Combination therapies with kras modulators

Abstract

Provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (II).

Description

COMBINATION THERAPIES WITH KRAS MODULATORS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 518,177 filed on August 8, 2023; the entire contents of which is incorporated herein by reference. BACKGROUND OF THE INVENTION

[0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p.1292-1292 e1). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017.7(8): p.818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.

[0003] Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification.

[0004] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS- mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. SUMMARY OF THE INVENTION

[0005] While the compounds disclosed herein are potent inhibitors of KRas signaling and exhibit single agent activity inhibiting the in vitro proliferation of cell lines harboring a KRas mutation or other KRAS-activating genetic alteration, the relative potency and / or observed maximal effect of any given KRas inhibitor can vary between KRAS mutant cell lines. The reason or reasons for the range of potencies and observed maximal effect is not fully understood but certain cell lines appear to possess differing intrinsic resistance to the mechanism of action, which relies on binding to certain conformational states of KRAS proteins. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index and / or clinical benefit of KRas inhibitors in vitro and in vivo. Due to known feedback loops in the Ras signaling pathway, upstream inhibition of RTK signaling or downstream inhibition of MAPK signaling may be required for complete blockade of KRas mutant activity in the presence of KRas inhibitors.

[0006] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L- N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl are optionally substituted with one or more R7; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle;each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl,C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12- membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O,=S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4.

[0007] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of a RTK-MAPK pathway inhibitor and a compound represented by the structure of Formula (II): or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selectedfrom -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0008] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein:M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl;R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle;each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0009] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; R2is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; n is selected from 0 to 3; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2- C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; Y is selected from a bond, O, S and NR5; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and each R5is independently selected from hydrogen or C1-C6alkyl. INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0012] FIG.1 illustrates that combination treatment enhances tumor growth inhibition and tumor regression as compared to single agent treatment. DETAILED DESCRIPTION OF THE INVENTION

[0013] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0014] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0016] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0017] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene- may be selected frommethylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0018] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0019] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0020] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0021] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0022] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms,for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C8alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5alkylene).

[0023] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5alkenylene).

[0024] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any twocarbons within the chain. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5alkynylene).

[0025] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0026] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like.

[0027] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rdis an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above.

[0028] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.

[0029] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0030] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0031] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0032] "Cycloalkylalkyl" refers to a radical of the formula –Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0033] "Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0034] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0035] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.

[0036] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0037] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like.

[0038] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0039] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0040] "Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.

[0041] “Heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”. In some cases, spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom. The spiro- heterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.

[0042] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group.

[0043] "Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein eachheteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^– electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.

[0044] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0045] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0046] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0047] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0048] As used herein, the term “electrophile” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and / or an excess of electrons, for example an —SH group). Electrophiles typically are electron poor or comprise atoms which are electron poor. In certain embodiments, an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge. In some embodiments, an electrophile comprises a conjugated double bond, for example an α,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound.

[0049] As used herein, the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionallysubstituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0050] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0051] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0052] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0053] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0054] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carriermust be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0055] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0056] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0057] The term “G12 mutants”, as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (i.e. G12X).

[0058] The term “RTK-MAPK pathway” refers to the signaling cascade between Receptor Tyrosine Kinases (RTKs), including positive regulators of RTK activity, e.g., SHP2 or SOS1, and the RAF-MEK-ERK (i.e. MAPK) pathway.

[0059] The term “RTK-MAPK pathway inhibitor” 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 protein within the RTK-MAPK pathway.

[0060] The term “RAF-MEK-ERK pathway” refers to the series of kinases activated sequentially downstream of activation of the RAS family of small GTPases.

[0061] The term “RAF-MEK-ERK pathway inhibitor” 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 protein within the RAF-MEK-ERK pathway.

[0062] The term "KRas G12D-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12D mutation.

[0063] The term "KRas G12V-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12V mutation.

[0064] The term "KRas wildtype-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas wildtype.

[0065] The terms “ERBB family” or “ERBB family member” refers to a member of a mammalian transmembrane protein tyrosine kinase family including: EGFR, ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

[0066] The term “ERBB family inhibitor” 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.

[0067] The term “EGFR inhibitor” 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 Epidermal Growth Factor Receptor (EGRF).

[0068] The terms “SHP-2” or “SHP2” refers to the mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signaling through the Ras- mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.

[0069] The terms a “SHP-2 inhibitor” or a “SHP2 inhibitor” refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of SHP-2 phosphatase.

[0070] The term “SOS1” refers to a mammalian Son of sevenless homolog 1 (SOS1) enzyme.

[0071] The term a “SOS1 inhibitor” refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the interaction of SOS1 with Ras family mutant or SOS1 activating mutation thereby reducing and / or modulating the nucleotide exchange activity of Ras family member - SOS1 complex.

[0072] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient,or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0073] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0074] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0075] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to the individual in need.

[0076] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0077] As used herein, a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination incomparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.

[0078] As used herein, “synergy,” “synergetic,” “synergism,” or “synergistic effect” refer to two or more compounds or compositions, that individually produce an effect, however, together produce a combined effect that is greater than their individual effects.

[0079] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.

[0080] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0081] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0082] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein. COMPOSITIONS AND INHIBITORS RTK-MAPK Pathway Inhibitors

[0083] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) a RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0084] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0085] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) a RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0086] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0087] In some embodiments, Formula (II) is represented by Formula (II*). RAF-MEK-ERK pathway inhibitor

[0088] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0089] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0090] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0091] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0092] In some embodiments, Formula (II) is represented by Formula (II*). ERBB family Inhibitors

[0093] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) a ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0094] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0095] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) a ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0096] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a ERBB family inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0097] In some embodiments, Formula (II) is represented by Formula (II*).

[0098] The ERBB family inhibitors used in the methods herein may be reversible or irreversible ERBB family inhibitors. In one embodiment, the ERBB family inhibitor inhibits the activity of more than one ERBB family member.

[0099] The modulation or inhibition of one or more ERBB family members 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 embodiments of the methods herein, the ERBB inhibitor refers to the use of a single ERBB inhibitor. In some embodiments of the methods herein, the term ERBB inhibitor refers to the use of two ERBB inhibitors.

[0100] In some embodiments, the ERBB family inhibitor is an irreversible inhibitor. In some cases, irreversible ERBB family inhibitors inhibit the activity of EGFR and HER2 by forming a covalent bond with the sulfhydryl group of cysteine 797 and cysteine 773, respectively, that blocks the binding of ATP to the intracellular catalytic domain. As such, these inhibitors are active against, for example, cell lines harboring EGFR exon 19 deletions / insertions, and L858R and T790M resistant mutations.

[0101] In some embodiments, exemplary irreversible ERBB family inhibitors for use in the methods include afatinib ((E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3- yl)oxy)quinazolin- 6-yl)-4-(dimethylamino)but-2-enamide); dacomitinib ((2E)-N-{4-[(3-Chloro- 4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl}-4-(l-piperidinyl)-2-butenamide); canertinib (N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide); poziotinib (l-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)oxy)piperidin-l-yl)prop-2-en-l-one); 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 ((2E)-N-[[4-[[(3-Chloro-4-[(3- fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6- quinolinyl]-4-(dimethylamino)-2-butenamide), and pharmaceutically acceptable salts or pharmaceutical compositions thereof. In some cases, the irreversible ERBB family inhibitor is afatinib. In one embodiment, the irreversible ERBB family inhibitor is dacomitinib. In somecases, the irreversible ERBB family inhibitors suitable for the provided compositions and methods include, but are not limited to, Afatinib; Dacomitinib; Canertinib; Poziotinib, AV 412; PF 6274484 and HKI 357.

[0102] In some embodiments, the ERBB family inhibitor is a reversible inhibitor. In some cases, reversible inhibitors include erlotinib ([6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3- ethynyl-phenyl)-amine)), gefitinib (4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, sapitinib (2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)piperidin-l-yl)-N-methylacetamide); varlitinib ((R)-N4-(3-chloro-4- (thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine); 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- l-yl)methyl)phenyl)-N-(l- phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine); tarloxotinib 3-[N- [4-(3-Bromo-4-chlorophenylamino)pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(l- methyl-4- nitro-lH-imidazol-5-ylmethyl)-2(E)-propen-l-aminium bromide ); BMS 599626 ((3S)- 3-Morpholinylmethyl-[4-[[l-[(3-fluorophenyl)methyl]-lH-indazol-5-yl]amino]-5- methylpyrrolo[2,l-f][l,2,4]triazin-6-yl]-carbamate dihydrochloride); and GW 583340 HC1 (N- [3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[[[2- (methylsulfonyl)ethyl]amino]methyl]- 4-thiazolyl]-4-quinazolinamine dihydrochloride), and pharmaceutically acceptable salts or pharmaceutical compositions thereof.

[0103] In some embodiments, the reversible ERBB family inhibitor is sapitinib. In some cases, the reversible ERBB family inhibitor is tarloxotinib.

[0104] In some embodiments, the ERBB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of two of: AG 1478 HC1 (7V-(3-Chlorophenyl)-6,7-dimethoxy-4-quinazolinanine hydrochloride); AG 494 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-phenyl-2-propenamide; AG 555 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-propenamide; AG 556 (E)-2- Cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-propenamide; AG 825 (E)-3-[3-[2- Benzothiazolythio)methyl]-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide; CP 724714 (2 -Methoxy-N-[(2E)-3-[4-[[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]phenyl]amino]-6- quinazolinyl]-2-propen-l-yl]acetamide; BIBU 1361 diHCl (N-(3-Chloro-4-fluorophenyl)-6-[4- [(diethylamino)methyl]-l-piperidinyl]-pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride); BIBU 1382 (N8-(3-Chloro-4-fluorophenyl)-N2-(l-methyl-4-piperidinyl)-pyrimido[5,4- ]pyrimidine-2,8-diamine dihydrochloride); JNJ 28871063 HC1 (5E-4-Amino-6-(4-benzyloxy-3- chlorophenylamino)pyrimidine-5-carboxaldehyde N-(2-morpholin-4-ylethyl) oxime hydrochloride); PD 153035 (4-[(3-Bromophenyl)amino]-6,7-dimethoxyquinazolinehydrochloride); PD 158780 (N4-(3-Bromophenyl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6- diamine), and pharmaceutically acceptable salts or a pharmaceutical compositions thereof.

[0105] In some embodiments, the ERBB family inhibitor is an anti-EGFR antibody, an anti- HER2 antibody or a combination of an anti-EGFR antibody and anti-HER2 antibody, or pharmaceutical compositions thereof. In some cases, antibodies, including monoclonal antibodies, antibody drug conjugates and bispecific antibodies, targeting EGFR and / or HER-2 are used.

[0106] In some embodiments, exemplary anti-EGFR monoclonal antibodies approved for human clinical use include, but are not limited to, necitumumab (Eli Lilly), panitumumab (Amgen) and cetuximab (ImClone). Other anti-EGFR antibodies suitable for use in the methods include EP384, Hl l, 11.6, 225 and 199.12 (Thermo Fisher), or GT133 (GeneTex).

[0107] In some embodiments, the anti-EGFR monoclonal antibody is cetuximab.

[0108] In some embodiments, exemplary anti-HER-2 monoclonal antibodies, include but are not limited to, pertuzumab (Roche), trastuzumab (Roche) and trastuzumab emtansine (Roche).

[0109] In some embodiments, the ERBB family inhibitor is an anti-EGFR antibody, an anti- HER2 antibody or a combination of an anti-EGFR antibody and anti-HER2 antibody, or pharmaceutical compositions thereof. In one embodiment, the anti-EGFR antibody is necitumumab, panitumumab or cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In some cases, the anti-HER2 antibodies suitable for use in the methods herein is pertuzumab, trastuzumab, or trastuzumab emtansine.

[0110] In some embodiments, the ERBB family inhibitor is a an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are independently selected from two agents selected from the group consisting of: AG 1478 HC1 (N-(3-Chlorophenyl)-6,7- dimethoxy-4-quinazolinanine hydrochloride); AG 494 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N- phenyl-2-propenamide; AG 555 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)- 2- propenamide; AG 556 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2- propenamide; AG 825 (E)-3-[3-[2-Benzothiazolythio)methyl]-4-hydroxy-5-methoxyphenyl]-2- cyano-2-propenamide; CP 724714 (2-Methoxy-N-[(2E)-3-[4-[[3-methyl-4-[(6-methyl-3- pyridinyl)oxy]phenyl]amino]-6-quinazolinyl]-2-propen-l-yl]acetamide; BIBU 1361 diHCl (N- (3-Chloro-4-fluorophenyl)-6-[4-[(diethylamino)methyl]-l-piperidinyl]-pyrimido[5,4- ]pyrimidin- 4-amine dihydrochloride); BIBU 1382 (N8-(3-Chloro-4-fluorophenyl)-N2-(l-methyl-4- piperidinyl)-pyrimido[5,4-J]pyrimidine-2,8-diamine dihydrochloride); JNJ 28871063 HC1 (5E- 4-Amino-6-(4-benzyloxy-3-chlorophenylamino)pyrimidine-5-carboxaldehyde N-(2- morpholin- 4-ylethyl) oxime hydrochloride); PD 153035 (4-[(3-Bromophenyl)amino]-6,7- dimethoxyquinazoline hydrochloride); PD 158780 (N4-3-Bromophenyl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine) or pharmaceutically acceptable salts or pharmaceutically compositions thereof. EGFR Inhibitors

[0111] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) a EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0112] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0113] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) a EGFR inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0114] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a EGFR inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0115] In some embodiments, Formula (II) is represented by Formula (II*).

[0116] In some embodiments, Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein tyrosine kinase of the ERBB receptor family. Upon binding epidermal growth factor (EGF), the EGFR receptor can homo-dimerize with another EGFR molecule or hetero-dimerize with another family member such as ErbB2 (HER2), ErbB3 (HER3), or ErbB4 (HER4). Homo- and / or heterodimerization of ERBB receptors results in the phosphorylation ofkey tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival. In some cases, overexpression of the EGFR gene has been identified in a variety of cancers including bladder, brain, head and neck, pancreas, lung, breast, ovary, colon, prostate, and kidney.

[0117] In some embodiments, the EGFR inhibitor is cetuximab. SHP-2 Inhibitors

[0118] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0119] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0120] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0121] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0122] In some cases, Formula (II) is represented by Formula (II*).

[0123] Src homology 2 (SH2) domain-containing phosphatase 2 (“SHP-2”) is a mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase (P13K)-AKT-mTOR pathways, SHP-2 polypeptide is comprised of two Src homology 2 (SH2) domains (N-SH2and C-SH2) located in the N-terminal region and two potential Grb2 SH2domain binding sites located in the C-terminal region.

[0124] In some embodiments, SHP-2 has been shown to exhibit non-mutational drug resistance mechanism in response to anti-tyrosine kinase inhibitors (TKIs). In some cases, an increase in SHP-2 phosphatase activity has been shown to confer resistance to the TKI inhibitor imatinib (e.g., see Li et. ah, (2018) Toxicol. Appl. Pharmacol.360-249-256). The addition of a SHP-2 inhibitor was shown to overcome resistance by blocking both the RAF / MEK / ERK pathway as well as the PI3K / AKT / mTOR pathways.

[0125] Several inhibitors exhibiting activity against SHP-2 have been developed. Exemplary SHP-2 inhibitors 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), RMC-4630 (Revolution Medicine) and TNO155 (Novartis). RMC-4630 and TNO155 are in Phase 1 human clinical trials for adult patients having particular advanced solid tumors.

[0126] In some embodiments, methods for manufacturing SHP-2 inhibitors are well known to those skilled in the art and SHP-2 inhibitors may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or human use. In addition, suitable SHP-2 inhibitors for use in the compositions and methods disclosed herein and methods for preparing such inhibitors are disclosed in US Patent Application Publication Nos: US20190127378; US20180251471; US 20180201623; US 20180186770; US20180170862; US 20180065949; US20170204080; US20170166510; US20170011975; US201200334186; US20120257184; US20110190315; US20090042788; US20080194563; US20080058431; US20080058431; US20040121384; US20040043434; and US20040110800. SOS1 Inhibitors

[0127] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of:i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0128] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0129] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0130] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0131] In some cases, Formula (II) is represented by Formula (II*).

[0132] In some embodiments, SOS1 inhibitors block the interaction between SOS1 and Ras- family members and prevent the recycling of KRas in to the active GTP-bound form and, therefore, may provide therapeutic benefit for a wide range of cancers, particularly Ras family member-associated cancers. These compounds negatively modulate the activity of KRas through blocking SOS1- KRas interaction in a cell for treating various forms of cancer, including Ras- associated cancer, SOS1-associated cancer and NFl / NF2-associated cancer.

[0133] In some embodiments, one SOS1 inhibitor that can be used for the methods describedherein is BI-I-13 (aka BI-3406). It has the following structure: KRAS Modulators

[0134] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. The compounds and salts may be used in combination with at least one other inhibitor (e.g., RTK-MAPK pathway inhibitor, RAF-MEK-ERK pathway inhibitor, ERBB family inhibitor, EGFR inhibitor, SHP-2 inhibitor, or SOS1 inhibitor). The compounds and salts may be used in combination with one other inhibitor (e.g., RTK-MAPK pathway inhibitor, RAF-MEK-ERK pathway inhibitor, ERBB family inhibitor, EGFR inhibitor, SHP-2 inhibitor, or SOS1 inhibitor). In some cases, a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof, may be used in the methods of the disclosure. In some cases, a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof, may be referred to as a KRAS inhibitor. In some cases, a compound of Formula (I), Formula (II), Formula (III), or Formula (II*), may be referred to as a KRAS inhibitor. In some cases, a compound of Formula (I), Formula (II), Formula (III), or Formula (II*), may be referred to as a KRAS modulator.

[0135] In some embodiments, a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R21)2, -L-NHC(=NH)NH2, -L- C(O)N(R21)2, -L-C1-C6haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L- S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L-OC(O)N(R21)2, or -LC(=O)OC1-C6alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl are optionally substituted with one or more R7; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12- membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4.

[0136] In some embodiments, Formula (I) is represented by Formula (II), Formula (II*), or Formula (III).

[0137] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a heterocycle wherein the heterocycle is optionally substituted with one or more substituents selected from R4. In some cases, Ring A includes at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some cases, the heteroatom of Ring A is nitrogen, wherein the nitrogen is optionally substituted with R3, wherein R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, the heteroatom of Ring A is sulfur, wherein the sulfur is optionally substituted with 1 or 2 oxygen atoms. In some cases, the heteroatom of Ring A is oxygen.

[0138] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a carbocycle, wherein the carbocycle is optionally substituted with one or more substituents selected from R4.

[0139] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2.

[0140] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2.

[0141] In some embodiments, for a compound or salt of Formula (I), each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O- C1-10alkyl, and oxo. In some cases, each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6alkyl.

[0142] In some embodiments, for a compound or salt of Formula (I), R2is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6.

[0143] In some embodiments, for a compound or salt of Formula (I), R2is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

[0144] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from an optionally substituted C1-C4alkylene; and wherein optionally two substituents onthe same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0145] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0146] In some embodiments, for a compound or salt of Formula (I), wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle. In some cases, each L is independently selected from.

[0147] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0148] In some embodiments, for a compound or salt of Formula (I), R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0149] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0150] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected fromandwherein the heterocycle portion is optionally substituted with one or more R6.

[0151] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected fromand, wherein the heterocycle portion is optionally substituted with one or more R6.

[0152] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In somecases, Y-R2is selected from, , and . In some cases, Y-R2is selected from

[0153] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, C1-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0154] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

[0155] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, C1- C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3alkyl, C1-C3alkoxy, and -N(R5)2.

[0156] In some embodiments, for a compound or salt of Formula (I), R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3alkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0157] In some embodiments, for a compound or salt of Formula (I), R2is selected from

[0158] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0159] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0160] In some embodiments, for a compound or salt of Formula (I), Y-R2is.

[0161] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from , and.

[0162] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15carbocycle.

[0163] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15fused carbocycle.

[0164] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic.

[0165] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0166] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0167] In some embodiments, for a compound or salt of Formula (I), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fusedcarbocycle is selected from, each of which is optionally substituted with one or more substituents.

[0168] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from, and, each of which is optionally substituted with one or more substituents.

[0169] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from,, each of which is optionally substituted with one or more substituents.

[0170] In some embodiments, for a compound or salt of Formula (I), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, - CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0171] In some embodiments, for a compound or salt of Formula (I), B is selected from

[0172] In some embodiments, for a compound or salt of Formula (I), for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, - NH2, CN, halogen, C1-C3alkyl.

[0173] In some embodiments, for a compound or salt of Formula (I), B is selected from

[0174] In some embodiments, for a compound or salt of Formula (I), each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4is independently selected from C1-6alkyl, oxo, and halogen.

[0175] In some embodiments, for a compound or salt of Formula (I), n is selected from 1 and 2. In some cases, n is 0.

[0176] In some embodiments, for a compound or salt of Formula (I), Y is O.

[0177] In some embodiments, for a compound or salt of Formula (I), R1is selected from optionally substituted 5- to 12-membered heterocycle.

[0178] In some embodiments, for a compound or salt of Formula (I), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1- 6 alkyl, C2-6alkenyl, and C2-6alkynyl.

[0179] In some embodiments, for a compound or salt of Formula (I), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, OC(O)N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl

[0180] In some embodiments, for a compound or salt of Formula (I), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2.

[0181] In some embodiments, for a compound or salt of Formula (I), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0182] In some embodiments, for a compound or salt of Formula (I), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0183] In some embodiments, for a compound or salt of Formula (I), R20of R1is selected from hydrogen and C1-3 alkyl.

[0184] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0185] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-membered heterocycle of R1is a saturated heterocycle.

[0186] In some embodiments, for a compound or salt of Formula (I), 5- to 12-membered heterocycle of R1is a bridged heterocycle.

[0187] In some embodiments, for a compound or salt of Formula (I), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0188] In some embodiments, for a compound or salt of Formula (I), R1is selected fromoptionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0189] In some embodiments, for a compound or salt of Formula (I), R1is selected from

[0190] In some embodiments, for a compound or salt of Formula (I), L is selected from C1-C4alkylene.

[0191] In some embodiments, for a compound or salt of Formula (I), L is selected from unsubstituted C1-C4alkylene.

[0192] In some embodiments, for a compound or salt of Formula (I), R2is -L-heterocycle, optionally substituted with one or more R6, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom.

[0193] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0194] In some embodiments, for a compound or salt of Formula (I), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

[0195] In some embodiments, for a compound or salt of Formula (I), R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

[0196] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0197] In some embodiments, a compound is represented by the structure of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3;R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl;R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, - N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or moresubstituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0198] In some embodiments, for a compound or salt of Formula (II), when M is NR3, Y is O, and R1is piperazine, the piperazine is substituted with one or more R9.

[0199] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2.

[0200] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2.

[0201] In some embodiments, for a compound or salt of Formula (II), each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O- C1-10alkyl, and oxo. In some cases, each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6alkyl.

[0202] In some embodiments, for a compound or salt of Formula (II), R3is selected from hydrogen and C1-6alkyl.

[0203] In some embodiments, for a compound or salt of Formula (II), M is selected from O, NH, and NMe. In some cases, M is O. In some cases, M is selected from NH and NMe.

[0204] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted 8- to 15- membered heterocycle. In some cases, B is an optionally substituted C8-C15carbocycle.

[0205] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15fused carbocycle.

[0206] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic.

[0207] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.

[0208] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0209] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0210] In some embodiments, for a compound or salt of Formula (II), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fusedcarbocycle is selected from, each of which is optionally substituted with one or more substituents.

[0211] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected fromeach of which is optionally substituted with one or more substituents.

[0212] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from,each of which is optionally substituted with one or more substituents.

[0213] In some embodiments, for a compound or salt of Formula (II), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, - CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0214] In some embodiments, for a compound or salt of Formula (II), B is selected from

[0215] In some embodiments, for a compound or salt of Formula (II), B is selected from ,.

[0216] In some embodiments, for a compound or salt of Formula (II), each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4is independently selected from C1-6alkyl, oxo, and halogen.

[0217] In some embodiments, for a compound or salt of Formula (II), n is selected from 1 and 2. In some cases, n is 0.

[0218] In some embodiments, for a compound or salt of Formula (II), Y is O.

[0219] In some embodiments, for a compound or salt of Formula (II), R1is selected from optionally substituted 5- to 12-membered heterocycle.

[0220] In some embodiments, for a compound or salt of Formula (II), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0221] In some embodiments, for a compound or salt of Formula (II), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0222] In some embodiments, for a compound or salt of Formula (II), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2.

[0223] In some embodiments, for a compound or salt of Formula (II), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0224] In some embodiments, for a compound or salt of Formula (II), R20of R1is selected from hydrogen and C1-3alkyl.

[0225] In some embodiments, for a compound or salt of Formula (II), the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0226] In some embodiments, for a compound or salt of Formula (II), the 5- to 12-membered heterocycle of R1is a saturated heterocycle.

[0227] In some embodiments, for a compound or salt of Formula (II), 5- to 12-membered heterocycle of R1is a bridged heterocycle.

[0228] In some embodiments, for a compound or salt of Formula (II), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl. In some embodiments, for a compound or salt of Formula (II), R1is selected from,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0229] In some embodiments, for a compound or salt of Formula (II), R1is selected from

[0230] In some embodiments, for a compound or salt of Formula (II), R1is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1is selected from, which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from, which is substituted with one or more substituents selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from, and.

[0231] In some embodiments, for a compound or salt of Formula (II), R1is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -OH, -C(O)NH2, - NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl; Y is O; R2is selected from -L- heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4alkylene. In some cases, R1is selected fromsome cases, B is selected from, , , , , , and. In some cases, B is selected from, , and . Insome cases, B is.

[0232] In some embodiments, for a compound or salt of Formula (II), each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl. In some cases, each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN. In some cases, each R9is independently selected from halogen, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -N(R20)2, -NO2, =O, and =NO(R20). In some cases, each R9is independently selected from halogen, and -N(R20)2.

[0233] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from an optionally substituted C1-C4alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0234] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6carbocycle is optionallysubstituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0235] In some embodiments, for a compound or salt of Formula (II), wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle. In some cases, each L is independently selected from.

[0236] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0237] In some embodiments, for a compound or salt of Formula (II), R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0238] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0239] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from, , wherein the heterocycle portion is optionally substituted with one or more R6.

[0240] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from and, wherein the heterocycle portion is optionally substituted with one or more R6.

[0241] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected fromthe heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In some cases, Y-R2is selected fromcases, Y-R2is selected from

[0242] In some embodiments, for a compound or salt of Formula (II), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, C1-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1- C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0243] In some embodiments, for a compound or salt of Formula (II), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

[0244] In some embodiments, for a compound or salt of Formula (II), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, C1- C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3alkyl, C1-C3alkoxy, and -N(R5)2.

[0245] In some embodiments, for a compound or salt of Formula (II), R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3alkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0246] In some embodiments, for a compound or salt of Formula (II), R2is selected from

[0247] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from

[0248] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from

[0249] In some embodiments, for a compound or salt of Formula (II), Y-R2is.

[0250] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from , and.

[0251] In some embodiments, for a compound or salt of Formula (II), L is selected from C1- C4alkylene.

[0252] In some embodiments, for a compound or salt of Formula (II), L is selected from unsubstituted C1-C4alkylene.

[0253] In some embodiments, for a compound or salt of Formula (II), R2is -L-heterocycle, optionally substituted with one or more R6, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom.

[0254] In some embodiments, for a compound or salt of Formula (II), R2is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6.

[0255] In some embodiments, for a compound or salt of Formula (II), R2is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

[0256] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0257] In some embodiments, for a compound or salt of Formula (II), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl. In some cases, R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen. In some cases, Y-R2is selected from

[0258] In some embodiments, for a compound or salt of Formula (II), M is selected from NR3. In some cases, M is selected from NH and NMe. In some cases, M is selected from NMe and NCH2CH3. In some cases, M is NMe. In some cases, M is selected from C1-6cyanoalkyl. In some cases, M is selected from C2 cyanoalkyl. In some cases, M is selected from NH. In some cases, R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from hydrogen, C1-6alkyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6alkyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C2-6alkyl, C1-6 alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selectedfrom hydrogen, C1-6alkyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6alkoxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, R3is. In some cases, R3is selected from C2-6alkyl.

[0259] In some embodiments, for a compound or salt of Formula (II), M is NR3, B is selected, each of which is optionally substituted; n is 0; Y is O; R2is selected from L-heterocycle, wherein the heterocycle is optionally substituted with one or more R6; R1is, which is optionally substituted. In some cases, R1is, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, R1is. , . In some cases,. , . some cases, the heterocycle of L-heterocycle is bicyclic. In some cases, the heterocycle of L-heterocycle is monocyclic. In some cases, L is selected from an C1-C4alkylene. In some cases, L is selected from an unsubstituted C1-C4alkylene. In some cases, L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, Y-R2is selected from ,, which is substituted with one or more substituents. In some cases,, which is substituted with one or more substituents. In some cases, B is selected from, which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, - C(O)NH2, -NH2, =O, -CN, -O-C1-C3haloalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In somewhich is substituted with one or more substituents selected from halogen, -O-C1-C3haloalkyl,and C1-6haloalkyl. In some cases,, which is substituted with one or more substituents selected from halogen. In some cases, B is selected from,substituted with one or more substituents selected from fluorine. In some cases, B is selectedwith one or more substituents selected from chlorine. In some cases, B is selected from. some cases, R3is selected from hydrogen and C1-6alkyl. In some cases, R3is selected from C1-6alkyl. In some cases, R3is methyl. In some cases, each R6is selected from halogen, oxo, and C1-6alkyl. In some cases, each R6is selected from halogen, and C1-6alkyl. In some cases, each R6is selected from halogen. In some cases, R1is selected from.

[0260] In some embodiments, a compound is represented by the structure of Formula (III):Formula (III) or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; R2is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; n is selected from 0 to 3; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2- C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; Y is selected from a bond, O, S and NR5; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituentsindependently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and each R5is independently selected from hydrogen or C1-C6alkyl.

[0261] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20,-N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0262] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2.

[0263] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2.

[0264] In some embodiments, for a compound or salt of Formula (III), each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O- C1-10alkyl, and oxo. In some cases, each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6alkyl.

[0265] In some embodiments, for a compound or salt of Formula (III), R2is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6.

[0266] In some embodiments, for a compound or salt of Formula (III), R2is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

[0267] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted C8-C15carbocycle.

[0268] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15fused carbocycle.

[0269] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.

[0270] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic.

[0271] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0272] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0273] In some embodiments, for a compound or salt of Formula (III), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from, each of which is optionally substituted with one or more substituents.

[0274] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused,each of which is optionally substituted with one or more substituents.

[0275] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from,each of which is optionally substituted with one or more substituents.

[0276] In some embodiments, for a compound or salt of Formula (III), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0277] In some embodiments, for a compound or salt of Formula (III), B is selected from,

[0278] In some embodiments, for a compound or salt of Formula (III), for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, - NH2, halogen, C1-C3alkyl.

[0279] In some embodiments, for a compound or salt of Formula (III), B is selected from ,.

[0280] In some embodiments, for a compound or salt of Formula (III), each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4is independently selected from C1-6alkyl, oxo, and halogen.

[0281] In some embodiments, for a compound or salt of Formula (III), n is selected from 1 and 2. In some cases, n is 0.

[0282] In some embodiments, for a compound or salt of Formula (III), Y is O.

[0283] In some embodiments, for a compound or salt of Formula (III), R1is selected from optionally substituted 5- to 12-membered heterocycle.

[0284] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0285] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0286] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2.

[0287] In some embodiments, for a compound or salt of Formula (III), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0288] In some embodiments, for a compound or salt of Formula (III), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0289] In some embodiments, for a compound or salt of Formula (III), R20of R1is selected from hydrogen and C1-3alkyl.

[0290] In some embodiments, for a compound or salt of Formula (III), the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0291] In some embodiments, for a compound or salt of Formula (III), the 5- to 12-membered heterocycle of R1is a saturated heterocycle.

[0292] In some embodiments, for a compound or salt of Formula (III), 5- to 12-membered heterocycle of R1is a bridged heterocycle.

[0293] In some embodiments, for a compound or salt of Formula (III), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0294] In some embodiments, for a compound or salt of Formula (III), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0295] In some embodiments, for a compound or salt of Formula (III), R1is selected from

[0296] In some embodiments, for a compound or salt of Formula (III), R1is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1is selected froman optionally substituted saturated 6-membered heterocycle. In some cases, R1is selected from, which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6alkyl. Insome cases, R1is selected from , which is substituted with one or more substituents selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from.

[0297] In some embodiments, for a compound or salt of Formula (III), R1is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -OH, -C(O)NH2, - NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl; Y is O; R2is selected from -L- bicyclic heterocycle, wherein the bicyclic heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4alkylene. In some cases, R1is selected fromsome cases, B is selected from. In some cases, B is selected from . Insome cases, B is

[0298] In some embodiments, for a compound or salt of Formula (III), L is selected from C1- C4alkylene.

[0299] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from an optionally substituted C1-C4alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0300] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0301] In some embodiments, for a compound or salt of Formula (III), wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle. In some cases, each L is independently selected from.

[0302] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, theheterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0303] In some embodiments, for a compound or salt of Formula (III), R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0304] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0305] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0306] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected fromand, wherein the heterocycle portion is optionally substituted with one or more R6.

[0307] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In somecases, Y-R2is selected fromcases, Y-R2is selected from

[0308] In some embodiments, for a compound or salt of Formula (III), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, C1-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1- C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0309] In some embodiments, for a compound or salt of Formula (III), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

[0310] In some embodiments, for a compound or salt of Formula (III), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, C1- C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3alkyl, C1-C3alkoxy, and -N(R5)2.

[0311] In some embodiments, for a compound or salt of Formula (III), R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3alkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0312] In some embodiments, for a compound or salt of Formula (III), R2is selected from

[0313] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from

[0314] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from

[0315] In some embodiments, for a compound or salt of Formula (III), Y-R2is.

[0316] In some embodiments, for a compound or salt of Formula (III), L is selected from unsubstituted C1-C4alkylene.

[0317] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0318] In some embodiments, for a compound or salt of Formula (III), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

[0319] In some embodiments, for a compound or salt of Formula (III), R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

[0320] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from.

[0321] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the carbocycle of R1is selected from C3-C12carbocycle, C3-C10carbocycle, C3-C9 carbocycle, C3-C8carbocycle, or C3-C6carbocycle. In some cases, the carbocycle of R1is selected from C3-C12carbocycle, C4-C12carbocycle, C5-C12carbocycle, C6-C12carbocycle, C7- C12carbocycle, C8-C12carbocycle, or C9-C12carbocycle.

[0322] In some embodiments, for a compound of Formula (I), the heterocycle of R1is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R1is a 5- to 11-memberedheterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R1is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R1is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered heterocycle. In some cases, the heterocycle of R1is saturated. The heterocycle may be optionally substituted as described elsewhere herein.

[0323] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1is saturated. The monocyclic heterocycle may be optionally substituted as described elsewhere herein.

[0324] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12-membered bridged heterocycle, or 8- to 12-membered bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 11-membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8- membered bridged heterocycle. In some cases, the heterocycle of R1is a 6- to 11-membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9-membered bridged heterocycle, or 6- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a bridged 7- to 11-membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9- membered bridged heterocycle, or 7- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered bridged heterocycle or 5- to 9-membered bridged heterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered bridged heterocycle. Insome embodiments, the heterocycle of R1is saturated. The bridged heterocycle may be optionally substituted as described elsewhere herein.

[0325] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is a 5- to 9-membered heterocycle, the 5- to 9- membered heterocycle contains at most 1 nitrogen atom. In some embodiments, R1is selected from optionally substituted 5- to 9- membered heterocycle, each of which is optionally substituted.

[0326] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R1contains at most 1 heteroatom atom. In some embodiments, the heterocycle of R1contains at most 2 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is selected fromand. In some cases, the heterocycle is selected from, , , , and. In some cases, the bridged heterocycle is selected fromThe heterocycle may be optionally substituted as described elsewhere herein.

[0327] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the spiroheterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the spiroheterocycle of R1contains at most 2 heteroatom atoms. In some embodiments, the spiroheterocycle of R1contains at most 3 heteroatom atoms. In some embodiments, the spiroheterocycle of R1contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R1contains at least 2 heteroatom atoms. In some cases, the spiroheterocycle of R1contains at least 3 heteroatom atoms. In some cases, the spiroheterocycle of R1contains at least 4 heteroatom atoms. In some cases, the spiroheterocycle of R1contains at least 2 nitrogen atoms. In some embodiments, the spiroheterocycle of R1contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R1contains at most 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the spiroheterocycle of R1is selected from,some embodiments, the spiroheterocycle of R1is selected fromThe spiroheterocycle may be optionally substituted as described elsewhere herein.

[0328] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from optionally substituted 7- to 8-membered spiroheterocycle. In some cases, R1is selected from optionally substituted 7-membered spiroheterocycle. In some cases, R1is selected from optionally substituted 8-membered spiroheterocycle.

[0329] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 7- to 11- membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6- membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein.

[0330] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1is selected from a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is selected from a 9- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is selected from a 10- to 12- membered fused heterocycle. The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6aminoalkyl, C1-6alkoxy,C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy,C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0331] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the fused heterocycle of R1contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle isThe fused heterocycle may be optionally substituted as described elsewhere herein.

[0332] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted.

[0333] In some embodiments, for a compound of Formula (I), R1is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12- membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6aminoalkyl, C1-6alkoxy,C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0334] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0335] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), for R1, R20of -OR20and -N(R20)2, is selected hydrogen and C1-6alkyl.

[0336] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C6-C7 carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, R1is selected from C6-C7carbocycle, each of which is optionally substituted.

[0337] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, - N(R20)C(O)N(R20)2, and C1-6alkyl.

[0338] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), one or more optional substituents of R1are independently selected from halogen, -OR20, - N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, the one or more optional substituents of R1are independently selected from -OR20, -N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6alkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, C1-6aminoalkyl, and C1-6hydroxyalkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, C1-6aminoalkyl, C1-6alkyl, and C1-6hydroxyalkyl. In some cases, the one or more optional substituents of R1are independently selected from -OR20, -N(R20)2, and C1-6alkyl. In some cases, the one or more optional substituents of R1are independently selected from -N(R20)C(O)N(R20)2.

[0339] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R1is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, - OR20, -SR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =N(R20), -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0340] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R1is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, - OR20, -SR20, -N(R20) S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0341] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, - N(R20)2, C1-6alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl.

[0342] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, - N(R20)2, C1-6alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl. In some cases, R1is selected from, , , , , , wherein each is optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2,C1-6cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl. In some cases, R1is selected from, , , , , , ,

[0343] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - OR20, -N(R20)2, C1-6alkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, -N(R20)C(O)N(R20)2, - N(R20)C(O)R20, and -B(OR20)2. In some cases, R1is selected fromeach of which is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6alkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, - N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2.

[0344] In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1is selected from, , , , , , ,, , , , , and .

[0345] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - N(R20)2, -OR20, and C1-6alkyl. In some cases, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, and C1-6alkyl. In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1is selected fromand , each of which is optionally substituted with one or more substituents independently selected from -OR20, and C1-6alkyl. In some cases, R1is selected from, , and .

[0346] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, , , , , ,, , , , , , , and, each of which are optionally substituted.

[0347] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, , , , each of which is optionally substituted with one or more substituents independently selected from -OH, -CN, oxo, C1-6cyanoalkyl.

[0348] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from,,

[0349] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from , each of which are optionally substituted.

[0350] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from , each of which are optionally substituted.

[0351] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, each of which are optionally substituted.

[0352] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1iswhich is optionally substituted.

[0353] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, , , ,

[0354] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, , , , and . In some cases, R1is . Insome cases, R1is .

[0355] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), wherein the 5- to 12-membered heterocycle of R1is unsaturated and a bridged heterocycle. In some cases, R1is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. In some cases, R1is selected from.

[0356] In some embodiments, for a compound of Formula (I) or Formula (II), R1is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2, C1-6cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl; R3is naphthalene, wherein naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6alkyl, C2-6alkynyl, C1-6aminoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl; R4is selected from hydrogen, halogen or C1-C3alkyl; Y is O; L is independently a C1-C4alkylene; R2is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2. In some cases, Y-R2is selected fromwherein the heterocycle portion is optionally substituted.

[0357] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom.

[0358] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 6- to 7-membered heterocycle. In some cases, R1is selected from 7- membered heterocycle. In some cases, R1is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7- membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to7-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R1is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R1is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R1is selected from, each of which is substituted. In some cases, R1is selected from,, ,, each of which is substituted. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, - NO2, =O, -CN, C1-6fluoroalkyl, and C2-6alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkenyl. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =O, -CN, and C2-6alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the substituents of R1are each selected from one or more halogen, -OH, -NHCN, =O, -CN, and C2-6alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6alkyl. In some cases, R1is selected from, , , a d . In some cases, R1is selected fromeach of which is optionally substituted. In some cases, R1is selected from, each of which is optionallysubstituted. In some cases, R1is selected fromeach of which is optionally substituted. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)-(C1-6alkoxy), -NH-C(O)-(C1-6hydroxyalkyl), -NH2, -NH(CN), =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OH, -CN, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6cyanoalkyl, C1-6alkyl, oxo, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, R1is selected from,, , , , , , ,, , , , , , and . In some cases, R1is selected from, , , , , , ,, , , , , , , , . In some cases, R1is selected from

[0359] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds. In some cases, R1is selected fromwherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is selected fromwherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is selected fromwherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is selected from, , , , ,. In some cases, R1is selected from,some cases, R1is selected from In some cases, R1is . In some cases, R1is selected from, wherein each is substituted with one or more substituents independently selected from halogen.

[0360] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6- to 7-membered heterocycle is substituted with one or more substituents selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R1is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen. In some cases, R1is selected from an unsaturated 7-membered heterocycle, substituted with at least one halogen. In some cases, R1is selected from,, , , , , , , and . In some cases1, R is selected from, , ,, , . In some cases, R1is selected from,, a d . In some cases, R1is selected fromand . Insome cases, R1is. In some cases, R1is. In some cases, R1is.

[0361] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is selected from

[0362] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 6-membered heterocycle. In some cases, the 6- membered heterocycle contains only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R1is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- membered heterocycle of R1is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R1is selected fromany of which is optionally substituted. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OR20, - N(R20)2, =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, - NH2, -NH(CN), =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In somecases, the one or more optional substituents of R1are each independently selected from fluorine, - OH, -NH2, -NH(CN), =O, -CN, C1-6hydroxyalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6- membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is a monocyclic 6-membered heterocycle. In some cases, the 6- membered heterocycle is not a bridged heterocycle. In some cases, R1is selected from, ,

[0363] In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 6-membered unsaturated heterocycle and 6- membered saturated heterocycle.

[0364] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0365] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6haloalkyl.

[0366] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from

[0367] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0368] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6haloalkyl. In some cases, R1is.

[0369] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, the 6- to 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each ofwhich is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, R1is selected from

[0370] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 10-membered heterocycle. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiro heterocycle. In some cases, the 10-membered heterocycle is a fused heterocycle. In some cases, the 10-membered heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom. In some cases, R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, -C(O)NR20OR20, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, R1is selected from,. In some cases, R1is selected from , and . In some cases, R1is selected fromInsome cases, R1is selected from. some cases, R1is selected from, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0371] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 10- membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 10-membered fused heterocycle. In some cases, R1is, which is optionally substituted. In some cases, the one or more optional substituents are selected from halogen, -OH, -C(O)N(R20)2, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, R1is, optionally substituted with one or more substituents selected from - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and C3-12carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0372] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from a 7- to 11-membered spiro heterocycle. In some cases, R1is selected from a 10-membered spiro heterocycle. In some cases, the spiro heterocycle has at least 3 nitrogen atoms. In some cases, the spiro heterocycle has at least 1 sulfur atom. In some cases, R1is selected from, each of which is optionally substituted. In some cases, the one or more optional substituents are independently selected from halogen, -OH, - N(R20)2, -NO2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, R1is selected from, and In some cases, R1is. In some cases, R1is. some cases, M is selected from O, and NR3. In some cases, M is selected from O. In some cases, M is selected from NR3. In some cases, R3is selected from C1-6alkyl. In some cases, R3is selected from C1-2 alkyl. In some cases, R3is selected from methyl.

[0373] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 8- to 10-membered fusedheterocycle. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R1is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 9- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1is selected fromand , each of which is optionally substituted with one or more substituents. In some cases, R1is, which is optionally substituted with one or more substituents. In some cases, R1is, which is optionally substituted with one or more substituents. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(=NR20)N(R20)2, -C(O)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, and 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionallysubstituted independently with one or more R1*. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1- 6 haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, -OH, -CN, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, -C(O)NR20OR20, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, C1-6alkyl-N(R20)2, - S(O)2(R20), -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from halogen, =O, - S(O)2(R20), -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from - C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20). In some cases, the optional one or more substituents are independently selected from -S(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from S(O)2(R20). In some cases, the optional one or more substituents are independently selected from S(O)R20(=NR20). In some cases, the optional one or more substituents are independently selected from -C(O)R20. In some cases, the optional one or more substituents are independently selected from -C(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from -C(O)NR20OR20. In some cases, R1is selected from, each of which is further optionally substituted. In some cases, the further one or more optional substituents are selected from halogen, -OH, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, thefurther one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6alkyl. In some cases, the further one or more optional substituents are selected from halogen, and C1-6alkyl. In some cases, the further one or more optional substituents are selected from halogen. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12-membered saturated heterocycle. In some cases, each R20is independently selected from 5- to 6-membered saturated heterocycle. In some cases, the heterocycle of R20has at least one nitrogen atom. In some cases, the heterocycle of R20has at least one sulfur atom. In some cases, the heterocycle of R20has at least one oxygen atom. In some cases, the heterocycle of R20contains only 1 heteroatom. In some cases, the heterocycle of R20has at least two heteroatoms. In some cases, the heterocycle of R20contains only 2 heteroatoms. In some cases, the optional one or more substituents of R1are independently selected from halogen, -CN, C2alkenyl,, , , ,cases, the optional one or more substituents of R1are independently selected from halogen,,, a d . In some cases, the optional one or more substituents of R1are independently selected from, , , , , ,. In some cases, the optional oneor more substituents of R1are independently selected from halogen,, ,, , , , , , and. In some cases, R1is selected from, ,, , , ,. In some cases, R1is selected from,, and . In some cases, R1is selected from, and . In some cases, R1is selected from, , ,, , . In some cases, the optional one or more substituents of R1are independently selected from halogen, and C1-6alkyl-N(R20)2. In some cases, the optional one or more substituents of R1are independently selected from halogen,, , and . In some cases, R1is selected from . In some cases, each R20is independently selected from hydrogen, C1-6alkyl, and C3-6 carbocycle. In some cases, R1is selected, and . In some cases, R1is selected, , , . In some cases, R1isselected from, which is optionally substituted with one more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OR20, and C1-6alkyl. In some cases, R1is selected from, which is optionally substituted with one more substituents independently selected from halogen and C1-6alkyl. In some cases, R1is selected from.

[0374] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from a, wherein is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and RBis selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, and -CN. In some cases, RBis selected from hydrogen, and halogen. In some cases, RBis chloride. In some cases, RBis hydrogen. In some cases,has at least 1, 2,3, or 4 heteroatoms. In some cases, has at least 1, 2, 3, or 4 nitrogen atoms. In some cases,has at least 1 oxygen atom. In some cases,is a monocyclic heterocycle. In some cases, is a bicyclic heterocycle. In some cases, is selected from an optionally substituted 5-membered heterocycle. In some cases, is selected from an optionally substituted 9-membered heterocycle. In some cases,is selected fromeach of which is optionally substituted with one or more R1*. In some cases,is selected from , ,, each of which is optionally substituted with one or more R1*. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, and C1-6alkyl. In some cases,is selected from, , ,

[0375] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), when R1is substituted with -C(O)R20, R20is selected from a 5- to 12-membered heterocycle, which is optionally substituted. In some cases, R1is substituted with - C(O)R20. In some cases, R20is selected from a 5- to 12-membered unsubstituted heterocycle. In some cases, R20is selected from a 5- to 6-membered heterocycle, which is optionally substituted. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has two heteroatoms. In some cases, the heterocycle of R20is selected from, each of which is optionally substituted. In some cases, R20is selected from. In some cases, the optional substituents are selected from C1-10alkyl, oxo, and =NH.

[0376] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH.

[0377] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is an optionally substituted 12- to 15-membered heterocycle. In some cases, R1is an optionally substituted 12-membered heterocycle. In some cases, R1is an optionally substituted 13-membered heterocycle. In some cases, R1is an optionally substituted 14- membered heterocycle. In some cases, R1is an optionally substituted 15-membered heterocycle. In some cases, the heterocycle of R1is tricyclic. In some cases, the heterocycle of R1contains a fused heterocycle. In some cases, the heterocycle of R1contains a spiro-heterocycle. In some cases, the heterocycle of R1contains a fused and spiro-heterocycle. In some cases, the heterocycle of R1is an unsaturated heterocycle. In some cases, the heterocycle of R1is a non- aromatic heterocycle. In some cases, the heterocycle of R1has at least one double bond. In some cases, the heterocycle of R1has at least two double bonds. In some cases, the heterocycle of R1has at least 2 heteroatoms. In some cases, the heterocycle of R1has at least 3 heteroatoms. In some cases, the heterocycle of R1has at least 4 heteroatoms. In some cases, the heterocycle of R1has at least 5 heteroatoms. In some cases, the heterocycle of R1has at least 6 heteroatoms. Insome cases, the heterocycle of R1has at least 7 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, the heterocycle of R1has at least 3, 4, or 5 nitrogen atoms, and at least 1 sulfur atom. In some cases, the heterocycle of R1has at least 3, 4, or 5 nitrogen atoms, and at least 1 oxygen atom. In some cases, the heterocycle of R1has at least 3, 4, or 5 nitrogen atoms. In some cases, the heterocycle of R1has at least 3, 4, or 5 nitrogen atoms and no other heteroatoms. In some cases, the heteroatoms are selected from nitrogen and sulfur. In some cases, the heteroatoms are selected from nitrogen and oxygen. In N N some cases, R1is selected from, , , ,each of which is optionally substituted with one or more substituents. In some cases, R1is selected from, , , , ,, , , , ,, , each of which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, =NH, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, C1-6alkyl, and -C(O)N(R20)2. In some cases, R1is selected from

[0378] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is an optionally substituted 12- to 15-membered heterocycle. In some cases, R1is, wherein Ring W is an optionally substituted heterocycle and Ring P is an optionally substituted carbocycle or optionally substituted heterocycle, wherein Ring P forms a spirocycle with Ring W. In some cases, Ring W is an optionally substituted fused heterocycle. In some cases, Ring P and Ring W combine to form a heterocycle having at least 12 atoms and most 15 atoms. In some cases, Ring P and Ring W have in total at least 12 atoms and most 15 atoms. In some cases, Ring W is an optionally substituted 10-membered fused heterocycle. In some cases, R1is , wherein Ring P is an optionally substituted carbocycle oroptionally substituted heterocycle. In some cases, R1is. In some cases, Ring P is an optionally substituted carbocycle. In some cases, Ring P is an optionally substituted heterocycle. In some cases, Ring P forms an optionally substituted C3-C6carbocycle or optionally substituted 4-to 6-membered heterocycle. In some cases, Ring P forms an optionally substituted C3carbocycle. In some cases, Ring P forms an optionally substituted C4carbocycle. In some cases, Ring P forms an optionally substituted C5carbocycle. In some cases, Ring P forms an optionally substituted 4-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P has at least 1, 2, or 3 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, Ring P has 1 sulfur atom. In some cases, Ring P has 1 nitrogen atom. In some cases, Ring P has 1 oxygen atom. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, -NHCN, =O, =NR20, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, =O, =NH, -CN, and C1-6alkyl. In some cases, the one or more optional substituents of Ring W are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of Ring W are independently selected fromhalogen, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(O)NR20OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, and C1-6alkyl. In some cases, the one or more optional substituents of Ring W are independently selected from -C(O)R20. In some cases, Ring P is substituted. In some cases, Ring W is substituted.

[0379] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, , , , , , , ,, , , , , , , , ,, and , each of which is optionally substituted with one or more substituents. In some cases, the one or more of the optional substituents are independently selected from halogen, -OH, -N(R20)2, -B(OH)2, -C(O)N(R20)2, -NHCN, -NO2, C1-6alkoxy, =O, -CN, C1-6alkyl, C2-6alkenyl, C1-6aminoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl. In some cases, R1isselected from, , , , , , ,.

[0380] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2is selected fromand, wherein the heterocycle portion is optionally substituted. In some cases, R2is selected fromand , wherein the heterocycle portion is optionallysubstituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3alkyl, - N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-C1-C3alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3alkyl, wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In somecases, Y-R2is selected from, , , ,, , , , , , ,, and . In some cases, Y-R2is selected from, , and . In s2ome cases, Y-R is selected from

[0381] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2is selected from -L-N(R21)2. In some cases, each R21is selected from hydrogen and C1-6alkyl. In some cases, each R21is selected from C1-6alkyl. In some cases, L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, L is. In some cases, R2is. In some cases, Y-R2is.

[0382] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), each R21is independently selected from hydrogen. In some cases, each R21is independently selected from hydrogen and C1-6alkyl. In some cases, each R21is independently selected from C1-6alkyl. In some cases, each R21is independently selected from hydrogen; and C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo.

[0383] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 8- to 10-membered fused heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R1is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturatedheterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10- membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1is selected from, each of which is optionally substituted with one or more substituents. In some cases, R1is selected from , each ofwhich is optionally substituted with one or more substituents. In some cases, R1is, which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents are independently selected from halogen, =O, -OH, -CN, -NHCN, - C(O)R20, -C(O)N(R20)2, -C(O)NR20OR20, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20, -C(O)N(R20)2, and - C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20. In some cases, the optional one or more substituents are independently selected from -C(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from -C(O)NR20OR20. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12-membered saturated heterocycle. In some cases, the optional one or more substituents of R1are independently selected from, and . In some cases, R1is selected from ,, , ,, and . In some cases, R1is selected from

[0384] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1is selected from , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from , which is substituted with one or more substituents selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from, and.

[0385] In some embodiments, for a compound or salt of Formula (I), R1is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6alkyl; B is selected from anoptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl; Ring A is selected from an optionally substituted heterocycle; Y is O; R2is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4alkylene. In some cases, R1is selected from, and. In some cases, B is selected from , , ,, , , . In some cases, B is selected from

[0386] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), B is an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10-membered fused carbocycle. In some cases, B is an unsubstituted 8- to 10- membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9-membered fused carbocycle. In some cases, B is, which is optionally substituted with one or more substituents. In some cases, B is, which is substituted with one or more substituents. In some cases, for B, the one ormore substituents are independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selected, , , , , , and which is substituted with one or more substituentsselected from halogen and C1-6haloalkyl. In some cases,, which is substituted with one or more substituents selected from halogen. In some cases, B is selected from,, , , , and . In some cases, B is , which is substituted with one or more substituents selected from fluorine. In some cases, B is selected fromsubstituted with one or more substituents selected from chlorine. In some cases, B is selected. In some cases, B is a substituted 10-membered fused carbocycle. In some cases, for the 10-membered fused carbocycle of B, the one or more substituents are independently selected from halogen, -NH2, C1-C3alkyl, -B(OH)2, -OH, - C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is, , , , , In some cases, for the 10-membered fused carbocycle of B, is substituted with at least one halogen. In some cases, B is selected from. In some cases, B is an unsubstituted 9- to 10-membered fused carbocycle. Insome cases, B is selectedand , each of which is unsubstituted. In some cases, B is. In some cases, B is

[0387] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1are independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl.

[0388] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is and the one or more optional substituents of R1are independently selectedfrom halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, -CN, C2-6alkynyl, - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from -C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from a 5-membered heterocycle and 9-membered heterocycle, each of which is optionally substituted independently with one or more R1*. In some cases, R1is substituted with at least one halogen atom and optionally substituted with one or more substituents are independently selected from -CN, C2-6alkynyl, -C(=NR20)N(R20)2, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least oxygen atom. In some cases, the heterocycle has at least one nitrogen atom and at least one oxygen atom. In some cases, heterocycle has at least two heteroatoms. In some cases, the heterocycle has at least three heteroatoms. In some cases, the heterocycle has at least four heteroatoms. In some cases, the heterocycle of the one or moreoptional substituents of R1is selected from, , , ,, , , , , , each of which is optionally substituted with one or more R1*. In some cases, the heterocycle of the one or more optional substituents of R1is selected from, which is optionally substituted with one or more R1*. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, and C1-6alkyl. In some cases, each R1*is independently selected from halogen. In some cases, each R1*is independently selected from C1-6alkyl. In some cases, each R1*is independently selected from -OR20. In some cases, each R1*is independently selected from -OH. In some cases, each R1*is independently selected from -OMe. In some cases, the heterocycle of the one or more optional substituents of R1is selected from

[0389] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1are independently selected from - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from optionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle is selected from,, each of which is optionally substituted with one or more R1*. In some cases, the one or more optional substituents of R1is selected from, , , ,

[0390] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, and C1-6alkyl. In some cases, each R1*is independently selected from halogen. In some cases, each R1*is independently selected from C1-6alkyl.

[0391] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, oxo, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -SO2R20, -NHCN, C1-6cyanoalkyl, C1-6alkyl, C1-6alkyl-N(R20)2, C2-6alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 9- membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1is selected, each of which is optionally substituted. In somecases, R1is selected , which is optionally substituted. In some cases, R1is selected,, , , and . In some cases, R1is selected, , . In some cases, R1is

[0392] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -NHCN, C1-6cyanoalkyl, C1-6alkyl, C2-6alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1is selected, , and , each of which is optionally substituted. In some cases, R1is selected, which is optionally substituted. In some cases, R1is selected, , and . In some cases, R1is selectedand . In some cases, M is selected from O, and NMe. In some cases, M is O. In some cases, M is NMe. In some cases, R2is selected from -L-N(R21)2and -L-heterocycle, optionally substituted with one or more R6. In some cases, Y-R2is selected from, ,In some cases, B is selected from an optionally substituted carbocycle. In some cases, B is selected from, each of which is optionally substituted. In some cases, B is selected from, ,F, ,, , and . In some cases, B is. In some cases, B is. In some cases, n is 0.

[0393] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from a compound in the Examples section. In some cases, Y is selected from a compound in the Examples section. In some cases, L is selected from a compound in the Examples section. In some cases, R2is selected from a compound in the Examples section. In some cases, B is selected from a compound in the Examples section.. In some cases, M is selected from a compound in the Examples section. In some cases, the optional substituents of the heterocycle for R1is selected from a compound in the Examples section.

[0394] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2is -L-N(R21)2. In some cases, R2is -L-OR21. In some cases, R2is heterocycle. In somecases, R2is C1-C6alkyl. In some cases, R2is -L-heterocycle. In some cases, R2is -L-aryl. In some cases, R2is -L-heteroaryl. In some cases, R2is -L-cycloalkyl. In some cases, R2is -L-N(R21)2. In some cases, R2is -L-NHC(=NH)NH2. In some cases, R2is -L-C(O)N(R21)2. In some cases, R2is -L-C1-C6haloalkyl. In some cases, R2is -L-OR21. In some cases, R2is -L-NR21C(O)-aryl. In some cases, R2is -L-COOH. In some cases, R2is -L-NR21S(O)2(R21). In some cases, R2is -L- S(O)2N(R21)2. In some cases, R2is -L-N(R21)C(O)(OR21). In some cases, R2is -L-OC(O)N(R21)2. In some cases, R2is or -LC(=O)OC1-C6alkyl. In some cases, the heterocycle, the aryl portion of - L-NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7. In some cases, when Y is a bond, O, or S, R2is further selected from hydrogen

[0395] In some embodiments, Formula (I) or Formula (II) is represented by Formula (II*):Formula (II*) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3is selected from hydrogen, C1-6alkyl, and C1-6cyanoalkyl; R1is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle;B is selected from C6-C15carbocycle, wherein the C6-C15carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkyl, - B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; R2is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4alkylene, wherein the C1-C4alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0396] In some embodiments, for a compound or salt of Formula (II*), R1is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, the heterocycle of R1has at least one nitrogen atom. In some cases, the at least one nitrogen at of the heterocycle of R1is bound to Formula (II*). In some cases, R1is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl. In some cases, R1is selected from, which is substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl- N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle is optionally substituted with one or more substituents selected fromhalogen, and C1-6alkyl. In some cases, R1is selected from,, , , ,, and . In some cases, R1is selected,, , , , , , and. In some cases, R1is . In some cases, M is selected from O. In some cases, M is NCH2CH3. In some cases, M is NMe. In some cases, the heterocycle of R2is a saturated heterocycle. In some cases, R6of R2is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl. In some cases, L of R2is selected from C1-C4alkylene andIn some cases, R2is selected from. In some cases, B is selected from an optionally substitutedC9-C10fused carbocycle. In some cases, B is selected from each of whichis optionally substituted. In some cases, B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-C1-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is optionally substituted with one or more substituents independently selected from halogen. In some cases, B is. In some cases, B is . In some cases, B is unsubstituted. Insome cases, B is substituted.

[0397] In some embodiments, for a compound or salt of Formula (II*), R1is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10- membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10-membered spiro heterocycle. In somecases, R1is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of R1has at least 3 heteroatoms. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)N(R20)2, - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl. Insome cases, R1is selected from , which is substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl. In some cases, R1is selected from, , , ,, , , . In some cases, R1is selected from and. In some cases, R1is. In some cases, M is selected from O. In some cases, M is NMe. In some cases, the heterocycle of R2is a saturated heterocycle. In some cases, R6of R2is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl. In some cases, L of R2is selected from C1-C4alkylene and. In some cases, R2is selected from, , , , . In some cases, B is selected from an optionally substitutedC9-C10fused carbocycle. In some cases, B is selected from, each of which is optionally substituted. In some cases, B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-C1-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is optionally substituted with one or more substituents independently selected from halogen. In some cases, B is. In some cases, B is . In some cases, B is unsubstituted. Insome cases, B is substituted.

[0398] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl. In some embodiments, for a compound or salt of Formula (I), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl. In some embodiments, for a compound or salt of Formula (II), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl. In some embodiments, for a compound or salt of Formula (III), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl.

[0399] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), each R20is independently selected from hydrogen; and C1-6alkyl.

[0400] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), is not substituted by C1-6cyanoalkyl.

[0401] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is not a piperazine. In some cases, R1is not a substituted piperazine.

[0402] In some embodiments, for a compound of Formula (I), wherein the compound is not a Michael acceptor.

[0403] In some embodiments, for a compound of Formula (I), the compound or salt does not include an electrophilic substituent.

[0404] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), does not contain an electrophile moiety.

[0405] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), does not contain a covalent modifier.

[0406] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), the one or more optional substituents of R1are not electrophiles.

[0407] In some embodiments, the compounds of Formula (I), (II), (III), or subformulas used in the methods include trifluoroacetic acid salts of the above compounds.

[0408] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0409] In some embodiments, a compound or salt of Formula (II) is administered once daily. In some embodiments, the compound or salt of Formula (II) is administered twice daily. In some embodiments, the compound or salt of Formula (II) is administered 3 times daily. In some embodiments, the compound or salt of Formula (II) is administered once weekly. In some embodiments, the compound or salt of Formula (II) is administered every other day. In some embodiments, the compound or salt of Formula (II) is administered every 3 days.

[0410] In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 150 mg. In some embodiments, the compound or salt of Formula (II) or a salt thereof is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 5 mg to 75 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0411] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered once daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0412] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) isadministered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, twice daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0413] In some embodiments, a compound of Formula (II) is administered as a capsule during the period of time. In some cases, a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, about25 mg to about 85 mg, about 25 mg to about 80 mg, about 25 mg to about 75 mg, about 25 mg to about 70 mg, about 25 mg to about 65 mg, about 25 mg to about 60 mg, about 25 mg to about 55 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg,about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of a compound of Formula (II) (e.g., compounds 53, 61, 63, 64, 69, and 96), or a pharmaceutically acceptable salt thereof.

[0414] In some embodiments, a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg,about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg,about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg,about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg), during a period of time.

[0415] In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mgto about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg toabout 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or about 400 mg), and oral administration of an inhibitor selected from: 1) RTK-MAPK pathway inhibitor; 2) RAF-MEK-ERK pathway inhibitor; 3) ERBB family inhibitor; 4) EGFR inhibitor; 5) SHP-2 inhibitor; and 6) SOS1 inhibitor; or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). In some cases, the inhibitor is an RTK-MAPK pathway inhibitor. In some cases, the inhibitor is an ERBB family inhibitor. In some cases, the inhibitor is an RAF-MEK-ERK pathway inhibitor. In some cases, the inhibitor is an EGFR inhibitor. In some cases, the inhibitor is an SHP-2 inhibitor. In some cases, the inhibitor is cetuximab. In some cases, the compound of Formula (II) is selected from a KRAS modulator described elsewhere herein. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 53. In some cases, the compound of Formula (II) is compound 61. In some cases, the compound of Formula (II) is compound 63. In some cases, the compound of Formula (II) is compound 64. In some cases, the compound of Formula (II) is compound 69. In some cases, the compound of Formula (II) is compound 96.

[0416] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0417] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0418] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:.

[0419] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0420] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0421] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, thecompounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0422] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0423] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0424] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0425] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0426] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0427] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein maybe in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0428] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0429] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0430] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0431] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Associationand Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0432] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations

[0433] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a compound of Formulas (I), (II), (II*), (III), an RTK-MAPK pathway inhibitor, an ERBB family inhibitor, an RAF-MEK-ERK pathway inhibitor, an EGFR inhibitor, an SHP-2 inhibitor, or an SOS1 inhibitor, or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”).

[0434] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0435] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In apreferred embodiment, when such pharmaceutical co...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound of Formula (II):( ) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion ofthe -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted withsubstituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

2. The method of claim 1, wherein the combination exhibits synergy.

3. The method of claims 1 or 2, wherein the therapeutically effective amount of the combination of the RTK-MAPK pathway inhibitor and the compound or salt of Formula (II) results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition, an increased duration of stable disease in the subjects relative to treatment with only the compound or salt of Formula (II), or any combination thereof.

4. The method of any one of claims 1 to 3, wherein the therapeutically effective amount of the compound or salt of Formula (II) of the combination is between about 0.01 to 100 mg / kg per day.

5. The method of any one of claims 1 to 4, wherein the therapeutically effective amount of the compound or salt of Formula (II) in the combination is between about 0.1 to 50 mg / kg per day.

6. The method of any one of claims 1 to 5, wherein the therapeutically effective amount of the RTK-MAPK pathway inhibitor of the combination is between about 0.01 to 100 mg / kg per day.

7. The method of any one of claims 1 to 6, wherein the therapeutically effective amount of the RTK-MAPK pathway inhibitor of the combination is between about 0.1 to 50 mg / kg per day.

8. The method of any one of claims 1 to 7, wherein the RTK-MAPK pathway inhibitor and the compound or salt of Formula (II) are administered on different days.

9. The method of any one of claims 1 to 8, wherein the compound or salt of Formula (II) is administered at a maximum tolerated dose.

10. The method of any one of claims 1 to 9, wherein the RTK-MAPK pathway inhibitor is administered at a maximum tolerated dose.

11. The method of any one of claims 1 to 10, wherein the RTK-MAPK pathway inhibitor and the compound or salt of Formula (II) are each administered at a maximum tolerated dose.

12. The method of any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is a RAF-MEK-ERK pathway inhibitor.

13. The method of any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is a ERBB family inhibitor.

14. The method of any one of claims 1 to 13, wherein the inhibitor is selected from the group consisting of afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, and cetuximab.

15. The method of any one of claims 1 to 14, wherein the inhibitor is cetuximab.

16. The method of any one of claims 1 to 15, wherein the RTK-MAPK pathway inhibitor is an epidermal growth factor receptor (EGFR) inhibitor.

17. The method of any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is a SHP-2 inhibitor.

18. The method of claim 17, wherein the SHP-2 inhibitor is SHP-099 (6-(4-Amino-4- methylpiperidin-l-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), RMC-4360 or TNO155 (Novartis).

19. The method of claim 17, wherein the SHP-2 inhibitor is RMC-4550.

20. The method of claim 17, wherein the SHP-2 inhibitor is RMC-4360.

21. The method of claim 17, wherein the SHP-2 inhibitor is TNO155.

22. The method of claim 17, wherein the SHP-2 inhibitor is SHP-099.

23. The method of any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is a SOS1 inhibitor.

24. The method of claim 23, wherein the SOS1 inhibitor is BI-3406.

25. The method of any one of claims 1 to 24, wherein the RTK-MAPK pathway inhibitor is administered orally.

26. The method of any one of claims 1 to 25, wherein the cancer is selected from: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

27. The method of any one of claims 1 to 26, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

28. The method of any one of claims 1 to 26, wherein the cancer is non-small cell lung cancer.

29. The method of any one of claims 1 to 26, wherein the cancer is small cell lung cancer.

30. The method of any one of claims 1 to 26, wherein the cancer is colorectal cancer.

31. The method of any one of claims 1 to 26, wherein the cancer is rectal cancer.

32. The method of any one of claims 1 to 26, wherein the cancer is pancreatic cancer.

33. The method of any one of claims 1 to 26, wherein the cancer is a solid tumor cancer.

34. The method of any one of claims 1 to 26, wherein the cancer is selected from a KRas mutant-associated cancer.

35. The method of any one of claims 1 to 26, wherein the cancer is selected from a KRas wildtype-associated cancer.

36. The method of any one of claims 1 to 26, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer.

37. The method of any one of claims 1 to 26, wherein the cancer is a KRas G12D-associated cancer.

38. The method of any one of claims 1 to 26, wherein the cancer is a KRas G12V-associated cancer.

39. The method of any one of claims 1 to 26, wherein the cancer is a KRas wildtype- associated cancer.

40. The method of any one of claims 1 to 39, wherein the RTK-MAPK pathway inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (II).

41. The method of claim 1, wherein when M is NR3, Y is O, and R1is piperazine, the piperazine is substituted with one or more R9, wherein each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

42. The method of any one of claims 1 to 41, wherein the compound or salt is selected from :, , , ,, , , , , or a salt of any one thereof.

43. The method of any one of claims 1 to 41, wherein the compound is selected from:,, , , ,, , , or a salt of any one thereof.

44. The method of any one of claims 1 to 42, wherein the compound is selected from:, , , ,, , and , or a salt of any one thereof.

45. The method of any one of claims 1 to 43, wherein the compound is selected from:, , , , or a salt of any one thereof.

46. The method of any one of claims 1 to 41, wherein the compound is selected from, , , ,, , or a salt of any one thereof.

47. The method of any one of claims 1 to 41, wherein the compound is selected fromor a salt of any one thereof.

48. The method of any one of claims 1 to 41, wherein the compound is selected from or a salt of any one thereof.

49. The method of any one of claims 1 to 41, wherein the compound is selected from, or a salt of any one thereof.

50. The method of any one of claims 1 to 41, wherein the compound is selected fromor a salt of any one thereof.

51. The method of any one of claims 1 to 41, wherein the compound is selected fromor a salt of any one thereof.

52. The method of any one of claims 1 to 41, wherein the compound is selected fromor a salt of any one thereof.

53. The method of any one of claims 1 to 51, wherein M is selected from O, NH, and NMe.

54. The method of claim 52, wherein M is O.

55. The method of any one of claims 1 to 51, wherein M is selected from NR3.

56. The method of claim 54, wherein M is selected from NH and NMe.

57. The method of claim 55, wherein M is NMe.

58. The method of any one of claims 1 to 56, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15carbocycle.

59. The method of claim 57, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15fused carbocycle.

60. The method of claim 59, wherein B is an optionally substituted 8- to 15-membered fused heterocycle.

61. The method of claim 60, wherein B is an optionally substituted unsaturated C8-C15fused carbocycle.

62. The method of any one of claim 59 to 61, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle are each independently bicyclic or tricyclic.

63. The method of claim 62, wherein for B the heterocycle and carbocycle are each independently bicyclic.

64. The method of claim 62, wherein for B the heterocycle and carbocycle are each independently tricyclic.

65. The method of any one of claims 59 to 64, wherein B is selected from, ,, , , , and , each of which is optionally substituted with one or more substituents.

66. The method of claim 65, wherein B is selected from, , , and , each of which is optionally substituted with one or more substituents.

67. The method of claim 66, wherein B is selected from, each of which is optionally substituted with one or more substituents.

68. The method of any of claims 58 to 67, wherein for B, the one or more optional substituents are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

69. The method of any one of claims 1 to 68, wherein B is selected from,.

70. The method of any of claims 58 to 67, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl.

71. The method of any of claims 58 to 67, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-C1-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl.

72. The method of any of claims 58 to 71, wherein B is selected from,73. The method of any one of claims 1 to 72, wherein each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen.

74. The method of claim 73, wherein each R4is independently selected from C1-6alkyl, oxo, and halogen.

75. The method of any one of claims 1 to 74, wherein n is selected from 1 and 2.

76. The method of any one of claims 1 to 75, wherein n is 0.

77. The method of any one of claims 1 to 76, wherein R1is selected from optionally substituted 5- to 12-membered heterocycle.

78. The method of claim 77, wherein R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

79. The method of claim 78, wherein R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

80. The method of claims 78 or 79, wherein R20is selected from hydrogen and C1-3 alkyl.

81. The method of any one of claims 77 to 79, wherein the 5- to 12-membered heterocycle of R1is unsaturated.

82. The method of any one of claims 77 to 79, wherein the 5- to 12-membered heterocycle of R1is saturated.

83. The method of any one of claims 77 to 79, wherein the 5- to 12-membered heterocycle of R1is a bridged heterocycle.

84. The method of any one of claims 77 to 83, wherein R1is selected from,, each of which is optionally substituted.

85. The method of claim 84, wherein the optional one or more substituents are each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

86. The method of claim 84, wherein R1is selected from,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

87. The method of claim 86, wherein R1is selected from, ,.

88. The method of any one of claims 77 to 83, wherein R1is selected from 6- to 8-membered heterocycle, which is optionally substituted.

89. The method of claim 88, wherein R1is selected from 7-membered saturated heterocycle, 8-membered bridged heterocycle, and 6- to 7-membered unsaturated heterocycle, each of which is optionally substituted.

90. The method of claim 89, wherein R1is selected from, each of which is optionally substituted.

91. The method of claim 90, wherein the one or more optional substituents are independently selected from -OH, -CN, oxo, C1-6cyanoalkyl.

92. The method of claims 90 or 91, wherein R1is selected from,.

93. The method of any one of claims 1 to 76, wherein R1is selected from an optionally substituted 6- to 7-membered heterocycle.

94. The method of claim 93, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle is optionally substituted.

95. The method of claim 94, wherein the 6- to 7-membered heterocycle of R1is bound to Formula (II) via the only 1 nitrogen atom.

96. The method of any one of claims 93 to 95, wherein R1is selected from an optionally substituted unsaturated 6-membered heterocycle.

97. The method of any one of claims 93 to 95, wherein R1is selected from an optionally substituted unsaturated 7-membered heterocycle.

98. The method of any one of claims 93 to 97, wherein R1is selected from,, any of which is optionally substituted.

99. The method of any one of claims 93 to 98, wherein R1is selected from, ,, any of which is optionally substituted.

100. The method of any one of claims 93 to 99, wherein the one or more optional substituents of R1are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, -NHCN, and C2-6alkynyl.

101. The method of any one of claims 93 to 100, each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

102. The method of any one of claims 93 to 101, wherein the one or more optional substituents of R1are each independently selected from halogen.

103. The method of any one of claims 93 to 102, wherein R1is selected from,104. The method of any one of claims 93 to 101, wherein R1is selected from,, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

105. The method of claim 104, wherein R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

106. The method of claim 105, wherein R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6haloalkyl.

107. The method of claim 106, wherein R1is selected from, , ,.

108. The method of any one of claims 93 to 101, wherein R1is selected from, which is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

109. The method of claim 108, wherein R1is selected from , which is optionally substituted with one or more substituents independently selected from halogen.

110. The method of claim 109, wherein R1is selected from111. The method of claim 93, wherein R1is selected from 6- to 7-membered heterocycle.

112. The method of claim 111, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur.

113. The method of claim 112, wherein the optionally one or more additional heteroatoms are selected from sulfur.

114. The method of any one of claims 111 to 113, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms.

115. The method of any one of claims 111 to 114, wherein the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle.

116. The method of any one of claims 112 to 115, wherein the 6- to 7-membered heterocycle of R1is bound to Formula (II) via the only 1 nitrogen atom.

117. The method of any one of claims 111 to 116, wherein R1is selected from , ,f which is optionally substituted.

118. The method of claim 117, wherein the one or more optional substituents of R1are each independently selected from halogen, -OH, -CN, C1-6cyanoalkyl, -NHCN, C1-6alkyl, oxo, and C2-6alkynyl.

119. The method of claim 113, wherein R1is selected from an optionally substituted 6- to 10- membered heterocycle.optionally substituted.

121. The method of claim 120, wherein the one or more optional substituents are independently selected from halogen, =O, -OH, -C(O)N(R20)2, C2-6alkynyl, -NHCN, -CN, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl.

122. The method of claim 121, wherein R1is selected from,123. The method of claim 77, wherein R1is selected from a 7- to 11-membered spiro heterocycle.

124. The method of claim 123, wherein R1is selected from a 10-membered spiro heterocycle.

125. The method of claims 123 or 124, wherein the spiro heterocycle has at least 3 nitrogen atoms.

126. The method of claim 125, wherein R1is selected from, each of which is optionally substituted.

127. The method of claim 126, wherein R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

128. The method of claim 127, wherein R1is selected from,129. The method of claim 77, wherein R1is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle.

130. The method of claim 129, wherein R1is selected from an optionally substituted unsaturated 10-membered heterocycle.

131. The method of claim 130, wherein, which is optionally substituted.

132. The method of claim 131, wherein, which is optionally substituted with one or more substituents selected from halogen, -OH, -C(O)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. 1 . The compound or salt of claim 132, wherein R1is selected fromoptionally substituted with one or more substituents selected from halogen, -OH, -N(R20)2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl.

134. The method of claim 77, wherein R1is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle.

135. The method of claim 134, wherein R1is selected from an optionally substituted unsaturated 10-membered heterocycle.

136. The method of claim 135, wherein, which is optionally substituted.

137. The method of claim 136, wherein the one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, -OR20, and C1-6alkyl.

138. The method of any one of claims 134 to 137, wherein R1is selected from139. The method of any one of claims 134 to 138, wherein R1is selected from,,.

140. The method of any one of claims 134 to 137, wherein the one or more optional substituents of R1are independently selected from halogen, -OH, -N(R20)2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, -C(O)N(R20)2, C1-6alkyl, and C2-6alkynyl.

141. The method of claim 140, wherein the one or more optional substituents of R1are independently selected from halogen, and -C(O)N(R20)2.

142. The method of claim 141, wherein R1is selected from.

143. The method of any one of claims 134 to 137, wherein the one or more optional substituents of R1are independently selected from halogen, -N(R20)2, -CN, C1-6alkyl, C1-6cyanoalkyl, C1-6alkyl-N(R20)2, C1-6alkyl-SO2-C1-6alkyl, C2-6alkenyl, - C(O)NR20OR20, -C(O)N(R20)2, -C(O)R20, and 5- to 10-membered heterocycle, wherein the 5- to10-membered heterocycle is optionally substituted independently with one or more R1*, wherein each R1*is independently selected from halogen, -OR20, and C1-6alkyl.

144. The method of claims 143, wherein the one or more optional substituents of R1are selected from chlorine, -NH2, -CN, C1alkyl, C2alkenyl,, , ,.

145. The method of claim 144, wherein R1is selected from,,146. The method of any one of claims 1 to 76, wherein R1is an optionally substituted 12- to 15-membered heterocycle.

147. The method of claim 146, wherein R1is an optionally substituted 12-membered heterocycle.

148. The method of claim 146, wherein R1is an optionally substituted 13-membered heterocycle.

149. The method of claim 146, wherein R1is an optionally substituted 14-membered heterocycle.

150. The method of claim 146, wherein R1is an optionally substituted 15-membered heterocycle.

151. The method of any one of claims 146 to 150, wherein the heterocycle of R1is tricyclic.

152. The method of any one of claims 146 to 151, wherein the heterocycle of R1contains a fused heterocycle.

153. The method of any one of claims 146 to 152, wherein the heterocycle of R1contains a spiro heterocycle.

154. The method of any one of claims 146 to 153, wherein the heterocycle of R1contains a fused and spiro-heterocycle.

155. The method of any one of claims 146 to 154, wherein the heterocycle of R1is an unsaturated heterocycle.

156. The method of any one of claims 146 to 155, wherein the heterocycle of R1is a non- aromatic heterocycle.

157. The method of any one of claims 146 to 156, wherein the heterocycle of R1has at least one double bond.

158. The method of any one of claims 146 to 157, wherein the heterocycle of R1has at least two double bonds.

159. The method of any one of claims 146 to 158, wherein the heterocycle of R1has two double bonds.

160. The method of any one of claims 146 to 159, wherein R1is selected from, ,, each of which is optionally substituted with one or more substituents.

161. The method of claim 160, wherein the optional one or more substituents are selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl.

162. The method of claim 161, wherein the optional one or more substituents are selected from halogen, -OH, C1-6alkyl, and -C(O)N(R20)2.

163. The method of any one of claims 146 to 162, wherein R1is selected from,164. The method of claim 93, wherein R1is selected from substituted 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle is substituted with at least one -NHCN, and further optionally substituted with one or more C1-6alkyl.

165. The method of claim 164, wherein R1is selected from.

166. The method of any one of claims 1 to 75, wherein R1is selected from 8- to 10-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)2, -C(O)R20, - C(O)OR20, -NHCN, C1-6cyanoalkyl, C1-6alkyl, C2-6alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl.1167. The method of claim 166, wherein R is selected , , and , each of which is optionally substituted.

168. The method of claim 167, wherein R1is selected , which is optionally substituted.

169. The method of claim 168, wherein R1is selected from,170. The method of claim 167, wherein R1is selected.

171. The method of any one of claims 1 to 170, wherein Y is O.

172. The method of any one of claims 1 to 171, wherein R2is -L-heterocycle, optionally substituted with one or more R6.

173. The method of claim 172, wherein L is selected from C1-C4alkylene.

174. The method of claim 173, wherein L is selected from unsubstituted C1-C4alkylene.

175. The method of claims 173, wherein each L is independently selected from a C1-C4alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

176. The method of claims 175, wherein the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

177. The method of claims 1 to 176, wherein Y-R2is selected fromand, wherein the heterocycle portion is optionally substituted with one or more R6.

178. The method of claim 177, wherein R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

179. The method of claim 178, wherein R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

180. The method of claim 177 to 179, wherein Y-R2is selected from,181. The method of any one of claims 171 to 175, wherein Y-R2is selected fromoptionally substituted with one or more R6.

182. The method of claim 181, wherein R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, oxo, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

183. The method of claim 182, wherein R6is selected from halogen and C1-C3alkyl.

186. The method of claim 1 to 171, wherein R2is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6.

187. The method of claim 186, wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

188. The method of claim 187, wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle.

189. The method of claim 188, wherein each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle.

190. The method of claim 189, wherein each L is independently selected from.

191. The method of claim 190, wherein Y-R2is.

192. The method of claim 1 to 176, wherein Y-R2is selected from, wherein the heterocycle is optionally substituted.

193. The method of claim 192, wherein the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-C1-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2,and-O-C1-C3alkyl, wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. , ,195. The method of any one of claims 1 to 176 or 186 to 190, wherein R2is selected from -L- N(R21)2.

196. The method of claim 195, wherein L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen.

197. The method t of claims 1, 195 or 196, wherein L is .N 198. The method of any one of claims 1, or 195 to 197, wherein R2is.,,,, , , ,, a d , or a pharmaceutically acceptable salt of any one thereof.

201. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (III):or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*;each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; R2is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; n is selected from 0 to 3; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; Y is selected from a bond, O, S and NR5; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and each R5is independently selected from hydrogen or C1-C6alkyl.

202. The method of claim 201, wherein R2is selected from L-pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

203. The method of any one of claims 201 to 202, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15carbocycle.

204. The method of claim 203, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15fused carbocycle.

205. The method of claim 204, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle.

206. The method of claim 204, wherein B is selected from an optionally substituted unsaturated C8-C15fused carbocycle.

207. The method of any one of claim 203 to 206, wherein for B the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle are each bicyclic and tricyclic.

208. The method of claim 207, wherein for B the heterocycle and carbocycle are each independently bicyclic.

209. The method of claim 207, wherein for B the heterocycle and carbocycle are each independently tricyclic.

210. The method of any one of claims 201 to 209, wherein B is selected from,each of which is optionally substituted with one or more substituents.

211. The method of claim 210, wherein B is selected from, , ,, each of which is optionally substituted with one or more substituents.

212. The method of claim 211, wherein B is selected from, each ofwhich is optionally substituted with one or more substituents.

213. The method of any of claims 201 to 212, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

214. The method of any one of claims 201 to 213, wherein B is selected from,.

215. The method of any of claims 201 to 212, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl.

216. The method of claim 205, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, - NH2, C1-C3alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl.

217. The method of any of claims 215 to 216, wherein B is selected from,218. The method of any one of claims 201 to 217, wherein each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen.

219. The method of claim 218, wherein each R4is independently selected from C1-6alkyl, oxo, and halogen.

220. The method of any one of claims 201 to 219, wherein n is selected from 1 and 2.

221. The method of any one of claims 201 to 219, wherein n is 0.

222. The method of any one of claims 201 to 211, wherein Y is O.

223. The method of any one of claims 201 to 212, wherein R1is selected from optionally substituted 5- to 12-membered heterocycle.

224. The method of claim 223, wherein R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

225. The method of claim 224, wherein R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

226. The method of claims 224 or 225, wherein R20is selected from hydrogen and C1-3alkyl.

227. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1is unsaturated.

228. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1is saturated.

229. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1is bridged.

230. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1is a spiro heterocycle. 1231. The method of claims 201 to 230, wherein R is selected from , ,, , , , , , , ,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

232. The method of claim 231, wherein R1is selected from,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

233. The method of claim 232, wherein R1is selected from.

234. The method of claims 201 to 233, wherein R2is -L-heterocycle, optionally substituted with one or more R6.

235. The method of claim 234, wherein L is selected from C1-C4alkylene.

236. The method of claim 235, wherein L is selected from unsubstituted C1-C4alkylene.

237. The method of any one of claims 234 to 236, wherein Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

238. The method of claim 237, wherein R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

239. The method of claim 238, wherein R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

240. The method of claim 239, wherein Y-R2is selected from.

241. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof wherein:R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, - L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R21)2,-L-NHC(=NH)NH2, -L- C(O)N(R21)2, -L-C1-C6haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), - L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L- heterocycle and the cycloalkyl portion of the -L-cycloalkyl may be optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl may be optionally substituted with one or more R7; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl;each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen,cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12- membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4.

242. The method of claim 241, wherein B is selected from an optionally substituted 5- to 15- membered heterocycle and optionally substituted C3-C15carbocycle.

243. The method of claim 242, wherein B is selected from an optionally substituted 8- to 15- membered fused heterocycle and optionally substituted C8-C15fused carbocycle.

244. The method of claim 243, wherein B is an optionally substituted 8- to 15-membered fused heterocycle.

245. The method of claim 243, wherein B is an optionally substituted unsaturated C8-C15fused carbocycle.

246. The method of any one of claim 241 to 245, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle are each independently bicyclic or tricyclic.

247. The method of claim 246, wherein for B, the heterocycle and carbocycle are each independently bicyclic.

248. The method of claim 246, wherein for B, the heterocycle and carbocycle are each independently tricyclic.

249. The method of any one of claims 241 to 248, wherein B is selected from,, each of which is optionally substituted with one or more substituents.

250. The method of claim 249, wherein B is selected from,, each of which is optionally substituted with one or more substituents.

251. The method of claim 250, wherein B is selected from,which is optionally substituted with one or more substituents.

252. The method of any of claims 241 to 251, wherein for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

253. The method of any one of claims 241 to 252, wherein B is selected from,.

254. The method of any one of claims 241 to 253, wherein each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen.

255. The method of claim 254, wherein each R4is independently selected from C1-6alkyl, oxo, and halogen.

256. The method of any one of claims 241 to 255, wherein Y is O.

257. The method of any one of claims 241 to 256, wherein R1is selected from optionally substituted 5- to 5-membered heterocycle.

258. The method of claim 257, wherein R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

259. The method of claim 258, wherein R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

260. The method of claims 258 to 259, wherein R20is selected from hydrogen and C1-3alkyl.

261. The method of any one of claims 241 to 260, wherein the 5- to 12-membered heterocycle of R1is unsaturated.

262. The method of any one of claims 241 to 260, wherein the 5- to 12-membered heterocycle of R1is saturated.

263. The method of any one of claims 241 to 260, wherein the 5- to 12-membered heterocycle of R1is bridged.

264. The method of any one of claims 245 to 260, wherein R1is selected from,, each of which is optionally substituted with one or more substituentsindependently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

265. The method of claim 264, wherein R1is selected from,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

266. The method of claim 265, wherein R1is selected from, ,.

267. The method of any one of claims 241 to 266, wherein R2is -L-heterocycle, optionally substituted with one or more R6.

268. The method of any one of claims 241 to 267, wherein L is selected from C1-C4alkylene.

269. The method of claims 267 or 268, wherein L is selected from unsubstituted C1-C4alkylene.

270. The method of any one of claims 231 to 259, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

271. The method of claim 270, wherein R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

272. The method of claim 271, wherein R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

273. The method of claim 272, wherein Y-R2is selected from, ,.

274. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (II*):or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3is selected from hydrogen, C1-6alkyl, and C1-6cyanoalkyl; R1is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; B is selected from C6-C15carbocycle, wherein the C6-C15carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkyl, - B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl;R2is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4alkylene, wherein the C1-C4alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle.

275. The method of claim 274, wherein R1is selected from an optionally substituted 7- to 10- membered spiro heterocycle and optionally substituted 7- to 10-membered fused heterocycle.

276. The method of claims 274 or 275, wherein the heterocycle of R1has at least one nitrogen atom.

277. The method of claim 276, wherein the at least one nitrogen at of the heterocycle of R1is bound to Formula (II*).

278. The method of any one of claims 275 to 277, wherein R1is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle.

279. The method of any one of claims 275 to 278, wherein the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl.

280. The method of any one of claims 275 to 279, wherein the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl.

281. The method of any one of claims 275 to 280, wherein R1is selected from, which is substituted.

282. The method of any one of claims 275 to 281, wherein R1is selected fromsubstituted with one or more substituents independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl.

283. The method of any one of claims 275 to 281, wherein R1is selected from, , , ,284. The method of any one of claims 275 to 282, wherein R1is selected,.

285. The method of claim 278, wherein R1is286. The method of claim 274, wherein M is selected from O.

287. The method of claim 274, wherein M is selected from NCH3 and NCH2CH3.

288. The method of claim 287, wherein M is NMe.

289. The method of any one of claims 224 to 238, wherein the heterocycle of R2is a saturated heterocycle.

290. The method of claim 289, wherein the heterocycle of R2is a saturated heterocycle.

291. The method of claim 290, wherein R6of R2is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

292. The method of claim 291, wherein L of R2is selected from C1-C4alkylene and293. The method of any one of claims 274 to 292, wherein R2is selected from,, , , ,a d .

294. The method of any one of claims 274 to 293, wherein B is selected from an optionally substituted C9-C10fused carbocycle.

295. The method of any one of claims 274 to 294, wherein B is selected from, and, each of which is optionally substituted.

296. The method of any one of claims 274 to 295, wherein B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, - OH, -O-C1-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl.

297. The method of claim 296, wherein B is optionally substituted with one or more substituents independently selected from halogen.

298. The method of claim 296, wherein B is selected fromand .

299. The method of claim 298, wherein B is300. The method of claim 298, wherein B is301. The method of claim 274, wherein B is unsubstituted.

302. The method of claim 274, wherein B is substituted.

303. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of any one thereof.

304. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RAF-MEK-ERK pathway inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

305. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a ERBB family inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

306. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a EGFR inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50,51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

307. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

308. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

309. The method of any one of claims 303 to 308, wherein the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

310. The method of any one of claims 303 to 309, wherein the compound of Formula (II) is selected from compound 53, or a pharmaceutically acceptable salt of thereof.

311. The method of any one of claims 303 to 309, wherein the compound of Formula (II) is selected from compound 61, or a pharmaceutically acceptable salt of thereof.

312. The method of any one of claims 303 to 309, wherein the compound of Formula (II) is selected from compound 63, or a pharmaceutically acceptable salt of thereof.

313. The method of any one of claims 303 to 309, wherein the compound of Formula (II) is selected from compound 64, or a pharmaceutically acceptable salt of thereof.

314. The method of any one of claims 303 to 309, wherein the compound of Formula (II) is selected from compound 69, or a pharmaceutically acceptable salt of thereof 315. The method of any one of claims 303 to 309, wherein the compound of Formula (II) is selected from compound 96, or a pharmaceutically acceptable salt of thereof.

316. The method of any one of claims 303 to 315, wherein the combination exhibits synergy.

317. The method of any one of claims 303 to 306 & 309 to 315, wherein the inhibitor is selected from the group consisting of afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, and cetuximab.

318. The method of any one of claims 303 to 306 and 309 to 315, wherein the inhibitor is cetuximab.

319. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound of Formula (II*),( ) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3is selected from hydrogen, C1-6alkyl, and C1-6cyanoalkyl; R1is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; B is selected from C6-C15carbocycle, wherein the C6-C15carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkyl, -B(OR20)2, - OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl;R2is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4alkylene, wherein the C1-C4alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle.

320. The method of claim of any one of claims 303 to 319, wherein the combination exhibits synergy.

321. The method of claims 303 or 319, wherein the therapeutically effective amount of the combination of the inhibitor and the compound or salt results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition, an increased duration of stable disease in the subjects relative to treatment with only the compound or salt, or any combination thereof.

322. The method of any one of claims 303 to 321, wherein the therapeutically effective amount of the compound or salt of the combination is between about 0.01 to 100 mg / kg per day.

323. The method of any one of claims 303 to 322, wherein the therapeutically effective amount of the compound or salt in the combination is between about 0.1 to 50 mg / kg per day.

324. The method of any one of claims 303 to 323, wherein the therapeutically effective amount of the inhibitor of the combination is between about 0.01 to 100 mg / kg per day.

325. The method of any one of claims 303 to 324, wherein the therapeutically effective amount of the inhibitor of the combination is between about 0.1 to 50 mg / kg per day.

326. The method of any one of claims 303 to 325, wherein the inhibitor and the compound or salt are administered on different days.

327. The method of any one of claims 303 to 326, wherein the compound or salt is administered at a maximum tolerated dose.

328. The method of any one of claims 303 to 327, wherein the inhibitor is administered at a maximum tolerated dose.

329. The method of any one of claims 303 to 328, wherein the inhibitor and the compound or salt are each administered at a maximum tolerated dose.

330. The method of claim 319, wherein the RTK-MAPK pathway inhibitor is a RAF-MEK- ERK pathway inhibitor.

331. The method of claim 319, wherein the RTK-MAPK pathway inhibitor is a ERBB family inhibitor.

332. The method of claim 319 or 331, wherein the inhibitor is selected from the group consisting of afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, and cetuximab.

333. The method of claim 319 or 332, wherein the inhibitor is cetuximab.

334. The method of claim 319, wherein the RTK-MAPK pathway inhibitor is an epidermal growth factor receptor (EGFR) inhibitor.

335. The method of claim 319, wherein the RTK-MAPK pathway inhibitor is a SHP-2 inhibitor.

336. The method of claim 335, wherein the SHP-2 inhibitor is SHP-099 (6-(4-Amino-4- methylpiperidin-l-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), RMC-4360 or TNO155 (Novartis).

337. The method of claim 335, wherein the SHP-2 inhibitor is RMC-4550.

338. The method of claim 335, wherein the SHP-2 inhibitor is RMC-4360.

339. The method of claim 335, wherein the SHP-2 inhibitor is TNO155.

340. The method of claim 335, wherein the SHP-2 inhibitor is SHP-099.

341. The method of claim 319, wherein the RTK-MAPK pathway inhibitor is a SOS1 inhibitor.

342. The method of claim 341, wherein the SOS1 inhibitor is BI-3406.

343. The method of any one of claims 319 to 342, wherein the RTK-MAPK pathway inhibitor is administered orally.

344. The method of any one of claims 303 to 343, wherein the cancer is selected from: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

345. The method of any one of claims 303 to 343, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

346. The method of any one of claims 303 to 343, wherein the cancer is non-small cell lung cancer.

347. The method of any one of claims 303 to 343, wherein the cancer is small cell lung cancer.

348. The method of any one of claims 303 to 343, wherein the cancer is colorectal cancer.

349. The method of any one of claims 303 to 343, wherein the cancer is rectal cancer.

350. The method of any one of claims 303 to 343, wherein the cancer is pancreatic cancer.

351. The method of any one of claims 303 to 343, wherein the cancer is a solid tumor cancer.

352. The method of any one of claims 303 to 351, wherein the cancer is selected from a KRas mutant-associated cancer.

353. The method of any one of claims 303 to 351, wherein the cancer is selected from a KRas wildtype-associated cancer.

354. The method of any one of claims 303 to 351, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer.

355. The method of any one of claims 303 to 351, wherein the cancer is a KRas G12D- associated cancer.

356. The method of any one of claims 303 to 351, wherein the cancer is a KRas G12V- associated cancer.

357. The method of any one of claims 303 to 351, wherein the cancer is a KRas wildtype- associated cancer.

358. The method of any one of claims 303 to 351, wherein the RTK-MAPK pathway inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt.

359. The method of any one of claims 1 to 40, wherein the compound is selected from, , , , , or a pharmaceutical acceptable salt thereof.

360. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an RTK-MAPK pathway inhibitor and a compound of Formula (II):or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen;each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo;each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

361. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an RTK-MAPK pathway inhibitor and a compound of Formula (II*), or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3is selected from hydrogen, C1-6alkyl, and C1-6cyanoalkyl; R1is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; B is selected from C6-C15carbocycle, wherein the C6-C15carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkyl, -B(OR20)2, - OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; R2is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4alkylene, wherein the C1-C4alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-6carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle.

362. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

363. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an EGFR inhibitor and a compound of Formula (II), wherein the compound is selected from: compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 24A, 26, 23A, 23B, 27A, 27B, 28A, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39A, 39B, 40, 41, 42, 43, 44, 45, 46A, 46B, 47, 48, 49, 50, 51A, 51B, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 64B, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, and 103, or a pharmaceutically acceptable salt of anyone thereof.

364. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an EGFR inhibitor and a compound of Formula (II), wherein the compound is selected from: compounds 53, 61, 63, 64, 65, 69, and 96, or a pharmaceutically acceptable salt of any one thereof.

365. The method of claim 364, wherein the compound is compound 53.

366. The method of claim 364, wherein the compound is compound 61.

367. The method of claim 364, wherein the compound is compound 63.

368. The method of claim 364, wherein the compound is compound 64.

369. The method of claim 364, wherein the compound is compound 65.

370. The method of claim 364, wherein the compound is compound 69.

371. The method of claim 364, wherein the compound is compound 96.

372. The method of any one of claims 360 to 371, wherein the cancer is selected from: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

373. The method of any one of claims 360 to 371, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

374. The method of any one of claims 360 to 371, wherein the cancer is non-small cell lung cancer.

375. The method of any one of claims 360 to 371, wherein the cancer is small cell lung cancer.

376. The method of any one of claims 360 to 371, wherein the cancer is colorectal cancer.

377. The method of any one of claims 360 to 371, wherein the cancer is rectal cancer.

378. The method of any one of claims 360 to 371, wherein the cancer is pancreatic cancer.

379. The method of any one of claims 360 to 371, wherein the cancer is a solid tumor cancer.

380. The method of any one of claims 360 to 371, wherein the cancer is selected from a KRas mutant-associated cancer.

381. The method of any one of claims 360 to 371, wherein the cancer is selected from a KRas wildtype-associated cancer.

382. The method of any one of claims 360 to 371, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer.

383. The method of any one of claims 360 to 371, wherein the cancer is a KRas G12D- associated cancer.

384. The method of any one of claims 360 to 371, wherein the cancer is a KRas G12V- associated cancer.

385. The method of any one of claims 360 to 371, wherein the cancer is a KRas wildtype- associated cancer.

386. The method of any one of claims 360 to 371, wherein the combination exhibits synergy.

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