- OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

53. The compound or salt of any one of claims 1-49, wherein W1is CH and W2is N, CH, or C-CH3or W2is N and W1is N, CH, or C-CH3. The compound or salt of claim 53, whereini55. The compound or salt of any one of claims 1-54, wherein R5is CF3, CF2H, CFH2, or CF2CH3.

56. The compound or salt of claim 55, wherein R5is CF3or CF2H.

57. The compound or salt of claim 56, wherein R5is CF2H.

58. The compound or salt of any one of claims 1-54, wherein R5is CH3, CH2CH3,59. The compound or salt of any one of claims 1-48, wherein W1is CH, W2is N, and R5is CF3, CF2H, or CFH2.

60. The compound or salt of claim 59, wherein R5is CF2H.

65. The compound or salt of any one of claims 1-64, wherein q is 0.

66. The compound or salt of any one of claims 1-64, wherein q is 1.

67. The compound or salt of any one of claims 1-64, wherein q is 2.

68. The compound or salt of any one of claims 1-67, wherein r is 0.

69. The compound or salt of any one of claims 1-67, wherein r is 1.

71. The compound of any one of claims 1-70, wherein o is 0.

72. The compound of any one of claims 1-70 wherein o is 1.

73. The compound of any one of claims 1-70, wherein o is 2.

74. The compound of any one of claims 1-70, wherein at least one R6is Br, Cl, F, or CN.

75. The compound or salt of claim 74, wherein at least one R6is F.

76. The compound or salt of any one of claims 1-70, wherein at least one R6is CH3, CH2F, CHF2, or CF3.

77. The compound or salt of any one of claims 1-70, wherein at least one R6is OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2.

78. The compound or salt of any one of claims 1-70, wherein at least one R6is oxo or =CH2.

79. The compound or salt of any one of claims 1-70, wherein at least one R6is cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl; wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

80. The compound or salt of claim 79, wherein at least one R6is cyclopropyl.

81. The compound or salt of any one of claims 1-70, wherein at least one R6is spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl, wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

82. The compound or salt of any one of clams 1-70, wherein two vicinal R6, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, or fused-cyclopentyl;wherein each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

83. The compound or salt of any one of claims 79-82, wherein each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

84. The compound or salt of any one of claims 1-70, wherein two non-neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge.

85. The compound or salt of claim 84, wherein two non-neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2-CH=CH— or —CH2OCH2—.

86. The compound or salt of any one of claims 1-70, wherein at least one R6is Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, or cyclopropyl, or two vicinal R6, together with the atoms to which they are attached, form fused- cyclopropyl, fused-cyclobutyl, or fused-cyclopentyl, or two non-neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2-CH=CH— or —CH2OCH2—; wherein each of the foregoing cycloalkyl groups is unsubstituted or substituted with 1-4 substituents, and each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

87. The compound or salt of any one of claims 1-70, wherein o is 0; or o is 1 and R6is H, CH3, or cyclopropyl.. 8 The compound or salt of claim 88, wherein91. The compound or salt of any one of claims 1-90, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl.

92. The compound or salt of claim 91, wherein Y’ is cyclopropyl or cyclobutyl.

93. The compound or salt of any one of claims 1-90, wherein Y’ is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, dioxolanyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, or thiomorpholinyl.

94. The compound or salt of claim 93, wherein Y’ is oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, or morpholinyl.

95. The compound or salt of claim 94, wherein Y’ is tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl.

96. The compound or salt of any one of claims 1-90, wherein Y’ is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl.

97. The compound or salt of claim 96, wherein Y’ is dihydrofuranyl or dihydropyranyl.

98. The compound or salt of any one of claims 1-90, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, dioxolanyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl.

99. The compound or salt of claim 98, wherein Y’ is oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, dihydrofuranyl or dihydropyranyl.

100. The compound or salt of claim 99, wherein Y’ is tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dihydrofuranyl or dihydropyranyl.

101. The compound or salt of any one of claims 1-100, wherein p is 0.

102. The compound or salt of any one of claims 1-100, wherein p is 1.

103. The compound or salt of any one of claims 1-100, wherein p is 2.

104. The compound or salt of any one of claims 1-100, wherein p is 3.

105. The compound or salt of any one of claims 1-100, wherein p is 4.

106. The compound or salt of any one of claims 1-100, wherein p is 5.

107. The compound or salt of any one of claim 102-106, wherein at least one R7is F, Cl, Br, CN, or CH2CN.

108. The compound or salt of claim 107, wherein at least one R7is F or CH2CN.

109. The compound or salt of any one of claims 102-106, wherein at least one R7is CH3, CH2CH3, CH2F, CHF2, or CF3.

110. The compound or salt of claim any one of claims 102-106, wherein at least one R7is OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, or CH2CH2OCH3.

111. The compound or salt of claim 110, wherein at least one R7is OH or CH2OCH3.

112. The compound or salt of any one of claims 102-106, wherein at least one R7is C(=O)OCH3.

113. The compound or salt of any one of claims 102-106, wherein at least one R7is oxo or =CH2.

114. The compound or salt of claim 102-106, wherein at least one R7is C0-4alkylene- cyclopropyl, C0-4alkylene-cyclobutyl, C0-4alkylene-cyclopentyl, C0-4alkylene-oxetanyl, C0-4alkylene- pyrrolidinyl, C0-4alkylene-phenyl, or C0-4alkylene-oxadiazolyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

115. The compound or salt of claim 114, wherein at least one R7is cyclopropyl.

116. The compound or salt of any one of claims 102-106, wherein at least one R7is spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, or spiro-tetrahydropyranyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

117. The compound or salt of any one of claims 103-106, wherein two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, fused-oxetanyl, fused-tetrahydrofuranyl, or fused-tetrahydropyranyl, wherein each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

118. The compound or salt of claim 117, wherein two vicinal R7, together with the atoms to which they are attached, form fused-tetrahydrofuranyl.

119. The compound or salt of any one of claims 103-106, wherein two vicinal R7, together with the atoms to which they are attached, form fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, fused-pyridazinyl, or fused-pyrazinyl; wherein each of the foregoing isunsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

120. The compound or salt of claim 119, wherein two vicinal R7, together with the atoms to which they are attached, form fused-pyrazolyl, fused-pyridyl, fused-pyridazinyl, or fused- pyrimidinyl; wherein each of the foregoing is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

121. The compound or salt of any one of claims 114-120, wherein each substituent independently is F, Cl, Br, CN, oxo, or CH3.

122. The compound or salt of any one of claims 1-100, wherein each R7independently is F, Cl, Br, CN, CH2CN, CH3, CH2CH3, CH2F, CHF2, CF3, OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, CH2CH2OCH3, C(=O)OCH3, oxo, =CH2, cyclopropyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro- oxetanyl, spiro-tetrahydrofuranyl, spiro-tetrahydropyranyl; or two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, fused-oxetanyl, fused- tetrahydrofuranyl, fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, fused-pyridazinyl, fused-pyrazinyl, fused-pyrimidinyl; wherein each of the pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl is unsubstituted or substituted with CH3.

123. The compound or salt of claim 122, wherein Y’ is substituted with F, CH2CN, CH3,on of any of the foregoing.

124. The compound or salt of any one of claims 1-90, wherein, ,129. The compound or salt of any one of claims 1-128, wherein Formula (I) exhibits a stereochemical configuration of Formula (or a pharmaceutically acceptable salt thereof.

130. The compound or salt of claim 1, wherein the compound of Formula (I) has a structure of Formula (II):pharmaceutically acceptable salt thereof, wherein:o is 0 or 1; R5is CHF2or CF3; and R6is C1-3alkyl or C3-7cycloalkyl.

131. The compound or salt of claim 130, wherein the compound of Formula (II) has a Formula (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt of any of the foregoing:

132. The compound or salt of claim 130 or 131, wherein is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1 or 2 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, halo, or CN.

135. The compound or salt of any one of claims 130-134, wherein Y’ is, ,136. The compound of claim 1, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt thereof.

137. The compound of claim 136, wherein the compound is a compound listed in Table A’, or a pharmaceutically acceptable salt thereof.

138. The compound of claim 136, wherein the compound is a compound listed in Table B, or a pharmaceutically acceptable salt thereof.

139. The compound of claim 138, wherein the compound is a compound listed in Table B’, or a pharmaceutically acceptable salt thereof.

140. A pharmaceutical composition comprising the compound or salt of any one of claims 1-139 and a pharmaceutically acceptable excipient.

141. A method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of claims 1-139, or the composition of claim 140.

142. The method of claim 141, wherein one or more cancer cells express KRAS G12C mutant protein.

143. The method of claim 141 or 142, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, a solid tumor, or any combination of the foregoing.

144. The method of claim 143, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

145. The method according to any one of claims 141-144, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of the compound, salt, or pharmaceutical composition.

146. The method according to any one of claims 141-145, further comprising simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ATR inhibitor, Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK2 inhibitor, CDK4 / 6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MAT2A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PARP inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, PRMT5 inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agents.

147. The compound or salt of any one of claims 1-139, or the composition of claim 140 for use as a medicament.

148. The compound or salt of any one of claims 1-139, or the composition of claim 140 for use in treating cancer.

149. The compound or salt of any one of claims 1-139 or the pharmaceutical composition of claim 140 for use in treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

150. The compound or salt of claim 148 or 149, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, or a solid tumor.

151. The compound or salt of claim 150, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

152. Use of a compound or salt of any one of claims 1-139 or the pharmaceutical composition of claim 140 for the manufacture of a medicament for the treatment of cancer.

153. Use of a compound or salt of any one of claims 1-139 or the pharmaceutical composition of claim 140 in the preparation of a medicament for treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

154. The use of claim 152 or 153, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, melanoma, a solid tumor, or any combination of the foregoing.

155. The use of claim 154, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

156. A compound listed in Table INT-A, INT-B, INT-D, INT-E, or INT, a protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing.

157. A method of preparing the compound or salt of any one of claims 1-139, comprising admixing a compound of Formula (nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, with a compound of Formula (Int-E):nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; halo2is F, Cl, Br, or I; is C2-6alkylene, C3-6alkenylene, heteroalkylene having 2-6 total atoms and 1-3 heteroatoms independently selected from N, O, and S, or heteroalkenylene having 3- 6 total atoms and 1 or 2 heteroatoms independently selected from N, O, and S; wherein is unsubstituted or substituted with 1-4 substituents, and each substituent independently is C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, halo, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C3-5cycloalkyl, C4-5cycloalkenyl, heterocycloalkyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4 or 5 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, phenyl, oxo, =CH2, spiro-C3-5cycloalkyl, spiro-C4-5cycloalkenyl, spiro-heterocycloalkyl having 3- 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal substituents, together with the atoms to which they are attached, form fused-C3-5cycloalkyl, fused-C4-5cycloalkenyl, fused-heterocycloalkyl having 3-5 total ring atoms and 1 or 2heteroatoms independently selected from N, O and S or fused-heterocycloalkenyl having 4 or 5 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; A is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; each of W1and W2independently is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C2-3alkenyl, C-C2-3alkynyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy, wherein each of the alkenyl and alkynyl is unsubstituted or substituted with 1-3 substituents and each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; Y’ is C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; each R3independently i3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, C1-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, or spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; R5is halo, C1-3haloalkyl, C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3thioalkyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, wherein each of the foregoing C1-6alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl independently is unsubstituted or substituted with 1-3 substituents, and each substituent independently is C1-3haloalkyl, C0-6alkylene-OH, C0-6alkylene-C1-3alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, heterocycloalkenyl having 4- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or phenyl; each R6independently is halo, CN, C1-3alkyl, C2-3alkenyl, C1-3haloalkyl, C0-3alkylene-OH, C0-3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, C1-4alkylene-N(RN1)2, oxo, =CH2, C3-7cycloalkyl, C4-7cycloalkenyl, heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C3-7cycloalkyl, spiro-C4-7cycloalkenyl, spiro-heterocycloalkyl having 4- 7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, or spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R6, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-C4-7cycloalkenyl, fused- heterocycloalkyl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O, and S; or two non- neighboring R6join together to form a C1-3alkylene bridge, a C2-3alkenylene bridge, a C1-3ether bridge, or a C1-3thioether bridge; wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl of each of the foregoing is unsubstituted or substituted with 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN; each R7independently is halo, C0-3alkylene-CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, oxo, =CH2, C0-4alkylene- C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; C0-4alkylene-C6-10aryl, C0-4alkylene-heteroaryl having 4-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; or two vicinal R7together with the atoms to which they are attached form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms independently selected from N, O and S, fused-C6-10aryl, or fused-heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of each of the foregoing is unsubstituted or substituted with 1-3 or more substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

Images