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 (II):, and pharmaceutically acceptable salts thereof, wherein the substituents are as described.

Description

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 Nos. 63 / 464,102, filed on May 4, 2023, and 63 / 632,098, filed April 10, 2024, each of which is hereby incorporated by reference in its entirety for all purposes, as if fully set forth herein. 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, pancreatic 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 (II):, or 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; 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; X is N or C-R5a; 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 1or 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; R5ais H, CN, halo, C1-3alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or C3-5cycloalkyl; R5bis 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, heterocycloalkenyl having 5- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or R5aand R5b, together with the atoms to which they are attached, form C3-7cycloalkyl; 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, heterocycloalkenylhaving 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0006] Yet another aspect of the disclosure provides a compound listed in Table A, Table B, Table C, or Table D, or a pharmaceutically acceptable salt of any of the foregoing.

[0007] Another aspect of the disclosure provides a pharmaceutical composition comprising a compound disclosed herein (such as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, or Table D, or a pharmaceutically acceptable salt of any of the foregoing), and a pharmaceutically acceptable excipient.

[0008] 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 as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, or Table D, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition described herein.

[0009] Still another aspect of the disclosure provides a compound described herein (such as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, or Table D, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition described herein, for use as a medicament.

[0010] Another aspect of the disclosure provides a compound disclosed herein (such as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, or Table D, 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 as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, or Table D, 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.

[0011] Still another aspect of the disclosure provides a compound of Formula (B):( ), or a nitrogen-protected analog, or a pharmaceutically acceptable salt of any of the foregoing, wherein: o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5;each R6s 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0012] Yet another aspect of the disclosure provides a method of preparing the compound or salt of the disclosure (such as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, orTable D, or a pharmaceutically acceptable salt of any of the foregoing), comprising admixing a compound of Formula (B): ) with a compound: , undercarbon-nitrogen bond-forming conditions to form:wherein PG is a protecting group

[0013] Still another aspect of the disclosure provides a method of preparing the compound or salt of the disclosure (such as a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, Table B, Table C, or Table D, or a pharmaceutically acceptable salt of any of the foregoing), comprising converting a compound listed in Table E, Table F, Table G, a compound selected from selected from the group consisting of 3-001.1, 3-001.2, 3-002.1, 3-002.2, 3-003.1, 3-003.2, 3-020.1, 3-020.2, 3-021.1, 3-021.2, 3-046.1, 3.046.2, 3-050.1, 3-050.2, 3-051.1, 3-051.2, 3-051.3, 3-051.4, 3-051.5, 3-052.1, 3-052.2, 3- 052.3, 3-052.4, 3-052.5, 3-053.1, 3-053.2, 3-053.3, 3-053.4, 3-053.5, 3-054-1, 3-054-2, 3-055.1, 3- 055.2, 3-055.3, 3-055.4, 3-055.5, 3-057.1, 3-057.2, 3-057.3, 3-058.1, 3-058.2-1, 3-058.2.2, 3-058.3, 3- 059.1, 3-060.1, 3-060.2, 3-060.3, 3-060.4, 3-060.5, 3-060.6, 3-060.7, 3-060.8, 3-060.9, 3-061.1, 3- 061.2, 3-061.3, 3-061.4, 3-061.5, 3-062.1-1, 3-062.1-2, 3-062.1-1, 3-062.2, 3-063.1, 3-063.2, 3-065.1, 3-065.2, 3-065.3, 3-065.4, 3-065.5, 3-067-1, 3-067-2, 3-069.1, 3-069.2, 3-073.1, 3-073.2, 3-073.3, 3- 073.4, 3-073.5, 3-074.1, 3-074.2, 3-074.3, 3-074.4, 3-075.1, 3-075.2, 3-075.3, 3-076.1, and 3-076.2, a protected analog of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, into a compound of the disclosure.

[0014] 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

[0015] 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 FORMULA (II)

[0016] Provided herein are compounds of Formula (II):, or 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; 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 substituentsand each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; X is N or C-R5a; 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; R5ais H, CN, halo, C1-3alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or C3-5cycloalkyl; R5bis 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, heterocycloalkenyl having 5- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or R5aand R5b, together with the atoms to which they are attached, form C3-7cycloalkyl; 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 substituentindependently 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; andeach RN1independently is H or C1-4alkyl.

[0017] In some cases, the compound of Formula (II) is a free base. In some cases, the compound of Formula (II) is a pharmaceutically acceptable salt.

[0018] 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, ormorpholinyl. 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 c1a 1b 2ases, R is H. In some cases, R and R together with the carbon atoms to which they are attached from. In some cases,, or. In some cases,isor. In some cases,isor. In some cases,is.

[0019] In some cases, m is 0, andis. In 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, is deuterated. In somecases,s fully deuterated and has a structure:. In 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 one R3isor, and each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or C3-5cycloalkyl. In some cases, m is 1 and R3isor. In some cases, each of RA1and RA2independently is H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl. In some cases,, or. In some cases,isor. In some cases, is or . In some3cases, at least one R isor . In some cases, at least on3e R is, or. In some cases, at least one R3is 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, CH2CH3, CF3, CHF2, CH2F,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, 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,, , , , , or. In some cases,is, , , or. In some cases,isorIn some cases,is. In some cases,is

[0020] 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,is, ,, or. In some cases,is, or. In some cases,is, or. In some cases,isor. In some cases,is, ,or.

[0021] In some cases, W1is N. In some cases, W1is CH. In some cases, W1is C-halo or C-CN. In some cases, W1is C-F, C-Cl, or C-Br. In some cases, W1is C-F, C-Cl, or C-CN. In some cases, W1is C-C1-3alkyl or C-C1-3haloalkyl. In some cases, W1is C-CH3, C-CH2CH3, C-CH2CH2CH3, C- CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, W1is C-CH3,C-CH2CH3, C-CH2F, C-CHF2, or C-CF3. In some cases, W1is C-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 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 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, 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, W2is N. In some cases, W2is CH. In some cases, W2is C-halo or C-CN. In some cases, W2is C-F, C-Cl, 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 some cases, X is N. In some cases, W1is CH and X is N. In some cases, W2is N and X is N. In some cases, W1is CH, W2is N, and X is N. In some cases, X is C-R5a. In some cases, W1is CH and X is C- R5a. In some cases, W2is N and X is C-R5a. In some cases, W1is CH, W2is N, and X is C-R5a. In some cases, W1is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; W2is N; and X is N or C-R5a. In some cases, R5ais H. In some cases, R5ais CN. In some cases, R5ais Br, Cl, or F. In some cases, R5ais C1-3alkyl or C1-3haloalkyl. In some cases, R5ais CH3, CH2CH3, CF3, CHF2, or CH2F. In some cases, R5ais CH3. In some cases, R5ais C2-6alkenyl or C2-6alkynyl. In some cases, R5ais C2-3alkenyl or C2-3alkynyl. In some cases, R5ais, , or. In some cases, R5ais or . In some cases, R5ais C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy. In some cases, R5ais OH, CH2OH, OCH3, or CH2OCH3. In some cases, R5ais C3-5cycloalkyl. In some cases, R5ais OH, CH2OH, OCH3, CH2OCH3, or. In some cases, R5ais5a. In some cases, R is H, CN, Br, Cl, F, CH3, CH2CH3, CF3, CHF2, CH2F,, OH, CH2OH, OCH3, CH2OCH3, or. In some cases, R5ais H, CN, or CH3. In some cases, R5ais CN or CH3. In some cases, X is N, C-CH3, or C-CN. In some cases, W1is CH; W2is N; and X is N, C-CH3, or C-CN.

[0022] In some cases, R5bis halo. In some cases, R5bis Br, Cl, or F. In some cases, R5bis C1-3haloalkyl. In some cases, R5bis CF3, CF2H, CFH2, or CF2CH3. In some cases, R5bis CF3or CF2H. In some cases, R5bis CF3. In some cases, R5bis CF2H. In some cases, R5bis CHF2. In some cases, R5bis C1-3alkoxy or C1-3thioalkyl. In some cases, R5bis OCH3, OCH2CH3, SCH3, or SCH2CH3. In some cases, R5bis OCH3or SCH3. In some cases, R5bis 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 isor, 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, R5bis 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 is substituted 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, R5bis CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,, or . In some cases,5bR is 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 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, R5bis cyclopropyl, cyclobutyl, cyclopentenyl, oxetanyl, or tetrahydrofuranyl. In some cases, R5bis CH3, CF3, CF2H, CFH2, CH2CH3, CH2CH2CH3, CH(CH3)2,, or. In some cases, R5bis Br, Cl, F, OCH3, SCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,, or. In some cases,is, X is N, C-CH3, or C-CN; and Rbis CF3or CF2H. In some cases,is. In some cases,is,, or. In some cases,is, , , , ,, or. In some cases,is, Insome cases,is, orIn some cases,is, or

[0023] 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 and r is 1. In some cases,is, , , or. In some cases,is. In some cases,is. In some cases,isIn some cases,is. In some cases, the compound of Formula (II) has a structure of Formula (IIA):Formula (IIB):), Formula (IIC): (IIC). In some cases, the compound is a compound of Formula(IIA), or a pharmaceutically acceptable salt thereof. In some cases, the compound is a compound of Formula (IIA), wherein W1is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; W2is N; and X is N or C-R5a, or a pharmaceutically acceptable salt thereof. In some cases, the compound is a compound of Formula (IIB), or a pharmaceutically acceptable salt thereof. In some cases, the compound is a compound of Formula (IIC), or a pharmaceutically acceptable salt thereof.

[0024] 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 (e.g., ). In some cases, two non-neighboring R6join together to form a C2alkylene bridge (e.g., ). In some cases, two non-neighboring R6join together to form a C3alkylene bridge (e.g., ). In some cases, two non-neighboring R6jointogether to form a C2alkenylene bridge (e.g.,). In some cases, two non-neighboring R6join together to form a C3alkenylene bridge (e.g.,). In some cases, two non-neighboring R6join together to form a C1-3ether bridge (e.g.,or). In some cases, two non- neighboring R6join together to form a C1-3thioether bridge (e.g.,or). In some cases, two non-neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2-CH=CH— or —CH2OCH2—. In some cases, 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. In some cases, o is 0; or o is 1 and R6is H, CH3, or cyclopropyl. In some cases, o is 0; or o is 1 and R6is CH3. In some cases,is, or . In some cases,is, or .In some cases,is, or. In some cases,, or . In some cases, is orIn some cases, is. In some cases,is

[0025] 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, cyclobutyl, cyclopentyl, or cyclopentenyl. 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 oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, or tetrahydropyranyl. In some cases, Y’ is tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl. In some cases, Y’ is tetrahydrofuranyl or tetrahydropyranyl. 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 dihydropyrrolyl, dihydrofuranyl or dihydropyranyl. 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, Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, dihydropyrrolyl, 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 R7is CH3, CH2CH3, CH2F, CHF2, or CF3. In some cases, at least one R7is CH3, CH2F, or CHF2. In some cases, at least one R7is 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, at least 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, spiro-tetrahydrofuranyl, or spiro-tetrahydropyranyl, 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. Insome 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, fused-pyridazinyl, or fused-pyrimidinyl; 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 is unsubstituted 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 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 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, CH3, CH2F, CHF2, OH, CH2OCH3, oxo,, or; or a combination of any of the foregoing. In some cases, Y’ is substituted with F, CH2CN, CH3, CH2F, CHF2, OH, CH2OCH3, oxo,, or; or a combination of any of the foregoing. In some cases,isor. In some cases,, or. In some cases,is, or. In some cases,, or. In some cases,is, or. In some cases,or. In some cases,is, or.

[0026] In some cases,is; is; is,. In some cases,, , , , o . In some cases,is,In some cases,, , , , , . In some cases, ,

[0027] In some cases,of Formula (II) isor. In some cases,exhibits the following stereochemical configuration:. In some cases,. In some cases,exhibits the following stereochemical configuration:6. In some cases, R is CH3.

[0028] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds.COMPOUNDS OF FORMULA (I)

[0029] Further provided herein are compounds of Formula (I):(), and 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; A is N, CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; W is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene- C1-4alkoxy; X is N or C-R5a; Y’ is cycloalkyl having 3 to 7 total ring atoms, cycloalkenyl having 4 to 7 total ring atoms, heterocycloalkyl having 3 to 7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5 to 7 total ring atoms and 1, 2, or 3 heteroatoms 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 selected from N, O, and S, or R1band R2together with the carbon atoms to which they are attached from agroup;each R3independently is C1-3alkyl, C1-3haloalkyl,, C0-3alkyleneCN, C0-3alkyleneOH, or C0-3alkylene-C1-3alkoxy; two geminal R3form an oxo group; two geminal R3together with the atom to which they are attached form a spiro-cycloalkyl ring having 3-7 total ring atoms or a spiro-heterocycloalkyl ring having 3-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; or two adjacent R3together with the atoms to which they are attached form a fused cycloalkyl ring having 3-7 total ring atoms; each R4independently is C1-3alkyl, C1-3haloalkyl, C0-3alkyleneCN, C1-3alkyleneOH, or C1-3alkylene-C1-3alkoxy; two geminal R3form an oxo group; or two geminal R4together with the atom to which they are attached form a spiro-cycloalkyl ring having 3-7 total ring atoms or a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; R5ais H, CN, halo, C1-3alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or cycloalkyl having 3-5 total ring atoms; R5bis C1-4alkyl, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, halo, C1-3alkoxy, C1-3thioalkoxy, cycloalkyl having 3-7 total ring atoms, cycloalkenyl having 5-7 total ring atoms, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, wherein each of the alkyl, alkenyl, and alkynyl groups independently is unsubstituted or substituted with 1 or more substituents, or R5aand R5btogether with the atoms to which they are attached form a cycloalkyl ring having 3-7 total ring atoms; each R6independently is halo, CN, C1-3alkyl, C1-3haloalkyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, deuterated C0-3alkylene-C1-3alkoxy, or C1-4alkylene-N(RN1)2; two geminal R6form an oxo group; two geminal R6together with the atom to which they are attached from a spiro-cycloalkyl ring having 3-7 total ring atoms or a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; or two adjacent R6together with the atoms to which they are attached form a fused cycloalkyl ring having 3-7 total ring atoms; wherein the cycloalkyl or heterocycloalkyl ring of any of the foregoing is unsubstituted or substituted with 1 or more substituents; or two non-adjacent R6join together to form a C1-3alkylene bridge or a C1-3ether bridge; each R7independently is halo, CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, C0-4alkylene-cycloalkyl having 3-7 total ringatoms, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S, C0-4alkylene-aryl having 6-10 total ring atoms, C0-4alkylene-heteroaryl having 5-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S; two geminal R7form CH2or an oxo group; two geminal R7together with the atom to which they are attached from a spiro-cycloalkyl ring having 3-7 total ring atoms or a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S; or two adjacent R7together with the atoms to which they are attached form a fused cycloalkyl ring having 3-7 total ring atoms, a fused heterocycloalkyl ring having 3-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O and S, a fused aryl ring having 6 total ring atoms, or a fused heteroaryl ring having 5-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring of any of the foregoing is unsubstituted or substituted with 1 or more substituents; each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or cycloalkyl having 3-5 total ring atoms; and each RN1independently is H or C1-4alkyl.

[0030] 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.

[0031] 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, each of R1a, R1b, and R2independently is H. In some cases, each of R1a, R1b, and R2independently is D. In some cases, at least one of R1a, R1b, and R2is halo (e.g., Br, Cl, or F). 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, andR2is 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 the heterocycloalkyl group contains 3-6 total ring atoms and 1 or 2 heteroatoms selected from N, O, and S. In some cases, the heterocycloalkyl is aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxathiolidinyl, isoxthiodinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, diazinyl, or morpholinyl. In some cases, the heterocycloalkyl 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, R1band R2together with the carbon atoms to which they are attached fromIn some cases, R1ais H. In some cases, R1band R2together with the carbon atoms to which they are attached from. In some cases,. In some cases,In some cases,

[0032] In some cases, m is 0, and. In 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,is deuterated. In some cases,is fully deuterated. In some cases,. In 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, 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 one R3is, and each of RA1and RA2independently is H, C1-3alkyl, C1-3haloalkyl, or cycloalkyl having 3-5 total ring atoms. In some cases, m is 1 and R3isA1 A2. In some cases, each of R and R independently is H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl. In some cases,. In some cases,, or. In some cases,. In some cases, at least one R3is. In some cases, at least one R3is, , , , o . In some cases, at least one R3is C0-3alkyleneCN. In some cases, at least one R3is CN, CH2CN, or CH2CH2CN. In some cases, atleast 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, two geminal R3form an oxo group (=O). In some cases, two geminal R3together with the atom to which they are attached form a spiro- cycloalkyl ring having 3-7 total ring atoms or a spiro-heterocycloalkyl ring having 3-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. In some cases, the spiro-cycloalkyl ring is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, the spiro-heterocycloalkyl ring is spiro-azetidinyl, spiro-oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, two geminal R3together with the atom to which they are attached form spiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl, spiro-azetidinyl, spiro-oxetanyl, spiro-pyrrolidinyl, spiro-imidazolidinyl, spiro-pyrazolidinyl, or spiro-tetrahydrofuranyl. In some cases, two adjacent R3, together with the atoms to which they are attached, form a fused cycloalkyl ring having 3-7 total ring atoms. In some cases, two adjacent R3, together with the atoms to which they are attached, form a fused-cyclopropyl ring, a fused-cyclobutyl ring, a fused-cyclopentyl ring, or a fused-cyclohexyl ring. In some cases, two adjacent R3, together with the atoms to which they are attached, form a fused-cyclopropyl ring or a fused-cyclobutyl ring. In some cases, each R3independently is CH3, CH2CH3, CF3, CHF2, CH2F,, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3; two geminal R3form an oxo group (=O); two geminal R3together with the atom to which they are attached form spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro- tetrahydrofuranyl group; or two adjacent R3together with the atoms to which they are attached form a fused cyclopropyl ring or a fused cyclobutyl ring. In some cases, m is 1 and R3is CH3, CF3, CHF2, CH2F, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl. In some cases,. In some cases,. In some cases,

[0033] 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-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 or C-C1-3haloalkyl. 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 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, 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, 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, OCH3, CH2OCH3, or CH2CH2OCH3. In some cases, two geminal R4form an oxo group (=O). In some cases, two geminal R4together with the atom to which they are attached from a spiro- cycloalkyl ring having 3-7 total ring atoms. In some cases, the spiro-cycloalkyl ring is spiro- cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, the spiro-cycloalkyl ring is spiro- cyclopropyl or spiro-cyclobutyl. In some cases, two geminal R4together with the atom to which they are attached form a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. In some cases, the spiro-heterocycloalkyl ring is spiro-oxetanyl or spiro- tetrahydrofuranyl. In some cases, the spiro-heterocycloalkyl ring is spiro-oxetanyl. In some cases, two geminal R4together with the atom to which they are attached form 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, OCH3, CH2OCH3, CH2CH2OCH3; or two geminal R4together with the atom to which they are attached from an oxo group, spiro- cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl. In some cases, each R4independently is CH3, CH2CH3, CH2CH2CH3, CH2F, CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, or two geminal R4together with the atom to which they are attached from spiro-cyclopropyl. In some cases, is. In some cases,, orIn some cases,isIn some cases,In some cases,In some cases,. In some cases,is o .

[0034] In some cases, W is CH. In some cases, W is C-halo (e.g., C-F, C-Cl, or C-Br) or C-CN. In some cases, W is C-F, C-Cl, or C-CN. In some cases, W is C-C1-3alkyl or C-C1-3haloalkyl. In some cases, W is C-CH3, C-CH2CH3, C-CH2CH2CH3, C-CH(CH3)2, C-CF3, C-CHF2, or C-CH2F. In some cases, W is C-CH3or C-CH2CH3. In some cases, W is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy. In some cases, W is C-OH, C-CH2OH, C-CH2CH2OH, C-OCH3, C-CH2OCH3, or C- CH2CH2OCH3. In some cases, W is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, W is 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, W is CH, C-F, C-Cl, C-CN, C-CH3, C-CH2CH3, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3. In some cases, X is N. In some cases, W is CH and X is N. In some cases, X is C-R5a. In some cases, W is CH and X is C-R5a. In some cases, R5ais H. In some cases, R5ais CN. In some cases, R5ais Br, Cl, or F. In some cases, R5ais C1-3alkyl or C1-3haloalkyl. In some cases, R5ais CH3, CH2CH3, CF3, CHF2, or CH2F. In some cases, R5ais CH3. In some cases, R5ais C2-6alkenyl or C2-6alkynyl. In some cases, R5ais C2-3alkenyl or C2-3alkynyl. In some cases, R5aisor . I5an some cases, R is. In some cases, R5ais C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy. In some cases, R5ais OH, CH2OH, OCH3, or CH2OCH3. In some cases, R5ais cycloalkyl having 3-5 total ring atoms. In some cases, R5ais . In5asome cases, R is H, CN, Br, Cl, F, CH3, CH2CH3, CF3,CHF2, CH2F,OH, CH2OH, OCH3, CH2OCH3, or. In some cases, R5ais H, CN, or CH3.

[0035] In some cases, R5bis C1-3haloalkyl. In some cases, R5bis CF3, CF2H, CFH2, or CF2CH3. In some cases, R5bis CF3. In some cases, R5bis CF2H. In some cases, R5bis CHF2. In some cases, R5bis halo. In some cases, R5bis Br, Cl, or F. In some cases, R5bis C1-3alkoxy or C1-3thioalkoxy. In some cases, R5bis OCH3, OCH2CH3, SCH3, or SCH2CH3. In some cases, R5bis OCH3, or SCH3. In some cases, R5bis C1-6alkyl (e.g., CH3, CH2CH3, CH2CH2CH3, CH(CH3)2), C2-4alkenyl (e.g., CH=CH2, CH=CHCH3), or C2-4alkynyl (e.g., CCH, CCH3), each of which is either unsubstituted or substituted with 1 or more substituents. In some cases, the C1-6alkyl, C2-4alkenyl, or C2-4alkynyl is unsubstituted. In some cases, R5bis CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some cases, the C1-6alkyl, C2-4alkenyl, or C2-4alkynyl is substituted with 1, 2, or 3 substituents. In some cases, each of the 1, 2, or 3 substituents independently is C1-3haloalkyl, C0-6alkylene(OH), C0-6alkylene-C1-3alkoxy, cycloalkyl having 3-7 total ring atoms, cycloalkenyl having 5-7 total ring atoms, heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, heterocycloalkenyl having 3-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, or phenyl. In some cases, each of the 1, 2, or 3 substituents independently is CH3, CF3, CF2H, CFH2, OH, OCH3, OCF3, CH2OH, CH2OCH3, cyclopropyl, cyclobutyl, or phenyl. In some cases, R5bis cycloalkyl having 3-7 total ring atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), cycloalkenyl having 5-7 total ring atoms (e.g., cyclopentenyl or cyclohexenyl), heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, or heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, wherein each of the foregoing is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-3alkyl, C1-3haloalkyl, C0-6alkylene(OH), or C0-6alkylene-C1-3alkoxy. In some cases, the heterocycloalkyl group 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. In some cases, the heterocycloalkenyl group is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl. In some cases, R5bis cyclopropyl, cyclobutyl, cyclopentenyl, oxetanyl, or tetrahydrofuranyl. In some cases, R5bis CF3, CF2H, CFH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,. In some cases5a 5b, R and R , together withthe atoms to which they are attached, form a fused cycloalkyl ring having 3-7 total ring atoms. In some cases, R5aand R5b, together with the atoms to which they are attached, form fused-cyclopropyl, fused-cyclobutyl, or fused-cyclopentyl. In some cases, W is CH; X is N; and R5bis CF3or CF2H. In some cases,. In some cases,, , . In some cases, W is CH; X is C-R5a; R5ais CN, Br, Cl, F, or CH3; and R5bis CF3, CF2H, or CFH2. In some cases,, , , . In some cases,, . In some cases,

[0036] In some cases, o is 0. In some cases, o is 1. In some cases, o 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 is H. 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, two geminal R6form an oxo group (=O). In some cases, two geminal R6together with the atom to which they are attached form a spiro- cycloalkyl ring having 3-7 total ring atoms or a spiro-heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. In some cases, two geminal R6together with the atom to which they are attached form spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro- tetrahydrofuranyl. In some cases, two geminal R6together with the atom to which they are attached form spiro-cyclopropyl. In some cases, two adjacent R6, together with the atoms to which they are attached, form a fused cycloalkyl ring having 3-7 total ring atoms. In some cases, two adjacent R6, together with the atoms to which they are attached, form a fused-cyclopropyl ring, a fused-cyclobutyl ring, or a fused-cyclopentyl ring. In some cases, the spiro-cycloalkyl ring, the spiro-heterocycloalkyl ring, and the fused-cycloalkyl ring is unsubstituted. In some cases, the spiro-cycloalkyl ring, the spiro- heterocycloalkyl ring, and the fused-cycloalkyl ring is substituted with 1 or more substituents. In some cases, the spiro-cycloalkyl ring, the spiro-heterocycloalkyl ring, and the fused-cycloalkyl ring is substituted with 1, 2, 3, or 4 substituents. In some cases, the spiro-cycloalkyl ring, the spiro- heterocycloalkyl ring, and the fused-cycloalkyl ring is substituted with 1 or 2 substituents. In some cases, the one or more (e.g., 1, 2, or 3 substituents or 1 or 2 substituents) are each independently halo, OH, C1-3alkoxy (e.g., OCH3, OCH2CH3), or CN. In some cases, two non-adjacent R6join together to form a C1-3alkylene bridge or a C1-3ether bridge. In some cases, two non-adjacent R6join together to form a C1alkylene bridge (e.g., ). In some cases, two non-adjacent R6join together to form aC2alkylene bridge (e.g.,). In some cases, two non-adjacent R6join together to form a C3alkylene bridge (e.g.,). In some cases, two non-adjacent R6join together to form a C1- 3ether bridge (e.g.,). In some cases,. In some cases,

[0037] In some cases, Y’ is cycloalkyl having 3 to 7 total ring atoms or cycloalkenyl having 4 to 7 total ring atoms. In some cases, Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl. In some cases, Y’ is heterocycloalkyl having 3 to 7 total ring atoms and 1, 2, 3 heteroatoms selected from N, O, and S; or heterocycloalkenyl having 5 to 7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. In some cases, Y’ is aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, oxazolidinyl, oxathiolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothipyranyl, dithianyl, morpholinyl, thiomorpholinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl. In some cases, Y’ is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, dioxanyl, morpholinyl, dihydropyrrolyl, dihydrofuranyl, dihydroisoxazolyl, or dihydropyranyl. In some cases, Y’ is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, or morpholinyl. In some cases, Y’ is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dihydrofuranyl, dihydroisoxazolyl, or dihydropyranyl. In some cases, Y’ is pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or dihydrofuranyl. In some cases, Y’ is pyrrolidinyl. In some cases, Y’ is tetrahydrofuranyl. In some cases, Y’ is tetrahydropyranyl. In some cases, Y’ is morpholinyl. In some cases, Y’ is dihydrofuranyl. In some cases, Y’ is dihydroisoxazolyl. In some cases, Y’ is 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, or CN. In some cases, at least one R7is F, Cl, Br, orCN. In some cases, at least one R7is C1-3alkyl, C1-3haloalkyl, or C2-3alkenyl. In some cases, at least one R7is CH3, CH2CH3, CH2CH2CH3, CH(CH3), CH2F, CHF2, or CF3. In some cases, at least one R7is CH3, CH2CH3, CH2F, CHF2, or CF3. In some cases, at least one R7is CH3. In some cases, at least one R7is CF3, CHF2, or CH2F. In some cases, at least one R7is 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 C(=O)OC1-3alkyl. In some cases, at least one R7is C(=O)OCH3. In some cases, at least one R7is C0-4alkylene-cycloalkyl having 3-7 total ring atoms. In some cases, the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl. In some cases, at least one R7is cyclopropyl, cyclobutyl, cyclopentyl, CH2-cyclopropyl, CH2-cyclobutyl, or CH2-cyclopentyl. In some cases, at least one R7is C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. In some cases, the heterocycloalkyl 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. In some cases, the heterocycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl. In some cases, at least one R7is oxetanyl, pyrrolidinyl, or CH2-pyrrolidinyl. In some cases, at least one R7is C0-4alkylene-aryl having 6-10 total ring atoms. In some cases, the aryl is phenyl. In some cases, at least one R7is phenyl or CH2-phenyl. In some cases, at least one R7is C0-4alkylene-heteroaryl having 5-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some cases, the heteroaryl is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or pyridyl. In some cases, the heteroaryl is thiophenyl. In some cases, the heteroaryl is pyrazolyl. In some cases, the heteroaryl is thiazolyl. In some cases, the heteroaryl is pyridyl. 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. In some cases, two geminal R7form CH2or an oxo group (=O). In some cases, two geminal R7together with the atom to which they are attached form a spiro-cycloalkyl ring having 3-7 total ring atoms or a spiro- heterocycloalkyl ring having 4-7 total ring atoms and 1 or 2 heteroatoms selected from N, O and S. In some cases, the spiro-cycloalkyl group is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-cyclopentyl. In some cases, the spiro-heterocycloalkyl is spiro-azetidinyl, spiro-oxetanyl, spiro-thietanyl, or spiro- tetrahydrofuranyl. In some cases, two geminal R7together with the atom to which they are attached from spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl. In some cases, two adjacent R7together with the atoms to which they are attached form a fused cycloalkyl ring having 3-7 total ring atoms or a fused heterocycloalkyl ring having 3-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. In some cases, the fused cycloalkyl ring is fused-cyclopropyl,fused-cyclobutyl, or fused-cyclopentyl. In some cases, two adjacent R7together with the atoms to which they are attached from fused-cyclopropyl or fused-cyclobutyl. In some cases, the fused heterocycloalkyl ring is fused-azetidinyl, fused-oxetanyl, fused-thietanyl, fused-pyrrolidinyl, fused- imidazolidinyl, fused-pyrazolidinyl, fused-tetrahydrofuranyl, or fused-tetrahydrothiophenyl. In some cases, two adjacent R7together with the atoms to which they are attached from the fused-oxetanyl. In some cases, two adjacent R7together with the atoms to which they are attached form a fused aryl ring having 6 total ring atoms. In some cases, two adjacent R7together with the atoms to which they are attached from a fused heteroaryl ring having 5-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. In some cases, the fused heteroaryl is fused-pyrrolyl, fused-furanyl, fused- thiophenyl, fused-pyrazolyl, fused-imidazolyl, fused-thiazolyl, fused-isothiazolyl, fused-oxazolyl, fused-isoxazolyl, fused-triazolyl, fused- thiadiazolyl, fused-oxadiazolyl, fused-pyridyl, fused- pyridazinyl, fused-pyrimidinyl, fused-pyrazinyl, or fused-triazinyl. In some cases, the heteroaryl is fused-pyrrolyl, fused-furanyl, fused-thiophenyl, fused-pyrazolyl, fused-imidazolyl, fused-thiazolyl, fused-isothiazolyl, fused-oxazolyl, fused-isoxazolyl, or fused-pyridyl. In some cases, the fused- heteroaryl is fused-thiazolyl, fused-pyrazolyl, fused-pyridyl, or fused-pyridazinyl. In some cases, the fused-heteroaryl is fused-thiazolyl. In some cases, the fused-heteroaryl is fused-pyrazolyl. In some cases, the fused-heteroaryl is fused-pyridyl. In some cases, the fused-heteroaryl is fused-pyridazinyl. In some cases, two adjacent R7together with the atoms to which they are attached form fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl, or fused-pyridazinyl. In some cases, any of the foregoing cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings is unsubstituted. In some cases, any of the forgoing cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings is substituted with 1 or more substituents. In some cases, any of the forgoing cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings is substituted with 1, 2, or 3 substituents. In some cases, each substituent independently is halo, CN, OH, C1-3alkoxy, oxo, C1-3alkyl, or C1-3haloalkyl. In some cases, each substituent independently is halo, CN, oxo, or C1-3alkyl. wherein each substituent independently is F, Cl, Br, CN, oxo, or CH3.

[0038] In some cases,. In some cases,. In some cases,. In some cases,orIn some cases,. In some cases,In some cases,, or. In some cases,is. In some cases,. In some cases,. In some cases,, or. In some cases,is . In some cases, In some cases, is. In some cases,,. In some cases, , or

[0039] In some cases,of Formula (I) isis; and. In some cases,of Formula (I) is, , , , ,, , , . In some cases,of Formula (I) is

[0040] In some cases, the compound of Formula (I) has a structure of 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.( ) ( )

[0041] In some cases,of Formula (I) isor. In some cases,exhibits the following stereochemical configuration:. In some cases,. In some cases,exhibits the following stereochemical configuration: . In some cases, R6is CH3.

[0042] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds.CONTEMPLATED COMPOUNDS OF FORMULAE (I) AND (II)

[0043] Specific contemplated compounds of Formulae (I) and (II) include, but are not limited to, compounds in the following Tables, and pharmaceutically acceptable salts thereof.

[0044] In some cases, the compound of Formula (I) or Formula (II) is a compound as listed in Table A, or a pharmaceutically acceptable salt thereof: Table A

[0045] In some cases, the compound of Formula (I) or Formula (II) is selected from the list of compounds in Table A.

[0046] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is C3-7cycloalkyl or C4-7cycloalkenyl. Examples of such compounds include, but are not limited to:, andand pharmaceutically acceptable salts thereof.

[0047] In some cases, the disclosure provides compounds of Formula (I) or (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is oxetanyl or dioxanyl. Examples of such compounds include, but are not limited to:, and pharmaceutically acceptable salts thereof.

[0048] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and p is 0. Examples of such compounds include, but are not limited to:, and, and pharmaceutically acceptable salts of any of the foregoing.

[0049] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and each p is CH2, oxo, halo, CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, C0-4alkylene-C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S, C0-4alkylene-C6-10aryl, C0-4alkylene- heteroaryl having 5-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. Examples of such compounds include, but are not limited to:and pharmaceutically acceptable salts of any of the foregoing.

[0050] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and two vicinal R7together with the atoms to which they are attached form optionally substituted fused-C3-7cycloalkyl or optionally substituted fused-C6-10aryl. In some cases, the cycloalkyl and aryl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl. Examples of such compounds include, but are not limited to:, , andand pharmaceutically acceptable salts thereof.

[0051] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and two vicinal R7together with the atoms to which they are attached form optionally substituted fused- heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, the heteroaryl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl. Examples of such compounds include, but are not limited to:pharmaceutically acceptable salts thereof.

[0052] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydropyranyl and p is 0. An example of such a compound is , and pharmaceuticallyacceptable salts thereof.

[0053] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydropyranyl and two vicinal R7, together with the atoms to which they are attached, form a fused thiazolyl ring, a fused thiophenyl ring, or a fused pyridyl ring. Examples of such compounds include, but are not limited to:, and and pharmaceutically acceptable salts thereof.

[0054] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is morpholinyl; p is 2 or 3; and two vicinal R7together with the atoms to which they are attached form optionally substituted fused- pyrazolyl. In some cases, the pyrazolyl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl. Examples of such compounds include, but are not limited to:and pharmaceutically acceptable salts thereof.

[0055] In some cases, the disclosure provides compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof, wherein Y’ is thiazolidinyl; p is 2, 3, or 4; and at least one R7is oxo. Examples of such compounds include, but are not limited to:, andand pharmaceutically acceptable salts of the foregoing.

[0056] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, wherein Y’ is optionally substituted pyrrolidinyl (e.g., such as with an oxo group to form pyrrolidinone). Examples of such compounds include, but are not limited to:and and pharmaceutically acceptable salts of the foregoing.

[0057] In some cases, the disclosure provides compounds of Formula (I) or Formula (II), and pharmaceutically acceptable salts thereof, wherein Y’ is optionally substituted dihyropyrrolyl, isoxazolyl, dihydrofuranyl or dihydropyranyl. Examples of such compounds include, but are not limited to:, and pharmaceutically acceptable salts of the foregoing.

[0058] In some cases, the compound of Formula (I) or Formula (II) is a compound listed in Table B, or a pharmaceutically acceptable salt thereof. Table B

[0059] In some cases, the disclosure provides a compound listed in Table C, below. If the stereochemistry of a structure or a portion of a structure in Table C is not explicitly shown (e.g., such as with dashed or bold lines), then the structure or portion of structure is either achiral or interpreted as being any of the possible stereoisomers of the structure or portion of the structure. In cases in which the stereochemistry of the structure or portion of the structure in Table C is explicitly shown, a single stereoisomer of the structure or portion of a structure is represented, with the understanding that the stereochemistry of the structure or portion of the structure shown in Table C has been arbitrarily assigned. Table C

[0060] In some cases, the compound of Formula (I) or Formula (II) is selected from the list of compounds in Table C. In some cases, the compound of Formulae (I) and (II) is compound selected from compound 3-001 through compound 3-104 (as shown in Table C).

[0061] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is C3-7cycloalkyl or C4-7cycloalkenyl. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-022, 3- 023, 3-036, 3-037, 3-038, 3-063, 3-073, 3-093, or 3-099, or a pharmaceutically acceptable salt of any of the foregoing.

[0062] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is oxetanyl or dioxanyl. In some cases, the compound of Formulae (I) or (II) is Compound 3-019 or 3-024, or a pharmaceutically acceptable salt of any of the foregoing.

[0063] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and p is 0. In some cases, the compound of Formulae (I) or (II) is Compound 3-025, 3-026, 3-039, 3-062-1, 3- 062-2, or 3-071, or a pharmaceutically acceptable salt of any of the foregoing.

[0064] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and each p is CH2, oxo, halo, CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, C(=O)OC1-3alkyl, C0-4alkylene-C3-7cycloalkyl, C0-4alkylene-heterocycloalkyl having 3-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S, C0-4alkylene-C6-10aryl, C0-4alkylene- heteroaryl having 5-7 total ring atoms and 1, 2, or 3 heteroatoms selected from N, O, and S. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-029, 3-030, 3-031, 3-044, 3-045, 3-058, or 3-074, or a pharmaceutically acceptable salt of any of the foregoing.

[0065] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and two vicinal R7together with the atoms to which they are attached form optionally substituted fused-C3-7cycloalkyl or optionally substituted fused-C6-10aryl. In some cases, the cycloalkyl and aryl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-015, 3- 018, 3-027, 3-028, 3-040, 3-041, or 3-042, or a pharmaceutically acceptable salt of any of the foregoing.

[0066] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydrofuranyl and two vicinal R7together with the atoms to which they are attached form optionally substituted fused- heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S. In some cases, the heteroaryl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-001, 3-043, 3-046, 3-047, 3-049, 3-079, 3-080, 3-086, 3-092, 3-095, 3-096, 3-102, 3-103, or 3-104, or a pharmaceutically acceptable salt of any of the foregoing.

[0067] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydropyranyl and p is 0.In some cases, the compound of Formula (I) or Formula (II) is Compound 3-035, or a pharmaceutically acceptable salt thereof.

[0068] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is tetrahydropyranyl and two vicinal R7, together with the atoms to which they are attached, form a fused thiazolyl ring, a fused thiophenyl ring, or a fused pyridyl ring. In some cases, the compound of Formula (I) or Formula (II) is 3-002, 3-064, 3-069, 3-085, 3-091, 3-092, or 3-094, or a pharmaceutically acceptable salt of any of the foregoing.

[0069] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is morpholinyl; p is 2 or 3; and two vicinal R7, together with the atoms to which they are attached, form optionally substituted fused- pyrazolyl. In some cases, the pyrazolyl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-076, 3-077, 3-078, 3-081, 3-082, 3-083, 3-084, 3-087-1, 3-087-2, 3- 088-1, 3-088-2, 3-089-1, 3-089-2, 3-090-1, 3-090-2, 3-097, 3-098, 3-100, or 3-101, or a pharmaceutically acceptable salt of any of the foregoing.

[0070] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is thiazolidinyl; p is 2, 3 or 4; and at least one R7is oxo. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-032, 3-033, or 3-034, or a pharmaceutically acceptable salt of any of the foregoing.

[0071] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is pyrrolidinyl. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-004, 3-013, 3-014, 3-016, 3-020, 3-048, or 3-075, or a pharmaceutically acceptable salt of any of the foregoing

[0072] In some cases, the disclosure provides a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts of any of the foregoing, wherein Y’ is optionally substituted dihyropyrrolyl, isoxazolyl, dihydrofuranyl or dihydropyranyl. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-003, 3-005, 3-006, 3-007, 3-008, 3-009, 3-010, 3-011, 3- 012, 3-017, 3-021, 3-050, 3-051, 3-052, 3-053, 3-054-1, 3-054-2, 3-055, 3-057, 3-059, 3-060, 3-061, 3-065, 3-066, 3-067-1, 3-067-2, 3-068-1, 3-068-2, 3-070, or 3-072, or a pharmaceutically acceptable salt of any of the foregoing.

[0073] In some cases, the compound of Formula (I) or Formula (II) is selected from the group consisting of Compound 3-001, 3-002, 3-003, 3-004, 3-005, 3-008, 3-009, 3-010, 3-011, 3-014, 3-015, 3-016, 3-017, 3-046, 3-049, 3-050, 3-051, 3-052, 3-053, 3-054-1, 3-054-2, 3-057, 3-058, 3-059, 3- 060, 3-061, 3-065, 3-066, 3-067-1, 3-067-2, 3-069, 3-074, 3-075, 3-076, 3-077, 3-078, 3-079, 3-080,3-081, 3-082, 3-083, 3-084, 3-085, 3-087-1, 3-087-2, 3-088-1, 3-088-2, 3-089-1, 3-089-2, 3-090-1, 3- 091-1, or 3-091-2, or a pharmaceutically acceptable salt of any of the foregoing.

[0074] In some cases, the compound of Formula (I) or Formula (II) is selected from the group consisting of Compound 3-001, 3-002, 3-004, 3-005, 3-008, 3-014, 3-046, 3-051, 3-052, 3-053, 3- 054-1, 3-054-2, 3-057, 3-059, 3-060, 3-061, 3-074, 3-076, 3-077, 3-078, 3-079, 3-080, 3-081, 3-082, 3-083, 3-084, 3-085, 3-087-1, 3-087-2, 3-088-1, 3-088-2, 3-089-1, 3-089-2, 3-090-1, or 3-091-1, or a pharmaceutically acceptable salt of any of the foregoing.

[0075] In some cases, the compound of Formula (I) or Formula (II) is selected from the group consisting of Compound 3-004, 3-005, 3-051, 3-052, 3-053, 3-054-1, 3-059, 3-061, 3-076, 3-077, 3- 078, 3-079, 3-081, 3-082, 3-083, 3-084, 3-085, 3-087-1, 3-087-2, 3-088-1, 3-088-2, 3-089-1, 3-089-2, 3-090-1, or 3-091-1, or a pharmaceutically acceptable salt of any of the foregoing.

[0076] In some cases, the compound of Formula (I) or Formula (II) is selected from the group consisting of Compound 3-076, 3-077, 3-078, 3-079, 3-081, 3-082, 3-083, 3-085, 3-087-1, 3-087-2, 3- 088-2, 3-089-1, 3-089-2, or 3-091-1, or a pharmaceutically acceptable salt of any of the foregoing.

[0077] In some cases, the compound of Formula (I) or Formula (II) is selected from the group consisting of Compound 3-092, 3-093, 3-094, 3-095, 3-096, 3-097, 3-098, 3-099, 3-100, 3-101, 3-102, 3-103, or 3-104, or a pharmaceutically acceptable salt of any of the foregoing.

[0078] In some cases, the compound of Formula (I) or Formula (II)is selected from the list of compounds in Table D, below. If the stereochemistry of a structure or a portion of a structure in Table D is not explicitly shown (e.g., such as with dashed or bold lines), then the structure or portion of structure is either achiral or interpreted as being any of the possible stereoisomers of the structure or portion of the structure. In cases in which the stereochemistry of the structure or portion of the structure in Table D is explicitly shown, a single stereoisomer of the structure or portion of a structure is represented, with the understanding that the stereochemistry of the structure or portion of the structure shown in Table D has been arbitrarily assigned. Table D

[0079] In some cases, the compound of Formula (I) or Formula (II) is Compound 3-001, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-002, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-052, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-076, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3- 077, or a pharmaceutically acceptable salt thereof. In some cases, the compound Formula (I) or Formula (II) is Compound 3-078, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-079, or a pharmaceutically acceptable saltthereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-085, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-089-1, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-090-1, or a pharmaceutically acceptable salt thereof. In some cases, the compound of Formula (I) or Formula (II) is Compound 3-091-1, or a pharmaceutically acceptable salt thereof.

[0080] Unless otherwise indicated, the depictions of partial structures do not represent any particular orientation of the partial structure. For example, compounds of Formulae (I) and (II) havinginclude compounds of Formula (I) depicted as:; and compounds of Formula (II) depicted as:Stereoisomers

[0081] 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.

[0082] 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 it. 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. For example,representsSimilarly, for example, the chemical name (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. In certain instances, 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.

[0083] The term “stereoisomer” or “stereoisomerically pure” compound, as used herein, 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 ofthe 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.

[0084] 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 (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, 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

[0085] 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. For example,represents. Similarly, 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 instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Isotopically-Labeled Compounds

[0086] Further, the scope of the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, such as the compounds of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), and Formula (IIC), 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 Formula (I) and Formula (II), for example, 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 using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed. BIOLOGICAL ACTIVITY

[0087] In some cases, the compounds disclosed herein (e.g., compounds of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), compounds listed in Table A, compounds listed in Table B, compounds listed in Table C, and compounds listed in Table D, and pharmaceutically acceptable salts of any 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, or less 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 the “SECTION 3: Biochemical and Cellular Assays.”. In some cases, the compounds and salts disclosed herein have an IC50value of less than 1 μM. In some cases, the compounds and salts disclosed herein have an IC50value of less than 0.5 μM. In some cases, the compounds and salts disclosed herein have an IC50value of less than 0.3 μM. In some cases, the compounds and salts disclosed herein have an IC50value of less than 0.1 μM. Also provided herein are compounds of the disclosure having an IC50of less than 5 μM in the 2h coupled exchange assay. Further provided herein are compounds of the disclosure having an IC50of less than 3 μM in the 2h coupled exchange assay. Still further provided herein are compounds of the disclosure having an IC50of less than 1 μM in the2h coupled exchange assay. 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.

[0088] 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

[0089] 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 (e.g., compounds of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), compounds listed in Table A, compounds listed in Table B, compounds listed in Table C, and compounds listed in Table D, and pharmaceutically acceptable salts 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.

[0090] 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.

[0091] 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.

[0092] 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 here is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein for use as a medicament. METHODS OF USE

[0093] The compound 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-stream effector 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.

[0094] 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.

[0095] 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).

[0096] 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)).

[0097] 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 and Cellular Assays), are useful for treatment of subjects having a cancer, including, but not limited to the cancers listed in the table below.

[0098] Another aspect of the disclosure provides a compound disclosed herein (e.g., a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, or a compound listed in Table D, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutically acceptable salt thereof, 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.

[0099] 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.

[0100] A further 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 (e.g., a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, or a compound listed in Table D, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition described 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 thatwas 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.

[0101] 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

[0102] 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 (e.g., a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, or a compound listed in Table D, 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.

[0103] 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 isadministered 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.

[0104] 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[5,4132zetidinelin-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.

[0105] 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.

[0106] 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 themethods 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.

[0107] 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.

[0108] 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).

[0109] 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.

[0110] 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 familyinhibitor 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Glutaminase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a glutaminase inhibitor 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.

[0115] 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).

[0116] 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-136zetidindin-2- ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one).

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 t137zetidinrib, 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.

[0121] 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.

[0122] 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.

[0123] 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).

[0124] 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).

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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

[0130] 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.

[0131] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification or claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

[0132] 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.

[0133] This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0134] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001 , the entire contents of which are hereby incorporated by reference.

[0135] As described herein, compounds described herein may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species described herein. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrases “substituted or unsubstituted” and "unsubstituted or substituted." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a givenstructure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. When the term "optionally substituted" precedes a list, said term refers to all of the subsequent substitutable groups in that list. If a substituent radical or structure is not identified or defined as "optionally substituted", the substituent radical or structure is unsubstituted. In some cases, the each substituent independently is deuterium, halo, oxo, carboxyl, CHO, NH2, amido, NO2, ester, thioester, C0-3alkyleneCN, C1-6alkyl, C1-6haloalkyl, C0-6alkylene-OH, C0-3alkylene-C1-4alkoxy, C0-3alkylene-C1-4haloalkoxy, C0-3alkylene-C1-4thioalkoxy, C0-6alkylene-C1-3alkoxy, deuterated C0-6alkylene-OC1-3alkoxy, amido, C0-2alkylene-cycloalkyl having 3-7 total ring atoms, C0-2alkylene-cycloalkenyl having 5-7 total ring atoms, C0-2alkylene- heterocycloalkyl having 3-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, C0-2alkylene-heterocycloalkenyl having 3-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S, and C0-2alkylene-C6-10aryl.

[0136] The compounds disclosed herein can be “deuterated,” wherein one or more hydrogen atoms bonded to a carbon atom (C-H) have been replaced with deuterium to form a carbon-deuterium bond (C-D). In some cases, the compounds disclosed herein are deuterated with one deuterium atom. In some cases, the compounds disclosed herein are deuterated with two or three deuterium atoms. In some cases, the compounds disclosed herein are deuterated with four or more deuterium atoms. In some cases, each hydrogen atom of a C-H bond in a particular functional group has been replaced with deuterium. In some cases, the entire compound is deuterated.

[0137] Selection of substituents and combinations of substituents contemplated herein are those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, specifically, their recovery, purification, and use for one or more of the purposes disclosed herein. In some cases, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

[0138] The term “halo” or “halogen” refers to fluoro (–F), chloro (-Cl), bromo (-Br), and / or iodo (- I).

[0139] The term “oxo” refers to a substituent oxygen atom connected to another atom by a double bond (e.g., =O). In some cases, a single R group can be an oxo group (e.g., wherein R7is halo, C1-3alkyl, or oxo). In some cases, two geminal R groups, together with the atom to which they are attached, can form an oxo group. Accordingly, the phrase “wherein two geminal R groups togetherwith the atom to which they are attached form an oxo group” results in a =O group attached to a single atom.

[0140] The term “carbonyl” refers to a divalent C=O radical, such as

[0141] The term “heteroatom,” unless otherwise stated herein, refers to an atom that is not carbon or hydrogen. Examples of heteroatoms include oxygen, sulfur, nitrogen, and phosphorus.

[0142] 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 the indicated number of carbon atoms. For example, a C1ether bridge () on a cyclohexylene ring cyclohexylene ring can be depicted as, for example,

[0143] 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 the bridge has the indicated number of carbon atoms. For example, a C1thioether bridge () on a cyclohexylene ring cyclohexylene ring can be depicted as, for example,.

[0144] The term “geminal” refers to two atoms, functional groups, and / or substituents attached to the same atom. Geminal R groups on a chain and ring can be depicted as:and , respectively.

[0145] The terms “vicinal” and “adjacent” are interchangeable and refer to two atoms, functional groups, and / or substituents that attached to atoms on a chain or a ring that are next to each other.Vicinal or adjacent R groups on a chain and a ring can be depicted asandrespectively.

[0146] The terms “non-neighboring” or “non-adjacent” are interchangeable and refer to two atoms, functional groups, and / or substituents that are attached to atoms on a chain or a ring that are not next to each other (e.g., not adjacent and not geminal). Non-neighboring or non-adjacent R groups on a chain and a ring can be depicted asrespectively.

[0147] The term “alkyl” refers to a saturated straight chain or saturated branched chain hydrocarbon containing the indicated number of carbon atoms. For example, C3alkyl means the alkyl group has 3 carbon atoms. C1-6alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), as well as encompassing all subgroups (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). Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0148] The term “alkylene” refers to a bivalent saturated aliphatic radical containing the indicated number of carbon atoms. For example, C3alkylene means the alkylene group has 3 carbon atoms. C1-6alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), as well as encompassing all subgroups (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). When the number of carbon atoms in an alkylene group is indicated as “C0,” then the alkylene group is not present and the recited substituent is 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)—).

[0149] 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,. A C2alkylene bridge ( ) on a cyclohexylene ring can be depicted as, for example, AC3alkylene bridge (on a cyclohexylene ring can be depicted as, for example,.

[0150] The term “haloalkyl” refers to an alkyl group, as previously defined herein, 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). The term further includes perfluorinated alkyl groups, such as CF3and CF2CF3. For example, the term “C1-4haloalkyl” refers to a C1-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of C1-4haloalkyl include, but are not limited to, 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.

[0151] The term “alkenyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and one or more double bonds. For example, C3alkenyl means the alkenyl group has 3 carbon atoms. C2-6alkenyl refers to an alkenyl group having a number of carbon atoms encompassing the entire range (e.g., 2, 3, 4, 5, or 6 carbon atoms), as well as encompassing all subgroups (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). Nonlimiting 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.

[0152] The term “alkynyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and one or more triple bonds. For example, C3alkynyl means the alkynyl group has 3 carbon atoms. C2-6alkynyl refers to an alkynyl group having a number of carbon atoms encompassing the entire range (e.g., 2, 3, 4, 5, and 6 carbon atoms), as well as encompassing all subgroups (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). Nonlimiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, butynyl (e.g., 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.

[0153] The term “hydroxy” or “hydroxyl” refers to an alcohol group (—OH).

[0154] The term “alkoxy” or “alkoxyl” refers to an alkyl group having the indicated number of carbon atoms, as previously defined herein, attached to the molecule through an oxygen atom (e.g., (—O-alkyl). For example, a C3alkoxy group means the alkoxy group has 3 carbon atoms (e.g., OCH2CH2CH3). C1-6alkoxy refers to an alkoxy group having a number of carbon atoms encompassing the entire range (e.g., 2, 3, 4, 5, or 6 carbon atoms), as well as encompassing all subgroups (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). Nonlimiting examples of alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.

[0155] The terms “thioalkyl” and “thioalkoxy” are interchangeable and refer to an alkyl group, as previously defined herein, attached to the molecule through a sulfur atom (e.g., -S-alkyl). For example, a C3thioalkyl group or a C3thioalkoxy group means the thioalkyl or thioalkoxy group has 3 carbon atoms (e.g., SCH2CH2CH3). C1-6thioalkyl or C1-6thioalkoxy refers to a thioalkyl or thioalkoxy group having a number of carbon atoms encompassing the entire range (e.g., 2, 3, 4, 5, or 6 carbon atoms), as well as encompassing all subgroups (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). Nonlimiting examples of thioalkyl / thioalkoxy groups include thiomethoxy, thioethoxy, thiopropoxy, thio-iso-propoxy, and butoxy. Additional examples of thioalkyl / thioalkoxy groups include methylthiyl, ethylthiyl, n-propylthiyl, isopropylthiyl, n-butylthiyl, isobutylthiyl, sec- butylthiyl, and tert-butylthiyl.

[0156] The terms “haloalkoxy” and “haloalkoxyl” are interchangeable and refer to an alkoxyl group, as previously defined herein, 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). The term includes perfluorinated alkyl groups, such as OCF3and OCF2CF3. Representative examples of C1-4haloalkoxy include, but are not limited to, OCH2F, OCHF2, OCF3, OCHFCl, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, and OCH(CH2F)(CF3). Additional examples of C1-4haloalkoxy includes OCH2Cl, OCHCl2, OCF3, OCHFCl, OCH2CCl3, OCClHCCl3, OCCl2CCl3, OCH(CCl3)2, OCCl(CHCl2)2, OCH(CH2Cl)CCl3, and OCH2CF(CH3)2.

[0157] The term “carbocyclic” or “carbocycle” refers to a ring (saturated, unsaturated, or aromatic) that contains only carbon atoms in the ring. Nonlimiting examples of carbocyclyl rings include cyclopropyl, cyclobutyl, cyclopentyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, spiro[4.4]nonanyl, and naphthalenyl.

[0158] The term “cycloalkyl” refers to an aliphatic cyclic hydrocarbon group containing the indicated number of carbon atoms in its ring. For example, C5cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring. C3-7cycloalkyl refers to cycloalkyl group having a number of carbon atoms encompassing the entire range (e.g., 3, 4, 5, 6, and 7 carbon atoms in the ring), as well as encompassing all subgroups (e.g., 3-4, 3-5, 3-6, 3-7, 4-5, 4-6, 4-7, 5-6, 5-7, and 6-7 carbon atoms in the ring). The terms “Cx-ycycloalkyl” and “a cycloalkyl group having X-Y total ring atoms” are interchangeable. Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “spiro-cycloalkyl” refers to a cycloalkyl group as previously defined herein that is attached to the compound through one common atom. For example, a methylpiperidine ring that has a spiro-cyclopropyl group as a substituent can be depicted as:. The terms “fused cycloalkyl ring” or “fused-cycloalkyl” can be used interchangeably and refer to a cycloalkyl group, as previously defined herein, that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring that has a fused cyclopropyl group as a substituent can be depicted as:.

[0159] The term “cycloalkenyl” refers to a cyclic hydrocarbon group containing the indicated number of carbon atoms in its ring and one or more double bonds. For example, C5cycloalkenyl refers to a cycloalkenyl group that has 5 carbon atoms in the ring. C5-7cycloalkenyl refers to cycloalkenyl group having a number of carbon atoms encompassing the entire range (e.g., 5, 6, and 7 carbon atoms in the ring), as well as encompassing all subgroups (e.g., 5-6, 5-7, and 6-7 carbon atoms in the ring). The terms “Cx-ycycloalkenyl” and “a cycloalkenyl group having X-Y total ring atoms” are interchangeable. Nonlimiting examples of cycloalkyl groups include cyclopentenyl, and cyclohexenyl. The term “spiro-cycloalkenyl” refers to a cycloalkenyl group as previously defined herein that is attached to the compound through one common atom. For example, a methylpiperidine ring that has a spiro-cyclopentenyl group as a substituent can be depicted as:. The terms “fused cycloalkenyl ring” or “fused-cycloalkenyl” can be used interchangeably and refers to a cycloalkenyl group, as previously defined herein, that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring that has a fused cyclopentenyl group as a substituent can be depicted as:

[0160] The term “heterocycloalkyl” refers to a saturated ring comprising carbon atoms and 1 or more heteroatoms (e.g., N, O, and / or S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring). For example, a heterocycloalkyl group having 5 total atoms and 2 heteroatoms selected from N and S, refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N or S. As another example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S refers to a ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. Thus, heterocycloalkyl having 5-7 total ring atoms and 1-3 heteroatoms 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, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, azepanyl, diazepanyl, triazepanyl, oxazepanyl, azocanyl, diazocanyl, triazocanyl, oxazocanyl, thiazepanyl, and thiazocanyl. The term “spiro-heterocycloalkyl” refers to a heterocycloalkyl group as previously defined herein that is attached to the compound through one common atom. For example, a methylpiperidine ring that has a spiro-oxetanyl group as a substituent can be depicted as:. The term “fused- heterocycloalkyl” refers to a heterocycloalkyl group as previously defined herein that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring that has a fused-azetidinyl group as a substituent can be depicted as:.

[0161] The term “heterocycloalkenyl” is defined similarly to “heterocycloalkyl” except that the ring contains one or more carbon-carbon double bonds. For example, a heterocycloalkenyl group having 5 total atoms and 2 heteroatoms selected from N 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 or S. As another example, a heterocycloalkenyl group having 5-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S refers to a ring having at least one double bond and a totalnumber of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. Thus, heterocycloalkenyl having 5-7 total ring atoms and 1-3 heteroatoms selected from N, O, and S encompasses rings containing at least one double bone 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, dihydrothiophenyl, dihydroisoxazolyl, tetrahydropyridyl, dihydropyranyl, and dihydrothiopyranyl. The term “spiro-heterocycloalkenyl” refers to a heterocycloalkenyl group as previously defined herein that is attached to the compound through one common atom. For example, a methylpiperidine ring that has a spiro-dihydropyrrolyl group as a substituent can be depicted as:. The term “fused-heterocycloalkenyl” refers to a heterocycloalkenyl group as previously defined herein that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring that has a fused-dihydrofuranyl group as a substituent can be depicted as:

[0162] The term “aryl” refers to an aromatic, carbocylic ring having the indicated number of carbon ring atoms. For example, C6aryl refers to an aryl group that has 6 carbon atoms in the ring (e.g., phenyl), and C10aryl refers to an aryl group that has 10 carbon atoms in the ring (e.g., naphthyl). Aryl groups can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl or anthracenyl). The term “fused-aryl” refers to an aryl group as previously defined herein that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring that has a fused-phenyl group as a substituent can be depicted as:

[0163] The term “heteroaryl” refers to an 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). For example, a heteroaryl group having 5 total atoms and 2 heteroatomsselected from N and S, refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, wherein each heieroatom of the ring independently is N or S. As another example, a heteroaryl having 5-7 total ring atoms and 1 -3 heteroatoms 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), as well as encompassing all subgroups (e.g., .5-6 or 6-7 total ring atoms), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. Thus, heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms 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 I heieroatom, 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. Nonlmiiting examples of heteroaryl groups include but are not limited to furanyl. imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyi. pyrrolyl, thiadiazolyl, thiazolyl, thiophenyl, tetrazolyl, triazinyl, triazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyL benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofurany l, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridmyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quiazolinyl, thiadiazolopy rimidyl, and thienopyridyl. The term “ fused -heteroaryl” refers to a heteroaryl group as previously defined herein that shares two adjacent atoms (i.e., one covalent bond) with the compound to which it is attached. For example, a methylpiperidine ring that has a fused-thiazolyl group as a substituent can be depicted as:

[0164] The term “bicyclic ring” refers a functional group tliat comprises two joined rings. Unless otherwise indicated, the bicyclic ring may be spirocyclic, in which the two rings share a single atom (e.g., a quaternary carbon atom), fused, in which the two rings share two adjacent atoms (i.e, one covalent bond), or bridged, in which to rings share three or more atoms and contain a bridge having at least one atom.

[0165] The terms "protecting group” and "protective group" as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In some cases, a protecting group has one or more, or specifically all, of the following characteristics: (a) is added selectively to a functional group in good y ield to give a protected substrate that is (b) stable to reactions occurring at one or more of the other reactive sites; and (c) is selectively removable in good yield by reagents tliat do not attack the regenerated,deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. 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), wherein the entire contents of each are hereby incorporated by reference. The term "nitrogen protecting group", as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in "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), wherein the entire contents of each are hereby incorporated by reference.

[0166] The terms “a bond” and “absent” are used interchangeably to indicate that a specified functional group is not present.

[0167] The term “pharmaceutically acceptable” as used herein refers to a composition or a component of a composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0168] The term “pharmaceutically acceptable salt” as used herein refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as 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, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like. Additional examples of such salts can be found in Berge et al., J. Pharm. Sci.66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2ndRevised Edition (2011).

[0169] The term “pharmaceutically acceptable excipient” as used herein refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare apharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.

[0170] The term “subject” as used herein refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In some cases, the subject is human.

[0171] The term “therapeutically effective amount” as used herein refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, a system, or subject that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0172] The term “metastatic” refers to a cancer that has spread from the place where it first formed to another part of the body. The term non-metastatic refers to a cancer that has not spread from the place where it first formed to another part of the body.

[0173] The term “coupled exchange assay” or “2h coupled exchange assay” as used herein refers to the assay described SECTION 3: Biochemical and Cellular Assays. GENERAL SYNTHETIC PROCEDURES

[0174] 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 alternative synthetic 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.

[0175] Generally, the compounds of Formula (I) and Formula (II) can be synthesized according to the following schemes. Variables used in the following schemes are the variables as defined for Formula (I) and Formula (II), 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.

[0176] In general, the compounds of Formula (I) can be synthesized according to Scheme 1A: Scheme 1A

[0177] A nitrogen-protected piperazine linker portion of Formula (I):can be synthesized by reacting a desired nitrogen-protected 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. The resulting nitrogen-protected piperazine linker portion of Formula (I)can be coupled to a desired, halogenated pyrimidine or pyridine core: , by firstdeprotecting the nitrogen of the azetidine and then conducting a nucleophilic aromatic substitution reaction in the presence of an appropriate base to form a protected core-linker portion of Formula (I)

[0178] The spiro tail of Formula (I) (B) can be synthesized, for example,according to Scheme A or Scheme B. Scheme A.

[0179] In Scheme A, a desired, optionally substituted, N-protected, piperidin-4-one compound: and a desired Z-Y-Z’ compound can undergo a nucleophilic addition reaction to form, respectively, 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 (B):

[0180] In Scheme B, 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 form In a next step, can undergoiodine-mediated cyclization, reduction, and deprotection to form compound (B):(B). 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. Finally, the Michael acceptor can be installed on the compound by deprotecting the nitrogen atom of the piperazine ring in the presence of an acid, such as TFA, and reacting the deprotected piperazine ring with a desired halogenated α,β- unsaturated ketone, such as acryloyl chloride to form the compound of Formula (I).

[0181] As such, further provided herein is a method for preparing compounds of Formula (I), and pharmaceutically acceptable salts thereof, comprising admixing a compound of Formula (B):, with a protected core-linker portion of Formula (I):under carbon-nitrogen bond-forming conditions to form intermediates having a structure:, wherein the variables are as previously defined herein. In some cases, the carbon-nitrogen bond forming conditions comprise performing a nucleophilic aromatic substitution reaction in the presence of a base, such as a sterically hindered, nitrogen base (e.g., DIPEA). In some cases, the carbon-nitrogen bond forming conditions comprise a palladium-catalyzed amination reaction. In some cases, the method further comprises deprotecting the piperazine of intermediate:, and admixing the resulting compound withwherein the variables are as previously defined herein, to form Formula (I):, as previously described herein. In some cases, the piperazine is deprotected under acidic conditions. In some cases, the piperazine is deprotected in the presence of a strong acid, such as trifluoroacetic acid (TFA). In some cases, the method further comprises preparing compounds of Formula (B) by cyclizing a compound:to formand then deprotecting the cyclized compound to form:), as previously described herein. In some cases, the method further comprises preparingor by coupling with, as previouslydescribed herein, and then subjecting the resultingto a cyclization reaction. In some cases, the method further comprises preparingby couplingwith , as previously described herein, and then subjecting the resultingto a cyclization reaction. In some cases, Z is an alkyne and the coupling occurs via an alkynylation reaction. In some cases, Z is a halogen and Y is an aryl or heteroaryl group, and the reaction is a nucleophilic aromatic substitution reaction. In some cases, the method further comprises preparing protected linker portion of Formula (I):by deprotecting to form and coupling thedeprotected compound tovia a nucleophilic aromatic substitution reaction in the presence of an appropriate base. In some cases, the method further comprises preparing a nitrogen- protected linker portion of Formula (I): by admixing a desired nitrogen-protected 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.

[0182] Compounds of Formula (II) can be prepared similarly to the schemes and methods described above relating to compounds of Formula (I), as shown in Scheme 1B:

[0183] As such, further provided herein is a method for preparing compounds of Formula (II), and pharmaceutically acceptable salts thereof, comprising admixing a compound of Formula (B’):with a protected core-linker portion of Formula (II):under carbon-nitrogen bond-forming conditions to form intermediates having a structure:wherein the variables are as previously defined herein. Further provided herein is a method of preparing compounds of Formula (II) wherein q is 1 and r is 1 comprising admixing a compound of Formula (B):(B), with a protected core-linker portion of Formula (II):under carbon-nitrogen bond-forming conditions to form intermediates having a structure:, wherein the variables are as previously defined herein. In some cases, the carbon-nitrogen bond forming conditions comprise performing a nucleophilic aromatic substitution reaction in the presence of a base, such as a sterically hindered, nitrogen base (e.g., DIPEA). In some cases, the carbon-nitrogen bond forming conditionscomprise a palladium-catalyzed amination reaction. In some cases, the method further comprises deprotecting the piperazine of intermediate:, and admixing the resulting compound with, wherein the variables are as previously defined herein, to form Formula (II):(I), as previously described herein. In some cases, the piperazine is deprotected under acidic conditions. In some cases, the piperazine is deprotected in the presence of a strong acid, such as trifluoroacetic acid (TFA). In some cases, the method further comprises preparing compounds of Formula (B’) using the same methods as described for preparing compounds of Formula (B). In some cases, the method further comprises preparing protected linker portion ofFormula (II):by deprotectingto formand coupling the deprotected compound tovia a nucleophilic aromatic substitution reaction in the presence of an appropriate base. In some cases, the method further comprises preparing a nitrogen- protected linker portion of Formula (II):by admixing a desired nitrogen-protected 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.

[0184] 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.

[0185] 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

[0186] 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.

[0187] Accordingly, the disclosure further provides a compound of Formula (B):, a nitrogen-protected analog, or a pharmaceutically acceptable salt of any of the foregoing, wherein: o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; each R6s 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0188] In some cases, the compound of Formula (B) is a free base (e.g., the nitrogen atom of the piperidine is free:). In some cases, the compound of Formula (B) is a pharmaceutically acceptable salt (e.g., a TFA salt). In some cases, the compound of Formula (B) is protected, such as with a nitrogen protecting group (PG):(e.g., di-tert-butyl dicarbonyl or “BOC” group). In some cases, the compound of Formula (B) is selected from the compounds listed in Table E, below, a free base thereof, a nitrogen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing. Table E

[0189] In some cases, the compound of Formula (B) is selected from Intermediate B-1 to B-34, a free base thereof, a nitrogen-protection version thereof, or a pharmaceutically acceptable salt thereof.

[0190] The disclosure further provides piperazine linker intermediates having a structure:a nitrogen- and / or oxygen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the variables are as previously described herein. In some cases, the piperazine linker intermediate is a compound listed in Table F, below, a nitrogen- and / or oxygen- protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some cases, the nitrogen protecting groups is a BOC or Bn. Table F

[0191] In some cases, the piperazine linker intermediate is selected from compound D-1 to D-10-1, a nitrogen- and / or oxygen-protected analog thereof, a nitrogen- and / or oxygen-deprotected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0192] The disclosure further provides intermediates having a structure:, a nitrogen- and / or oxygen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the variables are as previously described herein. In some cases, the piperazine linker intermediate is a compound listed in Table G, below, a nitrogen- and / or oxygen-protected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing.Table G

[0193] In some cases, the intermediate is selected from compound E-1 to E-8-1, a nitrogen- and / or oxygen-protected analog thereof, a nitrogen- and / or oxygen-deprotected analog thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0194] The disclosure further provides intermediates 3-001.1, 3-001.2, 3-002.1, 3-002.2, 3-003.1, 3-003.2, 3-020.1, 3-020.2, 3-021.1, 3-021.2, 3-046.1, 3.046.2, 3-050.1, 3-050.2, 3-051.1, 3-051.2, 3- 051.3, 3-051.4, 3-051.5, 3-052.1, 3-052.2, 3-052.3, 3-052.4, 3-052.5, 3-053.1, 3-053.2, 3-053.3, 3- 053.4, 3-053.5, 3-054-1, 3-054-2, 3-055.1, 3-055.2, 3-055.3, 3-055.4, 3-055.5, 3-057.1, 3-057.2, 3- 057.3, 3-058.1, 3-058.2-1, 3-058.2.2, 3-058.3, 3-059.1, 3-060.1, 3-060.2, 3-060.3, 3-060.4, 3-060.5, 3- 060.6, 3-060.7, 3-060.8, 3-060.9, 3-061.1, 3-061.2, 3-061.3, 3-061.4, 3-061.5, 3-062.1-1, 3-062.1-2, 3-062.1-1, 3-062.2, 3-063.1, 3-063.2, 3-065.1, 3-065.2, 3-065.3, 3-065.4, 3-065.5, 3-067-1, 3-067-2, 3-069.1, 3-069.2, 3-073.1, 3-073.2, 3-073.3, 3-073.4, 3-073.5, 3-074.1, 3-074.2, 3-074.3, 3-074.4, 3- 075.1, 3-075.2, 3-075.3, 3-076.1, and 3-076.2, as depicted in SECTION 2: Synthesis of Example Compounds, and pharmaceutically acceptable salts thereof.

[0195] Another aspect of the disclosure is a process for preparing a compound or salt described herein (such a compound of Formula (I), Formula (IA), Formula (IB), Formula (II), Formula (IIA), Formula (IIB), Formula (IIC), a compound listed in Table A, a compound listed in Table B, a compound listed in Table C, or a compound listed in Table D, or a pharmaceutically acceptable salt of any of the foregoing), comprising converting an intermediate described herein, such as an intermediate of Formula (B), or an intermediate listed in Table E, F, G, an intermediate selected from the group consisting of 3-001.1, 3-001.2, 3-002.1, 3-002.2, 3-003.1, 3-003.2, 3-020.1, 3-020.2, 3-021.1, 3-021.2, 3-046.1, 3.046.2, 3-050.1, 3-050.2, 3-051.1, 3-051.2, 3-051.3, 3-051.4, 3-051.5, 3- 052.1, 3-052.2, 3-052.3, 3-052.4, 3-052.5, 3-053.1, 3-053.2, 3-053.3, 3-053.4, 3-053.5, 3-054-1, 3- 054-2, 3-055.1, 3-055.2, 3-055.3, 3-055.4, 3-055.5, 3-057.1, 3-057.2, 3-057.3, 3-058.1, 3-058.2-1, 3- 058.2.2, 3-058.3, 3-059.1, 3-060.1, 3-060.2, 3-060.3, 3-060.4, 3-060.5, 3-060.6, 3-060.7, 3-060.8, 3- 060.9, 3-061.1, 3-061.2, 3-061.3, 3-061.4, 3-061.5, 3-062.1-1, 3-062.1-2, 3-062.1-1, 3-062.2, 3-063.1, 3-063.2, 3-065.1, 3-065.2, 3-065.3, 3-065.4, 3-065.5, 3-067-1, 3-067-2, 3-069.1, 3-069.2, 3-073.1, 3- 073.2, 3-073.3, 3-073.4, 3-073.5, 3-074.1, 3-074.2, 3-074.3, 3-074.4, 3-075.1, 3-075.2, 3-075.3, 3- 076.1, and 3-076.2, a protected analog of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing into a compound disclosed herein. FURTHER EMBODIMENTS

[0196] Provided herein as Embodiment B1 is a compound of Formula (II):or a 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; 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 substituentsand each substituent independently is halo, C1-3haloalkyl, C0-3alkyleneOH, or C0-3alkyleneC1-4alkoxy; X is N or C-R5a; 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; R5ais H, CN, halo, C1-3alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or C3-5cycloalkyl; R5bis 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, heterocycloalkenyl having 5- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or R5aand R5b, together with the atoms to which they are attached, form C3-7cycloalkyl; 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 substituentindependently 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; andeach RN1independently is H or C1-4alkyl.

[0197] Provided herein as Embodiment B2 is the compound or salt of Embodiment B1, wherein at least one of R1a, R1b, and R2is H or D.

[0198] Provided herein as Embodiment B3 is the compound or salt of Embodiment B1 or B2, wherein each of R1a, R1b, and R2independently is H or D.

[0199] Provided herein as Embodiment B4 is the compound or salt of Embodiment B1 or B2, wherein at least 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, 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; wherein each RN1independently is H or CH3.

[0200] Provided herein as Embodiment B5 is the compound or salt of Embodiment B4, wherein at least 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.

[0201] Provided herein as Embodiment B6 is the compound or salt of Embodiment B1 or B2, wherein

[0202] Provided herein as Embodiment B7 is the compound or salt of Embodiment B6, wherein

[0203] Provided herein as Embodiment B8 is the compound or salt of Embodiment B7, wherein

[0204] Provided herein as Embodiment B9 is the compound or salt of any one of Embodiments B1-8, wherein m is 0 or 1.

[0205] Provided herein as Embodiment B10 is the compound or salt of any one of Embodiments B1-8, wherein m is 2, 3, or 4.

[0206] Provided herein as Embodiment B11 is the compound or salt of any one of Embodiments B1-10, wherein at least one R3is C1-3alkyl or C1-3haloalkyl.

[0207] Provided herein as Embodiment B12 is the compound or salt of Embodiment B11, wherein at least one R3is CH3, CH2CH3, CF3, CHF2, or CH2F.

[0208] Provided herein as Embodiment B13 is the compound or salt of any one of Embodiments B1-10, wherein at least one R3is, C0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C4-7cycloalkenyl, spiro- heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, fused-C4-7cycloalkenyl, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; wherein each of RA1and RA2independently is H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl.

[0209] Provided herein as Embodiment B14 is the compound or salt of Embodiment B13, wherein at least one R3isCN, CH2CN, OH, CH2OH, CH2CH2OH,OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro- tetrahydrofuranyl, or two vicinal R3, together with the atoms to which they are attached, form fused- cyclopropyl or fused-cyclobutyl.

[0210] Provided herein as Embodiment B15 is the compound or salt of any one of Embodiments B1-10, wherein each R3independently is CH3, CH2CH3, CF3, CHF2, CH2F,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.

[0211] Provided herein as Embodiment B16 is the compound or salt of any one of Embodiments B1-8, wherein m is 0; or m is 1 and R3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

[0212] Provided herein as Embodiment B17 is the compound or salt of Embodiment B16, wherein m is 0; or m is 1 and R3is CH3.

[0213] Provided herein as Embodiment B18 is the compound or salt of any one of Embodiments B1-8, wherein,

[0214] Provided herein as Embodiment B19 is the compound or salt of Embodiment B18, wherein

[0215] Provided herein as Embodiment B20 is the compound or salt of any one of Embodiments B1-19, wherein A is N.

[0216] Provided herein as Embodiment B21 is the compound or salt of any one of Embodiments B1-19, wherein A is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy.

[0217] Provided herein as Embodiment B22 is the compound or salt of Embodiment B21, 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.

[0218] Provided herein as Embodiment B23 is the compound or salt of any one of Embodiments B1-22, wherein n is 0 or 1.

[0219] Provided herein as Embodiment B24 is the compound or salt of any one of Embodiments B1-23, wherein at least one R4is C1-3alkyl or C1-3haloalkyl.

[0220] Provided herein as Embodiment B25 is the compound or salt of Embodiment B24, wherein at least one R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, or CF3.

[0221] Provided herein as Embodiment B26 is the compound or salt of any one of Embodiments B1-23, wherein at least one R4is 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.

[0222] Provided herein as Embodiment B27 is the compound or salt of Embodiment B26, wherein at least one R4is CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, oxo, spiro- cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

[0223] Provided herein as Embodiment B28 is the compound or salt of any one of Embodiments B1-23, 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.

[0224] Provided herein as Embodiment B29 is the compound or salt of Embodiment B28, wherein

[0225] Provided herein as Embodiment B30 is the compound or salt of Embodiment B29, wherein

[0226] Provided herein as Embodiment B31 is the compound or salt of any one of Embodiments B1-30, wherein W1is N, CH, 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), or C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0227] Provided herein as Embodiment B32 is the compound or salt of Embodiment B31, wherein W1is CH.

[0228] Provided herein as Embodiment B33 is the compound or salt of any one of Embodiments B1-32, wherein W2is N, CH, 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), or C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0229] Provided herein as Embodiment B34 is the compound or salt of Embodiment B33, wherein W2is N.

[0230] Provided herein as Embodiment B35 is the compound or salt of any one of Embodiments B1-30, wherein W1is CH and W2is N.

[0231] Provided herein as Embodiment B36 is the compound or salt of any one of Embodiments B1-35, wherein X is N.

[0232] Provided herein as Embodiment B37 is the compound or salt of any one of Embodiments B1-35, wherein X is C-R5aand R5ais H, CN, Br, Cl, F, CH3, CH2CH3, CF3, CHF2, CH2F,OH, CH2OH, OCH3, CH2OCH3, or.

[0233] Provided herein as Embodiment B38 is the compound or salt of Embodiment B37, wherein R5ais CN or CH3.

[0234] Provided herein as Embodiment B39 is the compound or salt of any one of Embodiments B1-35, wherein X is N, C-CH3, or C-CN.

[0235] Provided herein as Embodiment B40 is the compound or salt of any one of Embodiments B1-30, wherein W1is CH; W2is N; and X is N, C-CH3, or C-CN.

[0236] Provided herein as Embodiment B42 is the compound or salt of any one of Embodiments B1-40, wherein R5bis Br, Cl, F, CF3, CF2H, CFH2, CF2CH3, OCH3, SCH3CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,, or.

[0237] Provided herein as Embodiment B42 is the compound or salt of Embodiment B41, wherein R5bis CF3or CF2H.

[0238] Provided herein as Embodiment B43 is the compound or salt of any one of Embodiments B1-30, wherein , X is N, C-bCH3, or C-CN; and R is CF3or CF2H.

[0239] Provided herein as Embodiment B44 is the compound or salt of any one of Embodiments B1-30, wherein, , ,

[0240] Provided herein as Embodiment B45 is the compound or salt of Embodiment B44, wherein

[0241] Provided herein as Embodiment B46 is the compound or salt of any one of Embodiments B1-45, wherein q is 0.

[0242] Provided herein as Embodiment B47 is the compound or salt of any one of Embodiments B1-45, wherein q is 1.

[0243] Provided herein as Embodiment B48 is the compound or salt of any one of Embodiments B1-45, wherein q is 2.

[0244] Provided herein as Embodiment B49 is the compound or salt of any one of Embodiments B1-45, wherein r is 0.

[0245] Provided herein as Embodiment B50 is the compound or salt of any one of Embodiments B1-45, wherein r is 1.

[0246] Provided herein as Embodiment B51 is the compound or salt of any one of Embodiments B1-45, wherein

[0247] Provided herein as Embodiment B52 is the compound of any one of Embodiments B1-51, wherein o is 0, 1, or 2.

[0248] Provided herein as Embodiment B53 is the compound of any one of Embodiments B1-51, wherein o is 3 or 4.

[0249] Provided herein as Embodiment B54 is the compound of any one of Embodiments B1-53, wherein at least one R6is Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl; 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 cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro- tetrahydrofuranyl, fused-cyclopropyl, fused-cyclobutyl, and fused-cyclopentyl independently 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.

[0250] Provided herein as Embodiment B55 is the compound or salt of Embodiment B54, wherein each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

[0251] Provided herein as Embodiment B56 is the compound or salt of 54 or 55, wherein at least one R6is Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, 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.

[0252] Provided herein as Embodiment B57 is the compound or salt of any one of Embodiments B1-51, wherein o is 0; or o is 1 and R6is H, CH3, CH2OH, or two non-neighboring R6join together to form —CH2CH2—.

[0253] Provided herein as Embodiment B58 is the compound or salt of any one of Embodiments B1-51, wherein

[0254] Provided herein as Embodiment B59 is the compound or salt of Embodiment B58, wherein

[0255] Provided herein as Embodiment B60 is the compound or salt of any one of Embodiments B1-30, wherein the compound is a compound of Formula (IIA), Formula (IIB), or Formula (IIC):(IIC), or a pharmaceutically acceptable salt of any of the foregoing.

[0256] Provided herein as Embodiment B61 is the compound or salt of any one of Embodiments B1-60, 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.

[0257] Provided herein as Embodiment B62 is the compound or salt of Embodiment B61, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, dihydropyrrolyl, dihydrofuranyl or dihydropyranyl.

[0258] Provided herein as Embodiment B63 is the compound or salt of any one of Embodiments B1-62, wherein p is 0 or 1.

[0259] Provided herein as Embodiment B64 is the compound or salt of any one of Embodiments B1-62, wherein p is 2, 3, or 4.

[0260] Provided herein as Embodiment B65 is the compound or salt of any one of Embodiments B1-64, 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,, oxetanyl, 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 phenyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0261] Provided herein as Embodiment B66 is the compound or salt of Embodiment B65, wherein each R7independently is F, Cl, Br, CN, CH3, CH2CH3, CH2F, OH, CH2OH, CH2OCH3, CH2CH2OCH3, oxo, =CH2,, oxetanyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused- phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl; wherein each of the phenyl, pyrazolyl, and pyridyl is unsubstituted or substituted with CH3.

[0262] Provided herein as Embodiment B67 is the compound or salt of any one of Embodiments B1-59, wherein,

[0263] Provided herein as Embodiment B68 is the compound or salt of any one of Embodiments B1-59, wherein

[0264] Provided herein as Embodiment B69 is the compound or salt of Embodiment B68, wherein

[0265] Provided herein as Embodiment B70 is the compound or salt of Embodiment B1, wherein:

[0266] Provided herein as Embodiment B71 is the compound of Embodiment B70, wherein

[0267] Provided herein as Embodiment B72 is the compound or salt of Embodiment B70 or B71, wherein

[0268] Provided herein as Embodiment B73 is the compound or salt of any one of Embodiments B1-30, wherein q is 1; r is 1; W1is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; W2is N; and X is N or C-R5a.

[0269] Provided herein as Embodiment B74 is the compound of Embodiment B1, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt thereof.

[0270] Provided herein as Embodiment B75 is the compound of Embodiment B1, wherein the compound is a compound listed in Table C, or a pharmaceutically acceptable salt thereof.

[0271] Provided herein as Embodiment B76 is a pharmaceutical composition comprising the compound or salt of any one of Embodiments B1- 75 and a pharmaceutically acceptable excipient.

[0272] Provided herein as Embodiment B77 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 B1-76, or the composition of Embodiment B77.

[0273] Provided herein as Embodiment B78 is the method of Embodiment B77, wherein one or more cancer cells express KRAS G12C mutant protein.

[0274] Provided herein as Embodiment B79 is the method of Embodiment B77 or B78, 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.

[0275] Provided herein as Embodiment B80 is the method of Embodiment B79, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

[0276] Provided herein as Embodiment B81 is the method according to any one of Embodiments B77-80, 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.

[0277] Provided herein as Embodiment B82 is the method according to any one of Embodiments B77-81, 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.

[0278] Provided herein as Embodiment B83 is the compound or salt of any one of Embodiments B1-75, or the composition of Embodiment B76 for use as a medicament.

[0279] Provided herein as Embodiment B84 is the compound or salt of any one of Embodiments B1-75, or the composition of Embodiment B76 for use in treating cancer.

[0280] Provided herein as Embodiment B85 is the compound or salt of any one of Embodiments B1-75 or the pharmaceutical composition of Embodiment B76 for use in treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

[0281] Provided herein as Embodiment B86 is the compound or salt of Embodiment B84 or B85, 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.

[0282] Provided herein as Embodiment B87 is the compound or salt of Embodiment B86, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

[0283] Provided herein as Embodiment B88 is a use of a compound or salt of any one of Embodiments B1-75 or the pharmaceutical composition of Embodiment B76 for the manufacture of a medicament for the treatment of cancer.

[0284] Provided herein as Embodiment B89 is a use of a compound or salt of any one of Embodiments B1-75 or the pharmaceutical composition of Embodiment B76 in the preparation of a medicament for treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

[0285] Provided herein as Embodiment B90 is the use of Embodiment B88 or B89, 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.

[0286] Provided herein as Embodiment B91 is the use of Embodiment B90, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

[0287] Provided herein as Embodiment B92 is a compound of Formula (B):(B), or a nitrogen-protected analog, or a pharmaceutically acceptable salt of any of the foregoing, wherein: o is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, 4, or 5; each R6s 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0288] Provided herein as Embodiment B93 is a method of preparing the compound or salt of any one of Embodiments B1-75, comprising converting a compound of Embodiment B92, a protectedanalog of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, into a compound of any one of Embodiments B1-75. ADDITIONAL EMBODIMENTS

[0289] Provided herein as Embodiment A1 is a compound of Formula (II):or a 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; 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; X is N or C-R5a; 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; R5ais H, CN, halo, C1-3alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or C3-5cycloalkyl; R5bis 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, heterocycloalkenyl having 5- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or R5aand R5b, together with the atoms to which they are attached, form C3-7cycloalkyl; 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

[0290] Provided herein as Embodiment A2 is the compound or salt of Embodiment A1, wherein at least one of R1a, R1b, and R2is H or D.

[0291] Provided herein as Embodiment A3 is the compound or salt of Embodiment A2, wherein each of R1a, R1b, and R2independently is H or D.

[0292] Provided herein as Embodiment A4 is the compound or salt of Embodiment A3, wherein each of R1a, R1b, and R2is H.

[0293] Provided herein as Embodiment A5 is the compound or salt of Embodiment A3, wherein each of R1a, R1b, and R2is D.

[0294] Provided herein as Embodiment A6 is the compound or salt of Embodiment A1 or A2, wherein at least one of R1a, R1b, and R2is halo.

[0295] Provided herein as Embodiment A7 is the compound or salt of Embodiment A6, wherein R1ais halo and each of R1band R2is H.

[0296] Provided herein as Embodiment A8 is the compound or salt of Embodiment A6 or A7, wherein each halo independently is Br, Cl, or F.

[0297] Provided herein as Embodiment A9 is the compound or salt of Embodiment A1 or A2, wherein at least one of R1a, R1b, and R2is C1-4alkyl or C1-4haloalkyl.

[0298] Provided herein as Embodiment A10 is the compound or salt of Embodiment A9, wherein at least one of R1a, R1b, and R2is CH3, CH2F, CHF2, or CF3.

[0299] Provided herein as Embodiment A11 is the compound or salt of Embodiment A1 or A2, 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.

[0300] Provided herein as Embodiment A12 is the compound or salt of Embodiment A11, wherein each RN1independently is H or CH3.

[0301] Provided herein as Embodiment A13 is the compound or salt of Embodiment A12, wherein each RN1is H.

[0302] Provided herein as Embodiment A14 is the compound or salt of Embodiment A11 or A12, 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.

[0303] Provided herein as Embodiment A15 is the compound or salt of Embodiment A1 or A2, 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.

[0304] Provided herein as Embodiment A16 is the compound or salt of Embodiment A15, wherein the heterocycloalkyl is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.

[0305] Provided herein as Embodiment A17 is the compound or salt of Embodiment A15 or A17, 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.

[0306] Provided herein as Embodiment A18 is the compound or salt of Embodiment A1 or A2, wherein R1band R2, together with the carbon atoms to which they are attached, form.

[0307] Provided herein as Embodiment A19 is the compound or salt of Embodiment A1 or A2, wherein

[0308] Provided herein as Embodiment A20 is the compound or salt of Embodiment A19, wherein

[0309] Provided herein as Embodiment A21 is the compound or salt of Embodiment A20, wherein

[0310] Provided herein as Embodiment A22 is the compound or salt of any one of Embodiments A1-A21, wherein m is 0.

[0311] Provided herein as Embodiment A23 is the compound or salt of any one of Embodiments A1-A21, wherein m is 1.

[0312] Provided herein as Embodiment A24 is the compound or salt of any one of Embodiments A1-A21, wherein m is 2.

[0313] Provided herein as Embodiment A25 is the compound or salt of any one of Embodiments A1-A21, wherein m is 3.

[0314] Provided herein as Embodiment A26 is the compound or salt of any one of Embodiments A1-A21, wherein m is 4.

[0315] Provided herein as Embodiment A27 is the compound or salt of any one of Embodiments A23-A26, whereinis deuterated.

[0316] Provided herein as Embodiment A28 is the compound or salt of Embodiment A27, wherein

[0317] Provided herein as Embodiment A29 is the compound or salt of any one of Embodiments A23-A26, wherein at least one R3is C1-3alkyl or C1-3haloalkyl.

[0318] Provided herein as Embodiment A30 is the compound or salt of Embodiment A29, wherein at least one R3is CH3, CH2CH3, CF3, CHF2, or CH2F.

[0319] Provided herein as Embodiment A31 is the compound or salt of Embodiment A30, wherein at least one R3is CH3.

[0320] Provided herein as Embodiment A32 is the compound or salt of any one of Embodiments A23-A26, wherein at least one R3is

[0321] Provided herein as Embodiment A33 is the compound or salt of Embodiment A32, wherein each of RA1and RA2independently is H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl.

[0322] Provided herein as Embodiment A34 is the compound or salt of Embodiment A32 or A33, wherein at least one R3is

[0323] Provided herein as Embodiment A35 is the compound or salt of any one of Embodiments A23-A26, wherein at least one R3is C0-3alkyleneCN.

[0324] Provided herein as Embodiment A36 is the compound or salt of Embodiment A35, wherein at least one R3is CN or CH2CN.

[0325] Provided herein as Embodiment A37 is the compound or salt of any one of Embodiments A23-A26, wherein at least one R3is C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy.

[0326] Provided herein as Embodiment A38 is the compound or salt of Embodiment A37, wherein at least one R3is OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, or CH2CH2OCH3.

[0327] Provided herein as Embodiment A39 is the compound or salt of any one of Embodiments A23-A26, wherein at least one R3is oxo.

[0328] Provided herein as Embodiment A40 is the compound or salt of any one of Embodiments A23-A26, 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.

[0329] Provided herein as Embodiment A41 is the compound or salt of Embodiment A40, wherein at least one R3is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or spiro-tetrahydrofuranyl.

[0330] Provided herein as Embodiment A42 is the compound or salt of any one of Embodiments A23-A26, 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.

[0331] Provided herein as Embodiment A43 is the compound or salt of any one of Embodiments A24-A26, 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.

[0332] Provided herein as Embodiment A44 is the compound or salt of Embodiment A43, wherein two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused- cyclobutyl.

[0333] Provided herein as Embodiment A45 is the compound or salt of any one of Embodiment A24-A26, 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.

[0334] Provided herein as Embodiment A46 is the compound or salt of any one of Embodiments A23-A26, wherein each R3independently is CH3, CH2CH3, CF3, CHF2, CH2F,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.

[0335] Provided herein as Embodiment A47 is the compound or salt of any one of Embodiments A1-A21, wherein m is 0; or m is 1 and R3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

[0336] Provided herein as Embodiment A48 is the compound or salt of Embodiment A47, wherein m is 0; or m is 1 and R3is CH3.

[0337] Provided herein as Embodiment A49 is the compound or salt of any one of Embodiments A1-A21, wherein

[0338] Provided herein as Embodiment A50 is the compound or salt of Embodiment A49, wherein

[0339] Provided herein as Embodiment A51 is the compound or salt of Embodiment A50, wherein

[0340] Provided herein as Embodiment A52 is the compound or salt of any one of Embodiments A1-A51, wherein A is N.

[0341] Provided herein as Embodiment A53 is the compound or salt of any one of Embodiments A1-A51, wherein A is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy.

[0342] Provided herein as Embodiment A54 is the compound or salt of Embodiment A53, wherein A is CH.

[0343] Provided herein as Embodiment A55 is the compound or salt of Embodiment A53, wherein A is C-F, C-Cl, or C-CN.

[0344] Provided herein as Embodiment A56 is the compound or salt of Embodiment A53, wherein A is C-C1-3alkyl.

[0345] Provided herein as Embodiment A57 is the compound or salt of Embodiment A56, wherein A is C-CH3.

[0346] Provided herein as Embodiment A58 is the compound or salt of Embodiment A53, wherein A is C-C1-3haloalkyl.

[0347] Provided herein as Embodiment A59 is the compound or salt of Embodiment A58, wherein A is C-CH2F, C-CHF2, or C-CF3.

[0348] Provided herein as Embodiment A60 is the compound or salt of Embodiment A53, wherein A is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy.

[0349] Provided herein as Embodiment A61 is the compound or salt of Embodiment A60, wherein A is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0350] Provided herein as Embodiment A62 is the compound or salt of Embodiment A53, 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.

[0351] Provided herein as Embodiment A63 is the compound or salt of any one of Embodiments A1-A62, wherein n is 0.

[0352] Provided herein as Embodiment A64 is the compound or salt of any one of Embodiments A1-A62, wherein n is 1.

[0353] Provided herein as Embodiment A65 is the compound or salt of any one of Embodiments A1-A62, wherein n is 2.

[0354] Provided herein as Embodiment A66 is the compound or salt of Embodiment A64 or A65, wherein at least one R4is C1-3alkyl or C1-3haloalkyl.

[0355] Provided herein as Embodiment A67 is the compound or salt of Embodiment A66, wherein at least one R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, or CF3.

[0356] Provided herein as Embodiment A68 is the compound or salt of Embodiment A67, wherein at least one R4is CH3.

[0357] Provided herein as Embodiment A69 is the compound or salt of Embodiment A64 or A65, wherein at least one R4is C0-3alkyleneCN.

[0358] Provided herein as Embodiment A70 is the compound or salt of Embodiment A69, wherein at least one R4is CN or CH2CN.

[0359] Provided herein as Embodiment A71 is the compound or salt of Embodiment A64 or A65, wherein at least one R4is C1-3alkyleneOH or C1-3alkylene-C1-3alkoxy.

[0360] Provided herein as Embodiment A72 is the compound or salt of Embodiment A71, wherein at least one R4is CH2OH, CH2CH2OH, CH2OCH3, or CH2CH2OCH3.

[0361] Provided herein as Embodiment A73 is the compound or salt of Embodiment A64 or A65, wherein at least one R4is oxo.

[0362] Provided herein as Embodiment A74 is the compound or salt of Embodiment A64 or A65, 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.

[0363] Provided herein as Embodiment A75 is the compound or salt of Embodiment A74, wherein at least one R4is spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

[0364] Provided herein as Embodiment A76 is the compound or salt of Embodiment A64 or A65, 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.

[0365] Provided herein as Embodiment A77 is the compound or salt of Embodiment A52, wherein

[0366] Provided herein as Embodiment A78 is the compound or salt of Embodiment A77, wherein .

[0367] Provided herein as Embodiment A79 is the compound or salt of Embodiment A78, wherein

[0368] Provided herein as Embodiment A80 is the compound or salt of Embodiment A79, wherein

[0369] Provided herein as Embodiment A81 is the compound or salt of Embodiment A53, wherein

[0370] Provided herein as Embodiment A82 is the compound or salt of any one of Embodiments A1-A81, wherein W1is N.

[0371] Provided herein as Embodiment A83 is the compound or salt of any one of Embodiments A1-A81, wherein W1is CH.

[0372] Provided herein as Embodiment A84 is the compound or salt of any one of Embodiments A1-A81, wherein W1is C-F, C-Cl, or C-CN.

[0373] Provided herein as Embodiment A85 is the compound or salt of any one of Embodiments A1-A81, wherein W1is C-C1-3alkyl or C-C1-3haloalkyl.

[0374] Provided herein as Embodiment A86 is the compound or salt of Embodiment A85, wherein W1is C-CH3,C-CH2CH3, C-CH2F, C-CHF2, or C-CF3.

[0375] Provided herein as Embodiment A87 is the compound or salt of any one of Embodiments A1-A85, 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.

[0376] Provided herein as Embodiment A88 is the compound or salt of Embodiment A87, wherein W1is C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), or C-CCH.

[0377] Provided herein as Embodiment A89 is the compound or salt of any one of Embodiments A1-A81, wherein W1is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy.

[0378] Provided herein as Embodiment A90 is the compound or salt of Embodiment A89, wherein W1is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0379] Provided herein as Embodiment A91 is the compound or salt of any one of Embodiments A1-A81, 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.

[0380] Provided herein as Embodiment A92 is the compound or salt of any one of Embodiments A1-A91, wherein W2is N.

[0381] Provided herein as Embodiment A93 is the compound or salt of any one of Embodiments A1-A91, wherein W2is CH.

[0382] Provided herein as Embodiment A94 is the compound or salt of any one of Embodiments A1-A91, wherein W2is C-F, C-Cl, or C-CN.

[0383] Provided herein as Embodiment A95 is the compound or salt of any one of Embodiments A1-A91, wherein W2is C-C1-3alkyl or C-C1-3haloalkyl.

[0384] Provided herein as Embodiment A96 is the compound or salt of Embodiment A95, wherein W2is C-CH3,C-CH2CH3, C-CH2F, C-CHF2, or C-CF3.

[0385] Provided herein as Embodiment A97 is the compound or salt of any one of Embodiments A1-A91, 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.

[0386] Provided herein as Embodiment A98 is the compound or salt of Embodiment A97, wherein W2is C-CH=CH2, C-C(OH)=CH2, C-CH=CH(OH), or C-CCH.

[0387] Provided herein as Embodiment A99 is the compound or salt of any one of Embodiments A1-A91, wherein W2is C-C0-3alkyleneOH or C-C0-3alkylene-C1-4alkoxy.

[0388] Provided herein as Embodiment A100 is the compound or salt of Embodiment A99, wherein W2is C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

[0389] Provided herein as Embodiment A101 is the compound or salt of any one of Embodiments A1-A91, 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.

[0390] Provided herein as Embodiment A102 is the compound or salt of any one of Embodiments A1-A81, wherein each of W1and W2independently is N, CH, or C-CH3.

[0391] Provided herein as Embodiment A103 is the compound or salt of Embodiment A102, wherein W1is CH and W2is N, CH, or C-CH3.

[0392] Provided herein as Embodiment A104 is the compound or salt of Embodiment A102, wherein W2is N and W1is N, CH, or C-CH3.

[0393] Provided herein as Embodiment A105 is the compound or salt of Embodiment A102, wherein W1is CH and W2is N.

[0394] Provided herein as Embodiment A106 is the compound or salt of any one of Embodiments A1-A105, wherein X is N.

[0395] Provided herein as Embodiment A107 is the compound or salt of any one of Embodiments A1-A105, wherein X is C-R5a.

[0396] Provided herein as Embodiment A108 is the compound or salt of Embodiment A107, wherein R5ais H.

[0397] Provided herein as Embodiment A109 is the compound or salt of Embodiment A107, wherein R5ais CN.

[0398] Provided herein as Embodiment A110 is the compound or salt of Embodiment A107, wherein R5ais Br, Cl, or F.

[0399] Provided herein as Embodiment A111 is the compound or salt of Embodiment A107, wherein R5ais C1-3alkyl or C1-3haloalkyl.

[0400] Provided herein as Embodiment A112 is the compound or salt of Embodiment A111, wherein R5ais CH3, CH2CH3, CF3, CHF2, or CH2F.

[0401] Provided herein as Embodiment A113 is the compound or salt of Embodiment A112, wherein R5ais CH3.

[0402] Provided herein as Embodiment A114 is the compound or salt of Embodiment A107, wherein R5ais C2-6alkenyl or C2-6alkynyl.

[0403] Provided herein as Embodiment A115 is the compound or salt of Embodiment A114, wherein R5ais

[0404] Provided herein as Embodiment A116 is the compound or salt of Embodiment A115, wherein R5ais.

[0405] Provided herein as Embodiment A117 is the compound or salt of Embodiment A107, wherein R5ais C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or C3-5cycloalkyl.

[0406] Provided herein as Embodiment A118 is the compound or salt of Embodiment A117, wherein R5ais OH, CH2OH, OCH3, CH2OCH3, or .

[0407] Provided herein as Embodiment A119 is the compound or salt of Embodiment A107, wherein R5ais CN or CH3.

[0408] Provided herein as Embodiment A120 is the compound or salt of any one of Embodiments A1-A105, wherein X is N, C-CH3, or C-CN.

[0409] Provided herein as Embodiment A121 is the compound or salt of any one of Embodiments A1-A81, wherein W1is CH; W2is N; and X is N, C-CH3, or C-CN.

[0410] Provided herein as Embodiment A122 is the compound or salt of any one of Embodiments A1-A121, wherein R5bis Br, Cl, or F.

[0411] Provided herein as Embodiment A123 is the compound or salt of any one of Embodiments A1-A121, wherein R5bis C1-3haloalkyl.

[0412] Provided herein as Embodiment A124 is the compound or salt of Embodiment A123, wherein R5bis CF3, CF2H, CFH2, or CF2CH3.

[0413] Provided herein as Embodiment A125 is the compound or salt of Embodiment A124, wherein R5bis CF3or CF2H.

[0414] Provided herein as Embodiment A126 is the compound or salt of any one of Embodiments A1-A121, wherein R5bis C1-3alkoxy or C1-3thioalkyl.

[0415] Provided herein as Embodiment A127 is the compound or salt of Embodiment A126, wherein R5bis OCH3or SCH3.

[0416] Provided herein as Embodiment A128 is the compound or salt of any one of Embodiments A1-A121, wherein R5bis 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.

[0417] Provided herein as Embodiment A129 is the compound or salt of Embodiment A128, wherein R5bis CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH=CH2, CH=CHCH3,, orand 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.

[0418] Provided herein as Embodiment A130 is the compound or salt of Embodiment A129, wherein each substituent independently is CH3, CF3, CF2H, CFH2, OH, OCH3, OCF3, CH2OH, CH2OCH3, cyclopropyl, cyclobutyl, or phenyl.

[0419] Provided herein as Embodiment A131 is the compound or salt of Embodiment A129 or A130, wherein R5bis CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,

[0420] Provided herein as Embodiment A132 is the compound or salt of any one of Embodiments A1-A121, wherein R5bis 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.

[0421] Provided herein as Embodiment A133 is the compound or salt of any one of Embodiments A1-A81, wherein , X is N, C-CH, orb3C-CN; and R is CF3or CF2H.

[0422] Provided herein as Embodiment A134 is the compound or salt of any one of Embodiments A1-A81, wherein

[0423] Provided herein as Embodiment A135 is the compound or salt of Embodiment A134, wherein

[0424] Provided herein as Embodiment A136 is the compound or salt of any one of Embodiments A1-A81, wherein

[0425] Provided herein as Embodiment A137 is the compound or salt of Embodiment A136, wherein

[0426] Provided herein as Embodiment A138 is the compound or salt of Embodiment A137, wherein

[0427] Provided herein as Embodiment A139 is the compound or salt of any one of Embodiments A1-A81, wherein

[0428] Provided herein as Embodiment A140 is the compound or salt of any one of Embodiments A1-A139, wherein q is 0.

[0429] Provided herein as Embodiment A141 is the compound or salt of any one of Embodiments A1-A139, wherein q is 1.

[0430] Provided herein as Embodiment A142 is the compound or salt of any one of Embodiments A1-A139, wherein q is 2.

[0431] Provided herein as Embodiment A143 is the compound or salt of any one of Embodiments A1-A142, wherein r is 0.

[0432] Provided herein as Embodiment A144 is the compound or salt of any one of Embodiments A1-A142, wherein r is 1.

[0433] Provided herein as Embodiment A145 is the compound or salt of any one of Embodiment A1-A139, whereinor

[0434] Provided herein as Embodiment A146 is the compound of any one of Embodiments A1- A145, wherein o is 0.

[0435] Provided herein as Embodiment A147 is the compound of any one of Embodiments A1- A145 wherein o is 1.

[0436] Provided herein as Embodiment A148 is the compound of any one of Embodiments A1- A145, wherein o is 2.

[0437] Provided herein as Embodiment A149 is the compound of any one of Embodiments A1- A145, wherein o is 3.

[0438] Provided herein as Embodiment A150 is the compound of any one of Embodiments A1- A145, wherein o is 4.

[0439] Provided herein as Embodiment A151 is the compound of any one of Embodiments A147- A150, wherein at least one R6is Br, Cl, F, or CN.

[0440] Provided herein as Embodiment A152 is the compound or salt of Embodiment A151, wherein at least one R6is F.

[0441] Provided herein as Embodiment A153 is the compound or salt of any one of Embodiments A147-A150, wherein at least one R6is C1-3alkyl or C1-3haloalkyl.

[0442] Provided herein as Embodiment A154 is the compound or salt of Embodiment A153, wherein at least one R6is CH3, CH2F, CHF2, or CF3.

[0443] Provided herein as Embodiment A155 is the compound or salt of any one of Embodiments A147-A150, 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.

[0444] Provided herein as Embodiment A156 is the compound or salt of Embodiment A155, wherein at least one R6is OH, CH2OH, OCH3, OCD3, CH2OCH3, or CH2N(CH3)2.

[0445] Provided herein as Embodiment A157 is the compound or salt of any one of Embodiments A147-A150, wherein at least one R6is oxo or =CH2.

[0446] Provided herein as Embodiment A158 is the compound or salt of any one of Embodiments A147-A150, 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.

[0447] Provided herein as Embodiment A159 is the compound or salt of Embodiment A158, 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.

[0448] Provided herein as Embodiment A160 is the compound or salt of Embodiment A159, wherein at least one R6is cyclopropyl.

[0449] Provided herein as Embodiment A161 is the compound or salt of any one of Embodiments A147-A150, 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.

[0450] Provided herein as Embodiment A162 is the compound or salt of Embodiment A161, 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.

[0451] Provided herein as Embodiment A163 is the compound or salt of clam A162, wherein at least one R6is spiro-cyclopropyl.

[0452] Provided herein as Embodiment A164 is the compound or salt of any one of Embodiments A148-A150, 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 1-3 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 1-4 substituents, and each substituent independently is halo, C1-3alkyl, C1-3haloalkyl, C0-2alkyleneOH, C0-2alkyleneC1-3alkoxy, or C0-2alkyleneCN.

[0453] Provided herein as Embodiment A165 is the compound or salt of Embodiment A164, 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.

[0454] Provided herein as Embodiment A166 is the compound or salt of any one of Embodiments A158, A159, A161, A162, A164, and A165, wherein each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

[0455] Provided herein as Embodiment A167 is the compound or salt of any one of Embodiments A148-A150, 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.

[0456] Provided herein as Embodiment A168 is the compound or salt of Embodiment A167, wherein two non-neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, — CH2-CH=CH— or —CH2OCH2—.

[0457] Provided herein as Embodiment A169 is the compound or salt of Embodiment A168, wherein two non-neighboring R6join together to form —CH2—, —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2—.

[0458] Provided herein as Embodiment A170 is the compound or salt of any one of Embodiments A1-A145, 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.

[0459] Provided herein as Embodiment A171 is the compound or salt of any one of Embodiments A1-A145, wherein o is 0; or o is 1 and R6is H, CH3, CH2OH, or two non-neighboring R6join together to form —CH2CH2—.

[0460] Provided herein as Embodiment A172 is the compound or salt of any one of Embodiments A1-A145, wherein

[0461] Provided herein as Embodiment A173 is the compound or salt of Embodiment A172, wherein

[0462] Provided herein as Embodiment A174 is the compound or salt of Embodiment A173, wherein

[0463] Provided herein as Embodiment A175 is the compound or salt of any one of Embodiments A1-A81, wherein the compound is a compound of Formula (IIA), Formula (IIB), or Formula (IIC):, or a pharmaceutically acceptable salt of any of the foregoing.

[0464] Provided herein as Embodiment A176 is the compound or salt of any one of Embodiments A1-A175, wherein Y’ is C3-7cycloalkyl or C4-7cycloalkenyl.

[0465] Provided herein as Embodiment A177 is the compound or salt of Embodiment A176 wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl.

[0466] Provided herein as Embodiment A178 is the compound or salt of Embodiment A177, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclopentenyl.

[0467] Provided herein as Embodiment A179 is the compound or salt of any one of Embodiments A1-A175, wherein Y’ is heterocycloalkyl having 3 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0468] Provided herein as Embodiment A180 is the compound or salt of Embodiment A179, 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.

[0469] Provided herein as Embodiment A181 is the compound or salt of Embodiment A180, wherein Y’ is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, or morpholinyl.

[0470] Provided herein as Embodiment A182 is the compound or salt of Embodiment A181, wherein Y’ is pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0471] Provided herein as Embodiment A183 is the compound or salt of any one of Embodiments A1-A175, wherein Y’ is heterocycloalkenyl having 5 to 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S.

[0472] Provided herein as Embodiment A184 is the compound or salt of Embodiment A183, wherein Y’ is dihydropyrrolyl, dihydrofuranyl, dihydrothiopheneyl, dihydroisoxazolyl, tetrahydropyridinyl, dihydropyranyl, or dihydrothipyranyl.

[0473] Provided herein as Embodiment A185 is the compound or salt of Embodiment A184, wherein Y’ is dihydropyrrolyl, dihydrofuranyl or dihydropyranyl.

[0474] Provided herein as Embodiment A186 is the compound or salt of any one of Embodiments A1-A175, 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.

[0475] Provided herein as Embodiment A187 is the compound or salt of Embodiment A186, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, dihydropyrrolyl, dihydrofuranyl or dihydropyranyl.

[0476] Provided herein as Embodiment A188 is the compound or salt of any one of Embodiments A1-A187, wherein p is 0.

[0477] Provided herein as Embodiment A189 is the compound or salt of any one of Embodiments A1-A187, wherein p is 1.

[0478] Provided herein as Embodiment A190 is the compound or salt of any one of Embodiments A1-A187, wherein p is 2.

[0479] Provided herein as Embodiment A191 is the compound or salt of any one of Embodiments A1-A187, wherein p is 3.

[0480] Provided herein as Embodiment A192 is the The compound or salt of any one of Embodiments A1-A187, wherein p is 4.

[0481] Provided herein as Embodiment A193 is the compound or salt of any one of Embodiments A1-A187, wherein p is 5.

[0482] Provided herein as Embodiment A194 is the compound or salt of any one of Embodiment A189-A193, wherein at least one R7is F, Cl, Br, CN, or CH2CN.

[0483] Provided herein as Embodiment A195 is the compound or salt of Embodiment A194, wherein at least one R7is F or CH2CN.

[0484] Provided herein as Embodiment A196 is the compound or salt of any one of Embodiments A189-A193, wherein at least one R7is C1-3alkyl, C1-3haloalkyl, or C2-3alkenyl.

[0485] Provided herein as Embodiment A197 is the compound or salt of Embodiment A196, wherein at least one R7is CH3, CH2CH3, CH2F, CHF2, or CF3.

[0486] Provided herein as Embodiment A198 is the compound or salt of Embodiment A197, wherein at least one R7is CH3, CH2F, or CHF2.

[0487] Provided herein as Embodiment A199 is the compound or salt of any one of Embodiments A189-A193, wherein at least one R7is C0-3alkyleneOH or C0-3alkylene-C1-3alkoxy.

[0488] Provided herein as Embodiment A200 is the compound or salt of Embodiment A199, wherein at least one R7is OH, OCH3, OCH2CH3, CH2OH, CH2OCH3, or CH2CH2OCH3.

[0489] Provided herein as Embodiment A201 is the compound or salt of Embodiment A200, wherein at least one R7is OH or CH2OCH3.

[0490] Provided herein as Embodiment A202 is the compound or salt of any one of Embodiments A189-A193, wherein at least one R7is C(=O)OCH3.

[0491] Provided herein as Embodiment A203 is the compound or salt of any one of Embodiments A189-A193, wherein at least one R7is oxo or =CH2.

[0492] Provided herein as Embodiment A204 is the compound or salt of any one of Embodiments A189-A193, 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0493] Provided herein as Embodiment A205 is the compound or salt of Embodiment A204, 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.

[0494] Provided herein as Embodiment A206 is the compound or salt of Embodiment A205, wherein at least one R7is cyclopropyl.

[0495] Provided herein as Embodiment A207 is the compound or salt of any one of Embodiments A189-A193, 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

[0496] Provided herein as Embodiment A208 is the compound or salt of Embodiment A207, wherein at least one R7is spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, or spiro-tetrahydropyranyl.

[0497] Provided herein as Embodiment A209 is the compound or salt of any one of Embodiments A190-A193, 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.

[0498] Provided herein as Embodiment A210 is the compound or salt of Embodiment A209, 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.

[0499] Provided herein as Embodiment A211 is the compound or salt of Embodiment A210, wherein two vicinal R7, together with the atoms to which they are attached, form fused- tetrahydrofuranyl.

[0500] Provided herein as Embodiment A212 is the compound or salt of any one of Embodiments A190-A193, 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.

[0501] Provided herein as Embodiment A213 is the compound or salt of Embodiment A212, 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.

[0502] Provided herein as Embodiment A214 is the compound or salt of Embodiment A213, 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.

[0503] Provided herein as Embodiment A215 is the compound or salt of any one of Embodiments A204-A214, wherein each substituent independently is F, Cl, Br, CN, oxo, or CH3.

[0504] Provided herein as Embodiment A216 is the compound or salt of any one of Embodiments A1-A187, 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.

[0505] Provided herein as Embodiment A217 is the compound or salt of any one of Embodiments A1-A175, wherein

[0506] Provided herein as Embodiment A218 is the compound or salt of any one of Embodiments A1-A175, wherein,

[0507] Provided herein as Embodiment A219 is the compound or salt of Embodiment A218, wherein

[0508] Provided herein as Embodiment A220 is the compound or salt of Embodiment A1, wherein: and.

[0509] Provided herein as Embodiment A221 is the compound of Embodiment A220, wherein

[0510] Provided herein as Embodiment A222 is the compound or salt of Embodiment A220 or A221, wherein

[0511] Provided herein as Embodiment A223 is the compound or salt of any one of Embodiments A1-A81, wherein q is 1; r is 1; W1is CH, C-halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; W2is N; and X is N or C-R5a.

[0512] Provided herein as Embodiment A224 is the compound of Embodiment A1, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt thereof.

[0513] Provided herein as Embodiment A225 is the compound of Embodiment A224, wherein the compound is a compound listed in Table B, or a pharmaceutically acceptable salt thereof.

[0514] Provided herein as Embodiment A226 is the compound of Embodiment A1, wherein the compound is a compound listed in Table C, or a pharmaceutically acceptable salt thereof.

[0515] Provided herein as Embodiment A227 is the compound of Embodiment A226, wherein the compound is a compound listed in Table D, or a pharmaceutically acceptable salt thereof.

[0516] Provided herein as Embodiment A228 is a pharmaceutical composition comprising the compound or salt of any one of Embodiments A1- A227 and a pharmaceutically acceptable excipient.

[0517] Provided herein as Embodiment A229 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 A1-227, or the composition of Embodiment A228.

[0518] Provided herein as Embodiment A230 is the method of Embodiment A229, wherein one or more cancer cells express KRAS G12C mutant protein.

[0519] Provided herein as Embodiment A231 is the method of Embodiment A229 or A230, 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...

Claims

What is claimed is:

1. A compound of Formula (II):or a 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; 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; X is N or C-R5a; 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 1or 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; R5ais H, CN, halo, C1-3alkyl, C1-3haloalkyl, C2-6alkenyl, C2-6alkynyl, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, or C3-5cycloalkyl; R5bis 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, heterocycloalkenyl having 5- 7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S, or R5aand R5b, together with the atoms to which they are attached, form C3-7cycloalkyl; 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, heterocycloalkenylhaving 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 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 1 or 2, wherein each of R1a, R1b, and R2independently is H or D.

4. The compound or salt of claim 1 or 2, wherein at least 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, C1-2alkylene-heterocycloalkyl having 3-6 total ring atoms and 1or 2 heteroatoms independently selected from N, O, and S, or R1band R2, together with the carbon atoms to which they are attached, form; wherein each RN1independently is H or CH3.

5. The compound or salt of claim 4, wherein at least 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.

6. The compound or salt of claim 1 or 2, wherein7. The compound or salt of claim 6, wherein8. The compound or salt of claim 7, wherein9. The compound or salt of any one of claims 1-8, wherein m is 0 or 1.

10. The compound or salt of any one of claims 1-8, wherein m is 2, 3, or 4.

11. The compound or salt of any one of claims 1-10, wherein at least one R3is C1-3alkyl or C1-3haloalkyl.

12. The compound or salt of claim 11, wherein at least one R3is CH3, CH2CH3, CF3, CHF2, or CH2F.

13. The compound or salt of any one of claims 1-10, wherein at least one R3isC0-3alkyleneCN, C0-3alkyleneOH, C0-3alkylene-C1-3alkoxy, oxo, spiro-C3-7cycloalkyl, spiro-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, spiro-C4-7cycloalkenyl, spiro-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; two vicinal R3, together with the atoms to which they are attached, form fused-C3-7cycloalkyl, fused-heterocycloalkyl having 3-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S, fused-C4-7cycloalkenyl, or fused-heterocycloalkenyl having 4-7 total ring atoms and 1 or 2 heteroatoms independently selected from N, O and S; wherein each of RA1and RA2independently is H, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl.

14. The compound or salt of claim 13, wherein at least one R3is, CN, CH2CN, OH, CH2OH, CH2CH2OH, OCH3, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, or two vicinal R3, together with the atoms to which they are attached, form fused-cyclopropyl or fused-cyclobutyl.

15. The compound or salt of any one of claims 1-10, wherein each R3independently is CH3, CH2CH3, CF3, CHF2, CH2F,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.

16. The compound or salt of any one of claims 1-8, wherein m is 0; or m is 1 and R3is CH3, CH2F, CHF2, CF3, CN, CH2CN, CH2OH, CH2OCH3, or spiro-oxetanyl.

17. The compound or salt of claim 16, wherein m is 0; or m is 1 and R3is CH3.

18. The compound or salt of any one of claims 1-8, wherein,19. The compound or salt of claim 18, wherein.

20. The compound or salt of any one of claims 1-19, wherein A is N.

21. The compound or salt of any one of claims 1-19, wherein A is CH, C-halo, C-CN, C- C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy.

22. The compound or salt of claim 21, 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.

23. The compound or salt of any one of claims 1-22, wherein n is 0 or 1.

24. The compound or salt of any one of claims 1-23, wherein at least one R4is C1-3alkyl or C1-3haloalkyl.

25. The compound or salt of claim 24, wherein at least one R4is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, or CF3.

26. The compound or salt of any one of claims 1-23, wherein at least one R4is 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.

27. The compound or salt of claim 26, wherein at least one R4is CN, CH2CN, CH2OH, CH2CH2OH, CH2OCH3, CH2CH2OCH3, oxo, spiro-cyclopropyl, spiro-cyclobutyl, or spiro-oxetanyl.

28. The compound or salt of any one of claims 1-23, 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.

29. The compound or salt of claim 28, wherein,30. The compound or salt of claim 29, wherein or.

31. The compound or salt of any one of claims 1-30, wherein W1is N, CH, 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), or C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

32. The compound or salt of claim 31, wherein W1is CH.

33. The compound or salt of any one of claims 1-32, wherein W2is N, CH, 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), or C-CCH, C-OH, C-CH2OH, C-OCH3, or C-CH2OCH3.

34. The compound or salt of claim 33, wherein W2is N.

35. The compound or salt of any one of claims 1-30, wherein W1is CH and W2is N.

36. The compound or salt of any one of claims 1-35, wherein X is N.

37. The compound or salt of any one of claims 1-35, wherein X is C-R5aand R5ais H, CN, Br, Cl, F, CH3, CH2CH3, CF3, CHF2, CH2F,OH, CH2OH, OCH3, CH2OCH3, or .

38. The compound or salt of claim 37, wherein R5ais CN or CH3.

39. The compound or salt of any one of claims 1-35, wherein X is N, C-CH3, or C-CN.

40. The compound or salt of any one of claims 1-30, wherein W1is CH; W2is N; and X is N, C-CH3, or C-CN.

41. The compound or salt of any one of claims 1-40, wherein R5bis Br, Cl, F, CF3, CF2H, CFH2, CF2CH3, OCH3, SCH3CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,.

42. The compound or salt of claim 41, wherein R5bis CF3or CF2H.

43. The compound or salt of any one of claims 1-30, whereinis , X is N, C-CH, or C-CN; and Rbis CF or CFH.3 3 244. The compound or salt of any one of claims 1-30, whereinis ,<img src='' class="img-anchor img-center" img-id="IMGF000402_0001" / >45. The compound or salt of claim 44, wherein<img src='' class="img-anchor img-center" img-id="IMGF000403_0002" / >46. The compound or salt of any one of claims 1-45, wherein q is 0.

47. The compound or salt of any one of claims 1-45, wherein q is 1.

48. The compound or salt of any one of claims 1-45, wherein q is 2.

49. The compound or salt of any one of claims 1-45, wherein r is 0.

50. The compound or salt of any one of claims 1-45, wherein r is 1.

51. The compound or salt of any one of claim 1-45, whereinis<img src='' class="img-anchor img-center" img-id="IMGF000403_0004" / >52. The compound of any one of claims 1-51, wherein o is 0, 1, or 2.

53. The compound of any one of claims 1-51, wherein o is 3 or 4.

54. The compound of any one of claims 1-53, wherein at least one R6is Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro- oxetanyl, or spiro-tetrahydrofuranyl; 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 cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, spiro- cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, spiro-tetrahydrofuranyl, fused-cyclopropyl, fused- cyclobutyl, and fused-cyclopentyl independently 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.

55. The compound or salt of claim 54, wherein each substituent independently is F, Cl, OH, OCH3, OCH2CH3, or CN.

56. The compound or salt of 54 or 55, wherein at least one R6is Br, Cl, F, CN, CH3, CH2F, CHF2, CF3, OH, CH2OH, OCH3, OCD3, CH2OCH3, CH2N(CH3)2, oxo, =CH2, 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.

57. The compound or salt of any one of claims 1-51, wherein o is 0; or o is 1 and R6is H, CH3, CH2OH, or two non-neighboring R6join together to form —CH2CH2< / sub>—.

58. The compound or salt of any one of claims 1-51, whereinisor<img src='' class="img-anchor img-center" img-id="IMGF000404_0003" / >59. The compound or salt of claim 58, whereinis<img src='' class="img-anchor img-center" img-id="IMGF000405_0002" / >60. The compound or salt of any one of claims 1-30, wherein the compound is a compound of Formula (IIA), Formula (IIB), or Formula (IIC):(IIC), or a pharmaceutically acceptable salt of any of the foregoing.

61. The compound or salt of any one of claims 1-60, 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.

62. The compound or salt of claim 61, wherein Y’ is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, tetrahydropyranyl, dihydropyrrolyl, dihydrofuranyl or dihydropyranyl.

63. The compound or salt of any one of claims 1-62, wherein p is 0 or 1.

64. The compound or salt of any one of claims 1-62, wherein p is 2, 3, or 4.

65. The compound or salt of any one of claims 1-64, 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,, oxetanyl, 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 phenyl, pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl is unsubstituted or substituted with 1-3 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl.

66. The compound or salt of claim 65, wherein each R7independently is F, Cl, Br, CN, CH3, CH2CH3, CH2F, OH, CH2OH, CH2OCH3, CH2CH2OCH3, oxo, =CH2,, oxetanyl, spiro-cyclopropyl, spiro-cyclobutyl, spiro-oxetanyl, or two vicinal R7, together with the atoms to which they are attached, form fused-cyclopropyl, fused-phenyl, fused-thiophenyl, fused-pyrazolyl, fused-thiazolyl, fused-pyridyl; wherein each of the phenyl, pyrazolyl, and pyridyl is unsubstituted or substituted with CH3< / sub>.

67. The compound or salt of any one of claims 1-59, wherein,,<img src='' class="img-anchor img-center" img-id="IMGF000409_0001" / >68. The compound or salt of any one of claims 1-59, wherein,<img src='' class="img-anchor img-center" img-id="IMGF000411_0001" / >69. The compound or salt of claim 68, wherein,<img src='' class="img-anchor img-center" img-id="IMGF000412_0001" / >70. The compound or salt of claim 1, wherein: ; and<img src='' class="img-anchor img-center" img-id="IMGF000413_0001" / >71. The compound of claim 70, wherein,<img src='' class="img-anchor img-center" img-id="IMGF000413_0003" / >72. The compound or salt of claim 70 or 71, wherein ,<img src='' class="img-anchor img-center" img-id="IMGF000414_0001" / >73. The compound or salt of any one of claims 1-30, wherein q is 1; r is 1; W1is CH, C- halo, C-CN, C-C1-3alkyl, C-C1-3haloalkyl, C-C0-3alkyleneOH, or C-C0-3alkylene-C1-4alkoxy; W2is N; and X is N or C-R5a< / sup>.

74. The compound of claim 1, wherein the compound is a compound listed in Table A, or a pharmaceutically acceptable salt thereof.

75. The compound of claim 1, wherein the compound is a compound listed in Table C, or a pharmaceutically acceptable salt thereof.

76. A pharmaceutical composition comprising the compound or salt of any one of claims 1- 75 and a pharmaceutically acceptable excipient.

77. 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 1-76, or the composition of claim 77.

78. The method of claim 77, wherein one or more cancer cells express KRAS G12C mutant protein.

79. The method of claim 77 or 78, 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.

80. The method of claim 79, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

81. The method according to any one of claims 77-80, 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.

82. The method according to any one of claims 77-81, 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.

83. The compound or salt of any one of claims 1-75, or the composition of claim 76 for use as a medicament.

84. The compound or salt of any one of claims 1-75, or the composition of claim 76 for use in treating cancer.

85. The compound or salt of any one of claims 1-75 or the pharmaceutical composition of claim 76 for use in treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

86. The compound or salt of claim 84 or 85, 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.

87. The compound or salt of claim 86, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

88. Use of a compound or salt of any one of claims 1-75 or the pharmaceutical composition of claim 76 for the manufacture of a medicament for the treatment of cancer.

89. Use of a compound or salt of any one of claims 1-75 or the pharmaceutical composition of claim 76 in the preparation of a medicament for treating cancer, wherein one or more cancer cells express KRAS G12C mutant protein.

90. The use of claim 88 or 89, 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.

91. The use of claim 90, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or solid tumor.

92. A compound of Formula (B):(B), or a nitrogen-protected analog, or a pharmaceutically acceptable salt of any of the foregoing, wherein: o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; each R6s 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, aC1-3ether 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 substituents, and each substituent independently is halo, CN, oxo, or C1-3alkyl; and each RN1independently is H or C1-4alkyl.

93. A method of preparing the compound or salt of any one of claims 1-75, comprising converting a compound of claim 92, a protected analog of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, into a compound of any one of claims 1-75.

Images