Combination cancer therapies with a KRAS modulator and an RTK-MAPK pathway inhibitor

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 (I).

Description

COMBINATION CANCER THERAPIES WITH A KRAS MODULATOR AND AN RTK-MAPK PATHWAY INHIBITORCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 600,143 filed on November 17, 2023, the entire content 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 el). 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):Formula (I), or a pharmaceutically acceptable salt thereof wherein:B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- 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, -C1-6 alkyl(=NOR20), - 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, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl- SO2R20, C1-6alkoxyalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12- membered heterocycle, wherein the C3-C12 carbocycle 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, -O-, -S-, and -N(R5)-; R2is selected from heterocycle, aryl, Cl-C6alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6 haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, 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, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, -N(R20)C(O)R20, -A N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3hydroxyalkyl, Cl-C3alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -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-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, - OC(O)heterocycle, -O-Cl-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1- C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl 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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4 haloalkyl, Cl-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6alkoxy, Cl-C4hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionallysubstituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R23is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0007] In an aspect, the present disclosure provides a compound of Formula (I-A)Formula (I-A), or a pharmaceutically acceptable salt thereof wherein: R1is selected from 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkoxyalkyl, C1-6alkyl, C2-6alkynyl, and 5- to 12-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, -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, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; B is selected from a 7- to 15-membered heterocycle and C7-C15carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; Y is selected from a bond, and -O-; R2is selected from heterocycle, aryl, Cl-C6 alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, 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, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6alkyl, C2-6alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, - N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F,(C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, - CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, - CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl), -OC(O)NH(C1- C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl 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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4haloalkyl, Cl-C4hydroxyalkyl, -C1-C3alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, Cl-C4 hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, 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-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted withone or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0008] In certain embodiments, Formula (I-A) is represented by Formula (I-B),Formula (I-B), or a pharmaceutically acceptable salt thereof wherein: Hh isoptionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -C1-6alkyl(=NOR20), -C(O)R20, =O, and 5- to 12-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, -OR20, -N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; Y is -O-; R2is selected from -L-heterocycle, and -L-N(R23)2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R6. B is selected from a 7- to 15-membered heterocycle, wherein the 7- to 15-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, =O, -N(R21)2, -OR21, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl; R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OR20, -C(O)R20, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; and each R20is independently selected from hydrogen; and C1-6alkyl, and C3-12carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo.

[0009] A method of treating cancer in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of cetuximab and a compound selected from ,one thereof. INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification areherein 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the invention are set forth with particularity in the appendedclaims. 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] FIGS. 1A-1B illustrate that combination treatment enhances tumor growth inhibitionand tumor regression as compared to single agent treatment in LS513, KRASG12D colorectal cancer (FIG.1A), and HPAC, KRASG12D pancreatic cancer (FIG.1B), xenograft models.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 athorough 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 thesame 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 solelyof carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). 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-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). 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., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). 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-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). 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 consistingsolely 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-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). 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 consistingsolely 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-C12 alkynyl). 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-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). 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 unsubstitutedunsaturated 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 hydrocarbonchain 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-C8 alkylene). 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-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). 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-C8 alkylene). 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-C5 alkylene).

[0023] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalenthydrocarbon 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-C10 alkenylene). 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-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). 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-C8 alkenylene). 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 divalenthydrocarbon 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-C10 alkynylene). 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-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). 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-C8 alkynylene). 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 aromaticmulticyclic 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 Rc is an alkylene chain asdefined above, for example, methylene, ethylene, and the like.

[0027] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylenechain 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 atomof 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 ofunsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0030] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radicalconsisting 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 polycyclichydrocarbon 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 Rc is analkylene chain as described above.

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

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

[0035] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, asdefined 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 ormore 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 oneor 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 oneor more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and thelike.

[0039] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by oneor 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 issubstituted 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 ringcomprising 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 aradical group.

[0043] "Heteroaryl" or “aromatic heterocycle” refers to a radical derived from aheteroaromatic ring radical that comprises one to eleven carbon atoms and at least oneheteroatom wherein each heteroatom 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 thering. 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 ofunsaturation 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 onone 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 oralkynylene chain.

[0048] As used herein, the term “electrophile” or “electrophilic moiety” is any moiety capableof 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 subsequentlydescribed 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, “optionally substituted 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 avariety 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 usedherein 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 thosecompounds, 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 acceptablecarrier” 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 carrier must 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 aspharmaceutically 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 ordisorder 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 KRASat amino acid position 12 (ie. G12X).

[0058] The term “RTK-MAPK pathway” refers to the signaling cascade between ReceptorTyrosine 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 orantibody, 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 activatedsequentially 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 compoundor 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 associatedwith or mediated by or having a KRas G12D mutation.

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

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

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

[0066] The terms “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 terms “EGFR inhibitor” refers to an agent, e.g., a compound or antibody, that iscapable 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 proteintyrosine 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 iscapable 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 negativelymodulating 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 andrefer 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, malechild, 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 describedinfra, 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” aredefined 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 thatamount 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 twocompounds 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 totwo 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 forthe 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 thisspecification 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 tobe construed as limiting the subject matter described.

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

[0083] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

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

[0087] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0088] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of: i) a RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0089] In some embodiments, the compound is compound 2. In some cases, the compoundis compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.

[0090] In some embodiments, the RTK-MAPK pathway inhibitor is selected from afatinib,dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, cetuximab, RMC-4550, 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, and TNO155 (Novartis). RAF-MEK-ERK pathway inhibitor

[0091] In an aspect, provided herein are methods of treating a disease or disorder in asubject 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0092] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0093] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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.

[0094] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-A), 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 needthereof, 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 (I-B), 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 needthereof, comprising administering to the subject a therapeutically effective amount of: i) a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0097] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0098] In some embodiments, the compound is compound 2. In some cases, the compoundis compound 3. In some cases, the compound is compound 4. In some cases, the compound iscompound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74. ERBB family Inhibitors

[0099] In an aspect, provided herein are methods of treating a disease or disorder in a subject inneed 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0100] In an aspect, provided herein are methods of treating a disease or disorder in asubject in need thereof, comprising administering to the subject a therapeutically effective amount of: i) a ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0101] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0102] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-A), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0103] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-B), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0104] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0105] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of: i) a ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0106] In some embodiments, the compound is compound 2. In some cases, the compoundis compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.

[0107] The ERBB family inhibitors used in the methods herein may be reversible orirreversible ERBB family inhibitors. In one embodiment, the ERBB family inhibitor inhibits the activity of more than one ERBB family member.

[0108] The modulation or inhibition of one or more ERBB family members may occurthrough modulating or inhibiting kinase enzymatic activity of one or more ERBB family member or by blocking homodimerization or heterodimerization of ERBB family members. In someembodiments 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.

[0109] In some embodiments, the ERBB family inhibitor is an irreversible inhibitor. Insome 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.

[0110] In some embodiments, exemplary irreversible ERBB family inhibitors for use in themethods 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 some cases, 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.

[0111] In some embodiments, the ERBB family inhibitor is a reversible inhibitor. In somecases, 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.

[0112] In some embodiments, the reversible ERBB family inhibitor is sapitinib. In somecases, the reversible ERBB family inhibitor is tarloxotinib.

[0113] In some embodiments, the ERBB family inhibitor is a combination of an EGFRinhibitor 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-dimethoxyquinazoline hydrochloride); PD 158780 (N4-(3-Bromophenyl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6- diamine), and pharmaceutically acceptable salts or a pharmaceutical compositions thereof.

[0114] 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.

[0115] In some embodiments, exemplary anti-EGFR monoclonal antibodies approved forhuman 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).

[0116] In some embodiments, the anti-EGFR monoclonal antibody is cetuximab.

[0117] In some embodiments, exemplary anti-HER-2 monoclonal antibodies, include but arenot limited to, pertuzumab (Roche), trastuzumab (Roche) and trastuzumab emtansine (Roche).

[0118] 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.

[0119] In some embodiments, the ERBB family inhibitor is a an EGFR inhibitor and a HER2inhibitor, 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

[0120] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an EGFR inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, andii) a compound of Formula (I), 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 needthereof, comprising administering to the subject a therapeutically effective amount of: i) an EGFR inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0122] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an EGFR inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I-A), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0123] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an EGFR inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I-B), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0124] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0125] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0126] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0127] In some embodiments, the compound is compound 2. In some cases, the compoundis compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.

[0128] In some embodiments, Epidermal Growth Factor Receptor (EGFR) is atransmembrane 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 of key 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.

[0129] In some embodiments, the EGFR inhibitor is selected from cetuximab, afatinib anderlotinib. SHP-2 Inhibitors

[0130] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0131] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of: i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0132] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-A), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0133] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0134] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0135] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0136] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of: i) a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0137] In some embodiments, the compound is compound 2. In some cases, the compoundis compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.

[0138] Src homology 2 (SH2) domain-containing phosphatase 2 (“SHP-2”) is a mammaliannon-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-SH2 and C-SH2) located in the N-terminal region and two potential Grb2 SH2 domain binding sites located in the C-terminal region.

[0139] In some embodiments, SHP-2 has been shown to exhibit non-mutational drugresistance 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.

[0140] Several inhibitors exhibiting activity against SHP-2 have been developed. ExemplarySHP-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 andTNO155 are in Phase 1 human clinical trials for adult patients having particular advanced solid tumors.

[0141] In some embodiments, methods for manufacturing SHP-2 inhibitors are well knownto 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

[0142] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0143] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeutically effective amount of: i) a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0144] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-A), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0145] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0146] In an aspect, provided herein are methods of treating a disease or disorder in asubject 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0147] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0148] In an aspect, provided herein are methods of treating cancer in a subject in needthereof, 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 selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0149] In some embodiments, the compound is compound 2. In some cases, the compoundis compound 3. In some cases, the compound is compound 4. In some cases, the compound iscompound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.

[0150] 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.

[0151] In some embodiments, one SOS1 inhibitor that can be used for the methodsdescribed herein is BI-I-13 (aka BI-3406). It has the following structure: KRAS Modulators

[0152] The following is a discussion of compounds and salts thereof that may be used in themethods 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 Formulas (I), (I-A), or (I-B), may be used in the methods of the disclosure. In some cases, a compound of Formulas (I), (I-A), or (I-B) may be referred to as a KRAS inhibitor. In some cases, a compound of Formulas (I), (I-A), or (I- B) may be referred to as a KRAS inhibitor. In some cases, a compound of Formulas (I), (I-A), or (I-B) may be referred to as a KRAS modulator.

[0153] In certain aspects, the present disclosure provides a compound represented by thestructure of Formula (I): R2Formula (I),or a pharmaceutically acceptable salt thereof wherein: B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- 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, -C1-6alkyl(=NOR20), - 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, C1-6 alkyl- N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl- SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12- membered heterocycle, wherein the C3-C12 carbocycle 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, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, -O-, -S-, and -N(R5)-; R2is selected from heterocycle, Cl-C6 alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6 haloalkyl, -L-OR23, - L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L- OC(O)N(R23)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, 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 -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6 alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-Cl-C3alkyl, Cl-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1- C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)Cl-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl), -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl 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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4haloalkyl, Cl-C4hydroxyalkyl, and -N(R5)2; each L is independently selected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, Cl-C4 hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituentson the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0154] In some embodiments, for a compound or salt for Formula (I), B is selected from anoptionally substituted 7- to 15-membered fused heterocycle and optionally substituted C7-C15fused carbocycle. In some cases, and optionally substituted C7-C15 fused carbocycle. In somecases, B is an optionally substituted 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 7- to 15-membered fused heteroaryl and optionally substituted C7-C15fused aryl. In some cases, B is an optionally substituted unsaturated C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 7- to 15- membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0155] In some embodiments, for a compound or salt for Formula (I), B is selected from anoptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle. In some cases, and optionally substituted C8-C15 fused carbocycle. In somecases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocycle. In some cases, B is anoptionally substituted 8- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 8- to 15-membered fused heteroaryl and optionally substituted C8-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C8-C15fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 8- to 15- membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0156] In some embodiments, for a compound or salt for Formula (I), B is selected from anoptionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining three rings (e.g., tricyclic). In some cases, B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining two rings (e.g., bicyclic). In some cases, for B the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are eachindependently bicyclic or tricyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is bicyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is tricyclic.

[0157] In some embodiments, for a compound or salt for Formula (I), the heterocycle orcarbocycle of B is bicyclic. In some cases, the heterocycle or carbocycle of B is tricyclic. In some cases, the tricyclic heterocycle contains three interconnected rings of atoms.

[0158] In some embodiments, for a compound or salt for Formula (I), for B, the heterocycleand carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently bicyclic.

[0159] In some embodiments, for a compound or salt for Formula (I), for B, the optionallysubstituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fusedcarbocycle are selected from , , , , and , each ofwhich is optionally substituted with one or more substituents. In some cases, for B, the optionally substituted 8- to 15-me b d f d h l d i ll b i d C C15fused carbocycle are selected from , , , , and, each of which is optionally substituted with one or more substituents. In some cases,and, each of which is optionally substituted with one or more substituents. In some cases, Biand, each of which is optionally substituted with one or more substituents. In some cases, B is selected from, , each of which is optionally substituted with one or more substituents.

[0160] In some embodiments, for a compound or salt for Formula (I), B is selected from,e ormore substituents. In some cases, B is selected from , , ,,substituents.

[0161] In some embodiments, for a compound or salt for Formula (I), for B, the optionalsubstituents of the heterocycle and carbocycle are each independently selected from halogen, - CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, -NO2, =O, - N(R21)2, -B(OR21)2, -OH, -SR21, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-Cl-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, =O, -NH2, -N(C1-6 alkyl)H -N(C1-6 alkyl)2, -OH, C1-6 aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, C1-C3 alkyl. In some cases for B the optionally substituted 8- to 15-membered fused heterocycle and optionallys,, , and . In some cases, B is selectedf , , , ,, , , , ,s, Bid.

[0162] In some embodiments, for a compound or salt for Formula (I), B is selected from anoptionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle. In some cases, the heterocycle of B has at least one sulfur atom. In some cases, the heterocycle of B has one or sulfur atoms. In some cases the heterocycle of B has at least one n ,, , , , , and , each of which is optionally substituted. In some cases, the one or more optional substituents of B are independently selectedat each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, - CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, -NH2, =O, and - , nd.

[0163] In some embodiments, for a compound or salt for Formula (I), B is selected from anoptionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. In some cases, s se ec e rom , , , , , eac o which is optionally substituted. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3alkyl, -OR20, -C(O)N(R20)2, - N(R20)2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3alkyl, -NH2, and -CN. In some cases B is substituted In some cases B is substituted with at least one -NH2In some cases B isselected from , , , , andNH2. Insome cases, B is substituted with at least one -NH2 at least one -CN. In some cases, B is selectedf .

[00164] In some embodiments, for a compound or salt for Formula (I), B is an optionallysubstituted 7- to 11-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, B is an optionally substituted 7-membered fused heterocycle. In some cases, B is an optionally substituted 8-membered fused heterocycle. In some cases, B is an optionally substituted 9-membered fused heterocycle. In some cases, B is an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, the heterocycle of B is a non-aromatic heterocycle. In some cases, B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases, ,h iso ,,, , , and each of which iso i ll bstituted. In some cases, B is selected from , , ,and , each of which is optionally substituted. In some cases, the one or more optionalsubstituents of B, are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-Cl-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least three substituents. In some cases, B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with a , , ,, , , and .

[0165] In some embodiments, for a compound or salt for Formula (I), R3 is selected fromhydrogen, halogen, -CN, -NO2, -N(R20)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, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl. In some cases, R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -C(O)N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl. In some cases, R3is selected from hydrogen, halogen, -CN, -NO2, -NH2, -N(C1-6alkyl)H -N(C1-6alkyl)2,-OH, -C(O)N(R20)2, -C(O) R20, -C(O)OR20, -OC(O) R20, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R3is selected from hydrogen, -CN, -C(O)R20, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R3is selected from hydrogen, -CN, -C(O)R20, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, R3is selected from hydrogen, -CN, -C(O)H, C1hydroxyalkyl, and C1-6alkyl. In some cases, R3is selected from hydrogen, fluorine, and -CN. In some cases, R3is selected from fluorine. In some cases, R3is selected from hydrogen. In some cases, R3is selected from -CN.

[0166] In some embodiments, for a compound or salt for Formula (I), Y is -O-. In somecases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R5)-.

[0167] In some embodiments, for a compound or salt for Formula (I), L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some embodiments, for a compound or salt for Formula (I), L is selected from C1- C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cases, each L is independently selected from a Cl-C4 alkylene optionally substituted; 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-C6 carbocycle 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. In some cases, the optional substituents of L are selected from Cl-C4 hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle; 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 b i l d fromh , , ,,, , , and . In some cases, L is selectedfrom . In somecases,eac s n epen en y se ec e rom a su s u e l- 4 a yene, an w erein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle 3- to 5- membered heterocycle. In some cases, each L is independently selected from a substituted C2-3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each L is independently selectedfrom. In some cases, each L isindependently selected from. In somecases, each L is independently selected fro. In some cases, each L is independently selected from a Cl-C4alkylene optionally substituted with one or more substituents independentlyselected from halogen and Cl-C4 alkyl. In some cases, L is selected fro, ,, .

[0168] In some embodiments, for a compound or salt for Formula (I), each L is independentlyselected from an unsubstituted Cl-C4 alkylene. In some cases, L is selected from and.In some cases, L is selected from.

[0169] In some embodiments, for a compound or salt for Formula (I), R2 is selected fromheterocycle, Cl-C6 alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, -L-heteroaryl, -L- cycloalkyl, -L-N(R23)2,-L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6haloalkyl, -L-OR23, -L- NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L- OC(O)N(R23)2, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, 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 -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

[0170] In some embodiments, for a compound or salt for Formula (I), R2 is selected fromheterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R23)2, wherein the heterocycle, theheterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

[0171] In some embodiments, for a compound or salt for Formula (I), R2 is -L-heterocycle,wherein the heterocycle portion is optionally substituted. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle. In some cases, R2is selected from a - L-5- to 10-membered heterocycle. In some cases, R2is selected from a -(C1-C2alkylene)-5- to 10-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered saturated heterocycle. In some cases, R2is a -L-5-membered heterocycle. In some cases, R2is a -L-8-membered heterocycle. In some cases, the heterocycle contains at least 1 nitrogen atom. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. In some cases, the bicyclic heterocycle contains 1 nitrogenatom. In some cases, Y-R2 is selected fro,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 portion is optionally substituted with one or more substituents selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, and Cl-C3 aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3 alkoxy, and Cl-C3 aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alk l and halogen. Insome cases, Y-R2is selected from , , , andsome cases, Y-R2is selected fro . Insome cases, Y-R2is selected from .

[0172] In some embodiments,for a compound or salt of Formula (I), R is selected fromoptionally 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 otherheteroatoms. In some cases, Y-R2 is selected fro, whereinthe heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In somecases, 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, Cl-C3alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-Cl-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2,and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, the heterocycle is substituted with at least one halogen. In some cases the heterocycle is substituted with at least one =CH2In somecases, Y-R2is selected from , , , ,,, , , , ,ctedf

[0173] In some embodiments, for a compound or salt of Formula (I), R2 is -L-heteroaryl,wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5- to 6-membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5- membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has two nitrogen atoms. In some cases, the heteroaryl has three nitrogen atoms. In some cases, theheteroaryl is selected from, , , which is optionally substituted. In somecases, the heteroaryl is, , , an , which is optionallysubstituted. In some cases, Y-R2 is selected from , ,, and , wherein the heteroaryl portion is optionally substitutedwith one or more R7. In some cases, each R7is independentl selected from Cl-C4 alkyl, halogen,a d C C h l lkyl. In some cases, Y-R2is selected fr d.In some cases, Y-R2 is selected from and . Insome cases, Y-R2is selected from ,,.

[0174] In some embodiments for a com ound or salt of Formula (I) R2 is -L-ar l o tionallys, wherein the heterocycle portion is optionally substituted with one or more R7. In some cases, Y-.

[0175] In some embodiments, for a compound or salt of Formula (I), R2 is -L-N(R23)2. In somec ,, and . In some embodiments, for a compound or salt of Formula (I), R2is heterocycle, optionallysubstituted with one or more R6. In some cases, t 2 is , which isuted. In some cases, the heterocycle of R2 is , In some cases, Y-R2 is.

[0176] In some embodiments, for a compound or salt of Formula (I), R2 is selected fromheterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L- heterocycle, are each optionally substituted with one or more R6; -L-aryl, and -L-heteroaryl,wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and -L-N(R23)2. In some cases, the heterocycle of R2is selected from, ithone or more R6; wherein the aryl and heteroaryl of R2is selected fr, and ryl and the heteroaryl are each optionally substituted with one or more R7; .In some cases, the heterocycle o 2f R is selected fr,,, , , , , , , ,wherein the heterocycle is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected from, , , , , and oreR7; and , . In some cases, each R6 is independently selected from halogen,hydroxy, Cl-C3 alkyl, Cl-C3 haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-Cl-C3 alkyl, whereinthe alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from Cl-C3 alkyl, halogen and Cl-C3 haloalkyl. In some cases, the heterocycle of R2, the aryl and heteroaryl of R2, and -N(R20)2 of R2i ,,,, , , ,and, wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are eachoptionally substituted with one or more R6,in the aryl of the -L-aryl, and theheteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and -R2i,, , , ,, , , ,, , , , ,2 is, , ,, , and .

[0177] In some embodiments, for a compound or salt of Formula (I), L is independentlyselected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from hydroxy, Cl-C4 hydroxyalkyl and Cl-C4 alkyl. In some cases, L isindependently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from Cl-C4 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2alkylene. In some cases, L i . In somecases, .

[00178] In some embodiments, for a compound or salt of Formula (I), each L is independentlyselected from an optionally substituted Cl-C4 alkylene; 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from Cl-C4hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0179] In some embodiments, for a compound or salt of Formula (I), each L is independentlyselected from a substituted Cl-C4 alkylene, 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl.

[0180] In some embodiments, for a compound or salt of Formula (I), each L is independentlyselected from a substituted Cl-C4alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come togetherto form a C3 carbocycle. In some cases, each L is independently selected from .

[0181] In some embodiments, for a compound or salt of Formula (I), R2 is 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.

[0182] In some embodiments, for a compound or salt of Formula (I), R2 is selected from, wherein the heterocycle portion is optionallysubstituted with one or more R6.

[0183] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from, wherein the heterocycle portion is optionally substituted withone or more R6.

[0184] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected fromn isoptionally substituted with one or more R6.

[0185] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected fromand, wherein the heterocycle portion is optionally substituted with one or more R6.

[0186] In some embodiments, for a compound or salt of Formula (I), R2 is 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-R2 is selected from,, and , whereinthe heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2isselected from , , and , wherein the heterocycle portionis optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In somecases, Y-R2 is selected from omecases, Y-R2 is selected from .

[0187] In some embodiments, for a compound or salt of Formula (I), Y is a bond. In somecases, R2is selected from an optionally substituted heteroaryl and optionally substituted aryl. In some cases, R2is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl only contain nitrogen atom(s). In some cases, the heteroaryl is a 6- membered heteroaryl. In some cases, the heteroaryl is a 5-membered heteroaryl. In some cases,the heteroaryl is selected from, each of which is optionally substituted.In some cases, the heteroaryl is selected fro, each of whichis optionally substituted. In some cases, R2is selected from an optionally substituted aryl. In some cases, the aryl is a phenyl. In some cases, the heteroaryl is optionally substituted with one or more R6, wherein each R6is selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3alkoxy, cyano, -CH2heterocycle, -C1-C3alkyl-N(R5)2, and -C(O)N(R5)2. In some cases, R6is selected from Cl-C3alkyl, -CH2heterocycle, and -C(O)N(R5)2. In some cases, the aryl is optionally substituted with one or more R7. In some cases, Y-R2is selected from andand.

[0188] In some embodiments, for a compound or salt of Formula (I), Y is -O- and R2 isselected from L-5-membered heteroaryl. In some cases, the heteroaryl has at least 1 nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroarylhas 3 nitrogen atoms. In some cases, L is selected from an optionally substituted C1-C4 alkylene. In some cases, L is independently selected from a Cl-C4 alkylene optionally substituted; 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-C6 carbocycle 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. In somecases, L is selected from ,. In some cases, L is selected from . In somecases, the heteroaryl is optionally substituted with one or more R7. In some cases, each R7is selected from halogen, Cl-C4 alkyl, and Cl-C4 haloalkyl. In some cases, Y-R2is selected from , ,, .

[0189] In some embodiments, for a compound or salt of Formula (I), each R6 is independentlyselected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, Cl-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -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(Cl-C3alkyl), -OC(O)NH(C1- C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(Cl-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0190] In some embodiments, for a compound or salt of Formula (I), each R6 is independentlyselected from halogen, -OH, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, -CN,and Cl-C3 aminoalkyl. In some cases, each R6is independently selected from halogen, Cl-C3 alkyl, and Cl-C3 haloalkyl.

[0191] In some embodiments, for a compound or salt of Formula (I), each R6 is independentlyselected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 aminoalkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, Cl- C3hydroxyalkyl, Cl-C3alkyl, Cl-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from Cl-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from halogen, hydroxy, Cl-C3 alkyl, Cl-C3 haloalkyl, -N(R5)S(O)2(R5), - OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3 alkyl is optionally substitutedwith substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from Cl-C3 alkyl, halogen and Cl-C3 haloalkyl.

[0192] In some embodiments, for a compound or salt of Formula (I), R6 is selected fromhalogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, and Cl-C3 aminoalkyl. In some cases, R6is selected from halogen and Cl-C3 alkyl. In some cases, R6is halogen. In some cases, R6is Cl-C3alkyl. In some cases, R6is selected from halogen and Cl-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0193] In some embodiments, for a compound or salt of Formula (I), R2 is selected from, , .

[0194] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from, , and .

[0195] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from, , and .[00196 I e embodiments, for a compound or salt of Formula (I), Y-R2 is.

[0197] In some embodiments, for a compound or salt of Formula (I), L is selected fromunsubstituted C1-C4 alkylene.

[0198] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[00199] In some embodiments, for a compound or salt of Formula (I), R6 of R2 isindependently selected at each occurrence from halogen, hydroxy, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, cyano, and Cl-C3aminoalkyl.

[0200] In some embodiments, for a compound or salt of Formula (I), R6 of R2 isindependently selected at each occurrence from C1-C3 alkyl and halogen.

[0201] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from.

[0202] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle of R1is selected from a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12- membered heterocycle, and 8- to 12-membered heterocycle. In some cases, the heterocycle of R1is selected from a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9- membered heterocycle, and 5- to 8-membered heterocycle. In some cases, the heterocycle of R1is selected from a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9- membered heterocycle, and 6- to 8-membered heterocycle. In some cases, the heterocycle of R1is selected from a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9- membered heterocycle, and 7- to 8-membered heterocycle. In some cases, the heterocycle of R1is selected from a 5- to 6-membered heterocycle and 5- to 9-membered heterocycle. In some cases, the heterocycle of R1is selected from an 8- to 9-membered heterocycle. In some cases, R1is selected from an optionally substituted 5- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted 7-membered heterocycle. In cases, the 5- to 12- membered heterocycle of R1is a bridged heterocycle. In cases, the 5- to 12-membered heterocycle of R1is not a bridged heterocycle. In some cases, the heterocycle of R1is saturated. In some cases, the heterocycle of R1is unsaturated. In some cases, the heterocycle of R1is an unbridged heterocycle. The heterocycle of R1is optionally substituted as described elsewhere herein.

[0203] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R1contains at most 1heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle of R1contains at most 2 heteroatom atoms. In some cases, the heterocycle of R1contains 1 nitrogen atom. In some cases, the heterocycle of R1contains only 1 nitrogen atom. In some cases, the heterocycle of R1contains only 1 nitrogen atom and no other heteroatoms.

[0204] In some embodiments, for a compound or salt of Formula (I), R1 is 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. In some cases, the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R1is selected from a saturated heterocycle and unsaturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R1is a saturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0205] In some embodiments, for a compound or salt of Formula (I), R1 is selected from 5-to 15-membered heterocycle, wherein the 5- to 15-membered heterocycle is optionally substituted. In some cases, R1is selected from an optionally substituted 6- to 15-membered heterocycle. In some cases, the heterocycle is a spiro heterocycle. In some cases, the heterocycle is a fused heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is an unsaturated heterocycle.

[0206] In some embodiments, for a compound or salt of Formula (I), R1 is a 6- to 12-membered fused heterocycle, which is optionally substituted.

[0207] In some embodiments, for a compound or salt of Formula (I), R1 is a 6- to 12-membered spiroheterocycle, which is optionally substituted. In some cases, R1is selected from optionally substituted 7- to 8-membered spiroheterocycle.

[0208] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1 isa 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-membered heterocycle, 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, theheterocycle of R1is saturated. The heterocycle is optionally substituted as described elsewhere herein.

[0209] In some embodiments, for a compound or salt of Formula (I), R1 is a 5- to 12-membered monocyclic heterocycle. In some cases, 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 is optionally substituted as described elsewhere herein.

[0210] In some embodiments, for a compound or salt of Formula (I), R1 is a bridgedheterocycle. In some cases, 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. In som h h l f R1is saturated. In some cases, the bridgedheterocycle is selected from , , and . In some cases, the bridgedheterocycle is selected from . Each bridgedheterocycle is optionally substituted as described elsewhere herein.

[0211] In some embodiments, for a compound or salt of Formula (I), R1 is a spiroheterocycle. The spiro heterocycle of R1is a 7- to 12-membered spiro heterocycle, 7- to 12- membered spiro heterocycle, or 8- to 12-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7- to 11-membered spiro heterocycle, 7- to 10-membered spiro heterocycle, 7- to 9-membered spiro heterocycle, or 7- to 8-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7- to 11-membered spiro heterocycle, 7- to 10-membered spiro heterocycle, 7- to 9-membered spiro heterocycle, or 7- to 8-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7- to 11-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is an 8-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 9-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 10-membered spiro heterocycle. In some cases, the spiro heterocycle of R1contains at most 1 nitrogen atom. In some cases, the spiro heterocycle of R1contains only 1 nitrogen atom. In some cases, the spiroheterocycle of R1contains at most 2 heteroatom atoms. In some cases, the spiro heterocycle of R1contains at least 2 heteroatom atoms. In some cases, the spiro heterocycle of R1contains at least 3 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the spiroheterocycle of R1is bound to the Formula via the nitrogen atom. ,, , , , and . In some cases, the spiroheterocycle of R1 is selected from . Each spiro heterocycle is optionallysubstituted as described elsewhereherein.

[0212] In some embodiments, for a compound or salt of Formula (I), R1 is a fusedheterocycle. In some cases, 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 9-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 10-membered fused heterocycle. In some cases, the fused heterocycle of R1is an 11-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 7-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 10-membered fused heterocycle. In some cases, the fusedheterocycle is selected from, , an. Each fused heterocycle is optionally substituted as described elsewhere herein.

[0213] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 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 saturatedring 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. Insome cases, R1 is selected from, each of which is optionally substitutedwith one or more substituents. In some cases, which is optionally substituted with one or more substituents. In some cases, , 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1- 6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle are each optionally substituted 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, 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, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, C1-6 alkyl-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 moresubstituents 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, R1 is selected fro, ,, and , 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 C2-6 alkynyl. In some cases, the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6 alkyl. 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 C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered saturated heterocycle. In some cases, each R20isindependently 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 independentlyselected from halogen, -CN, C2 alkenyl ,theoptional one or more substituents of R1are independently selected from halog, , 1arei ,, , , , , ,, , , and . In some cases the optional oneor more substituents of R1 are independently selected from halogen, , ,d,, , , ,,, and . In some cases, the optional one ormore substituents of R1are independently selected from halogen, and C1-6 alkyl-N(R20)2. In some cases, the optional one or more substituents of R1are independently selected from halogen,om m hydrogen, C1-6alkyl, and C3-6 carbocycle. In some cases, R1 is selecte,,, , and . 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 C1-6 alkyl. In some cases, R1is selected froand[ m 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 hydr and halogen. In some cases, RBis chloride. In somecases, 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 cas has at least 1 oxygen atom.B In some cases, is a monocyclic heterocycle. In some case is a bicyclicheterocycle. In some cases, is selected from an optionally substituted 5-memberedheterocycle. In some cases, is selected from an optionally substituted 9-memberedheterocycle. In some cases,,R1*.I,, each of which is optionally substituted with one ormore 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1*is independently selected from halogen, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*isindependently selected from halogen and C1-6 alkyl. In some cases is selected from ,,and .

[0215] In some embodiments, for a compound or salt of Formula (I), when R1 is substitutedwith -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 h , aIn some cases, the optional substituents are selected from C1-10alkyl, oxo, and =NH.

[0216] In some embodiments, for a compound or salt of Formula (I), each R20 isindependently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, 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, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, and =NH.

[0217] In some embodiments, for a compound or salt of Formula (I), each R21 isindependently 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10alkyl, oxo, and =NH. In some cases, each R21is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH.

[0218] In some embodiments, for a compound or salt of Formula (I), each R20 isindependently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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-C1-10 alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6 alkyl, 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, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, and =NH.

[0219] In some embodiments, for a compound or salt of Formula (I), each R23 isindependently 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, and =NH.

[0220] In some embodiments, for a compound or salt for Formula (I), R1 is selected from 5-to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents. In some cases, the one or more optional substituents are independently selected from halogen, -CN, -NO2, =O, -N(R20)2, -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, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents are independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the one or more optional substituents are independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6 haloalkyl. In some cases, R20is selected from hydrogen and C1-3 alkyl.

[0221] In some embodiments, for a compound or salt for Formula (I), R1 is selected from asaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents. In some cases, the 5- to 12-membered heterocycle of R1is bridged. In some cases, the 5- to 12-membered heteroc cle of R1is not brid ed In some cases the 5- to 12-memberedheterocycle is selected from , , , , , ,, ,, each of which is optionally substituted with one or moresubstituents.

[0222] In some embodiments, for a compound or salt of Formula (I), R1 is selected from,,, , , , , , , ,and, p y . me 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R1iss ,,,, , , , , , ,, ,,, , , , , ,, , , , , , , , , ,, , , , , , , , , ,,, , ,and

[0223] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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.

[0224] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1contains only 1 nitrogen atom and optionally one or more heteroatoms selected from oxygen, and sulfur. In some cases, the heterocycle is a fused heterocycle or a bridged heterocycle. 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 from and . The heterocycle is optionally substituted as described elsewhere herein.

[0225] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1has at most 1 nitrogen atom. In some cases, the heterocycle of R1has only 1 nitrogen atom and optionally one or more other heteroatoms selected from oxygen and sulfur. In some cases, the heterocycle of R1has only 1 nitrogen atom and no other heteroatoms.

[0226] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted 5- to 12-membered saturated 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 only one nitrogen atom and 0-2 other heteroatoms selected from nitrogen, oxygen, and sulfur. In some cases, the 5- to 12-membered unsaturated heterocycle has only one nitrogen atom and no furtherheteroatoms. In some cases, the 5- to 12-membered unsaturated heterocycle has three nitrogen atoms and no further heteroatoms.

[0227] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 only one nitrogen atom and no further heteroatoms.

[0228] In some embodiments, for a compound or salt of Formula (I), R1 is selected from 6- to7-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- to 7-membered heterocycle ofR1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R1is selected from ,, , , , , an , eac o w c s su st tute . n somecases, R1 is selected from, , , , , , and , each ofwhich 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, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl. 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, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, 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 C1-6 alkyl. In some cases, R1is selected fromand,rom 1R isselected fromeach of which is optionally substituted. Insome cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)-(C1-6 alkoxy), -NH-C(O)-(C1-6 hydroxyalkyl), -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, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. 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, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6 cyanoalkyl, C1-6alk l and C2 6alk n l In some cases R1is selected from ,,, , , , , , , ,, , , , , , ,R1is selected from , , , , , , , ,,, ,,,,, , , , , , , , and . Ins ,[,,, , , , , , and , eachof 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, C1-6 alkoxy, =O, -CN, C1-6 alkyl, C2-6 alkenyl, C1-6 aminoalkyl, C1-6hydroxyalkyl, and C1-6 haloalkyl. In some cases, R1 is selecte ,, , ,, , , , , , , , ,, ,,,, , , , , , ,,,,, ,,

[0230] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 from,, , , an wherein each is optionally substituted with one ormore substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is selected from,, , and wherein each is optionally substituted with one ormore substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alk h lk l h l lk l and C1-6alkyl. In some cases, R1is selected from, , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1is selected from ,R1 iss ,. Inand, wherein each is substituted with one or more substituents independently selected from halogen.

[0231] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anunsaturated 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,, R1i. In some cases, R1 is selected fromR1 iss R1 is. In some cases, R1is .

[0232] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1is selected from a i ll b i ed unsaturated 7-membered heterocycle. In some cases, R1is selectedfrom , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1is selected from .

[00233] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 toFormula (I) via the only 1 nitrogen atom. In some cases, R1 is selected from , and , anyof 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, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, 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, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -NH2, -NH(CN), =O, -CN, C1-6hydroxyalkyl, C1-6alkyl, 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. I ,,, , , , , and .

[0234] In some embodiments, for a compound of Formula (I), R1 is selected from anoptionally substituted 6-membered unsaturated heterocycle and 6-membered saturated heterocycle.

[0235] In some embodiments, for a compound or salt of Formula (I), R1 is selected from, wherein each is optionally substituted with one or more substituentsindependently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

[0236] In some embodiments, for a compound or salt of Formula (I), R1 is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.

[0237] In some embodiments, for a compound or salt of Formula (I), R1 is selected from.

[0238] In some embodiments, for a compound or salt of Formula (I), R1 is selected fromand , 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.

[0239] In some embodiments, for a compound or salt of Formula (I), R1 is selected fromand , wherein each is optionally substituted with two substituents independentlyselected from halogen, and C1-6 haloalkyl. In some cases, R1is .

[0240] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted 6- to 10-membered heterocycle. In some cases, the 6- to 10-memberedch isoptionally substituted with one or more substituents independently selected from halogen, =O, - OH, -CN, -NHCN, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered h , d.

[0241] In some embodiments, for a compound or salt of Formula (I), R1 is selected from 6- to7-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 anon-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R1is selected fr, , each of which is substituted. In somecases, R1 is selected fromh ofwhich 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, C1-6 fluoroalkyl, and C2-6 alkynyl; 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 C2-6 alkynyl; 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 C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6alkyl. In some cases, R1is selected from and.In some cases R1 is selected from ,rom,, , and , each of which is optionally substituted. In some cases, R1 isselected from each of which is optionally substituted. Insome cases, the one or more opt ona subst tuents 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, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. 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, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6cyanoalkyl, C1-6, , , ,, , , , , , , , ,, , , s, R1i ,,, , , and . In some cases, R1 is selected from , , ,,,,a,, , , and .

[0242] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-memberedheterocycle 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 .

[0243] In some embodiments, for a compound or salt of Formula (I), R1 is 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, C1-6 cyanoalkyl -N(R20)C(O)N(R20)2, =O, C1-6 hydroxyalkyl,halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6 aminoalkyl. In some cases, R1is selectedfr, ctedf, , , ,,

[0244] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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,, and , each of which is optionally substituted with one ormore substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, - C(O)NR20OR20C1-6 aminoalkyl C1-6 hydroxyalkyl C1-6 cyanoalkyl and C1-6 alkyl In somecases, R1 is selected from , , and . In some cases,In some cases, R1is selected fromallysubstituted 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.

[0245] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 somecases, 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, C1-6 aminoalkyl, C1-6 alkox C16 h drox alk l C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0246] In some embodiments, for a compound or salt of Formula (I), R1 is 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, thespiro heterocycle has at least 1 sulfur atom. In some cases, R1 is selected frand, 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6alkenyl, and C2-6 alkynyl. In some cases, R1 is selected fro, . Insome cases, R1is . In some cases, R1is .

[0247] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 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 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 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 fusedheterocycle 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, R1isselected from , each of which is optionallysubstituted with one or more substituents. In some cases, R1 is selected frand, each of which is optionally substituted with one or more substituents. In some cases, Rs , 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(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, 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, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, C1-6 alkyl-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 selectedfrom -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, R1 is selected fro,,, , each of which is further optionally substituted. In some cases, the further one or more optional substituents are selected from halogen, -OH, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6alkynyl. In some cases, the further one or more optional substituents are selected from halogen and C1-6 alkyl. 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 C1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, 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 ormore substituents of R1 are independently selected from haloge ,and. In som1e cases, the optional one or more substituents of R are independentlys ,,, , , ,1is s ,, , , an i e ormore substituents of R1are independently selected fr m h l n , , and.In some cases, R1 is selected from . In some cases, each R20is independently selected from hydrogen, C1-6alkyl, and C3-6carbocycle. In some cases, R1isome,,, , and .

[0248] In some embodiments, for a compound or salt of Formula (I), when R1 is substitutedwith -C(O)R20, R20is selected from a 5- to 12-membered heterocycle.

[0249] In some embodiments, for a compound or salt of Formulas (I), (I-A), or (I-B)R1 is, and 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, 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, C2-6 alkynyl, - 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 , , , ,,, , , , and , each of which isoptionally substituted with one or more R1*In m th h t r l f th n or moreoptional 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. 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, C1-6 alkyl-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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. 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 C1-6 alkyl. 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 fro, ,, , , , a .

[0250] In some embodiments, for a compound or salt of Formulas (I), (I-A), or (I-B), theone 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-memberedh t r l In m th h t r l i l t d fr m , , ,,, , , , and , each of which isoptionally substituted with one or more R1*. In some cases, the one or more optional substituents

[00251] In some embodiments, for a compound or salt of Formulas (I), (I-A), or (I-B), eachR1*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, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. 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, C1-6 alkyl-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, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1*is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. 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 C1-6 alkyl.

[0252] In some embodiments, for a compound or salt of Formula (I), R1 is 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, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. I h 1 heterocycle issubstituted. In some cases, R1 is selected , , , , and , each of which isoptionally substituted. In some cases, R1is selecte, which is optionally substituted. In s , ,, . Ins R1is . In some cases, R1is selected .

[0253] In some embodiments, for a compound or salt of Formula (I), R1 is selected from 5-to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10- membered heterocycle or preferably 8-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, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkynyl, 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 ormore R1*; each R1*is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1is selecte, each of which is optionally substituted. In some cases, R1is selecte, which is optionally substituted. In s , ,, , . , .

[0254] In some embodiments, for a compound or salt of Formula (I), R1 is selected from,, and .

[0255] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 (I). 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6 alkyl. In some cases, R1is selected from N, 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, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, 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, , , ,ses,,

[0256] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted 6- to 11-membered heterocycle, wherein the 6- to 11-membered heterocycle has at least one nitrogen atom. In some cases, the one or more optional substituents of R1is selected from halogen, -OR20, -C(O)N(R20)2, -C(O)R20, -S(O)2R20, =O, -C1-6alkyl(=NOR20), =NO(R20), - CN, -NHCN, C1-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1*is independently selected from halogen, and C1-6alkyl. In some embodiments, R1is selected from,, , , , ,, , , , 1isselected from hydrogen, , , , , ,, , , , .Insome cases, R1is selected from hydrogen, , ,, , and.

[0257] In some embodiments, for a compound or salt of Formula (I), R1 is selected fromhydrogen and optionally substituted 5- to 15-membered heterocycle. In some cases R1is selectedfrom , , , , , , , , and ,each of which is optionally substituted. In some cases, the optional one or more substituents of R1is selected from -OH, =NO(R20), -NHCN, and C1-6alkyl. In some cases, R1is selected fromh ,

[0258] In some embodiments, for a compound or salt of Formula (I), R1 is selected fromhydrogen and optionally substituted 7- to 10-membered heterocycle. In some cases, R1is selectedfeachof which is optionally substituted. In some cases, the optional one or more substituents of R1are independently selected from halogen, -NH2, -S(O)2(R20), -C(O)R20, -C(O)N(R20)2, =O,=NO(R20), -CN, -NHCN, C1-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1*is independently selected from halogen, and C1-6alkyl. In some cases, R1is selected from hydrogen,, , , , , , , ,, and.

[0259] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted 8- to 10-membered heterocycle. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle hasat least two nitrogen atoms. In some cases,, , , a , each ofwhich is optionally substituted. In some cases, the optional one or more substituents of R1areindependently selected from halogen, , oxo, , , , and 5- to 9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is substituted with at least one R1*, wherein the R1*is selected from halogen, and C1-6 alkyl. In some cases the optional one orm i f R1i l l f hl i ,, , , , , , , and, , ,, .

[0260] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted bridged 8- to 9-membered heterocycle. In some cases, the heterocycle of R1is selected from, , and , each of which is optionally substituted. In some cases, the one or more substituents of R1are selected from halogen C1-6 alkyl, -N(R20)2, and C1-6 aminoalkyl. Insome cases, R1is selected , , and .

[0261] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted bridged 8-membered heterocycle, wherein the heterocycle contains heteroatoms selected from nitrogen. In some cases, the one or more substituents of R1are selectedfrom C1-6 alkyl, -N(R20)2, and C1-6 aminoalkyl. In some cases, the heterocycle of R1is selected from , each of which is optionally substituted. In some cases, R1is seleca.

[0262] In some embodiments, for a compound or salt of Formula (I), R1 is hydrogen.

[0263] In some embodiments, for a compound or salt of Formula (I), R1 is an optionallysubstituted 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. In some 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 th h t r t m r selectedfrom nitrogen and oxygen. In some cases, R1 is selected from , ,N N N N H H ,, each of which is optionally substituted with one or moreNs, ,, , , and , 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 C2-6 alkynyl. 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, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 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,, , and .

[0264] In some embodiments, for a compound or salt of Formula (I) R1 is an optionallysubstituted 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, RingW is an optionally substituted 10-membered fused heterocycle. In some cases, R1is , wherein Ring P is an optionally substituted carbocycle or optionally substitutedheterocycle. In some cases, In some cases, Ring P is an optionallysubstituted carbocycle. In some cases, Ring P is an optionally substituted heterocycle. In some cases, Ring P forms an optionally substituted C3-C6 carbocycle or optionally substituted 4-to 6- membered heterocycle. In some cases, Ring P forms an optionally substituted C3 carbocycle. 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 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 from halogen, -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.

[0265] In some embodiments, for a compound or salt for Formula (I), R1 is selected from a5- to 12-membered bridged heterocycle, which is optionally substituted with one or more substituents. In some cases, R1is selected from an 8-membered bridged heterocycle, which isoptionally substituted with one or more substituents. In some cases, the bridged heterocycle has at least 1 heteroatom. In some cases, the bridged heterocycle has at least 2 heteroatoms. In some cases, the bridged heterocycle has at least 1 nitrogen atom. In some cases, the bridged heterocycle has at least 2 nitrogen atoms. In some cases, the bridged heterocycle has 2 nitrogenatoms. In some cases, R1 is selected fro,ses,R1is selected from , which is optionally substituted with one or more substituents.

[0266] In some embodiments, for a compound or salt for Formula (I), R1 is selected from anunsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents. In some cases, the unsaturated 5- to 12-membered heterocycle is selected from, , , , , each of which is optionally substituted withone or more substituents.

[0267] In some embodiments, for a compound or salt of Formula (I), 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. Insome cases, R1is selected from .

[0268] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 fromH ,each of which is optionally substituted with one ormore 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 somecases, R1 is selected fromses,roman . n some cases, s se ec e rom.In some cases, R1 is selected from , which is optionallysubstituted 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, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0269] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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-memberedfused 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 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 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, R1issoresubstituents. In some cases,, 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, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. 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 C1-6 alkyl, C3-12 carbocycle, 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 C1-6 alkyl, and 3- to 12-membered saturated heterocycl es, theoptional one or more substituents of R1are independently selected from ,s , a , ,, and .

[0270] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally 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 areindependently selected from halogen, -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, 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 C1-6 alkyl. Insome cases, R1 is selected from, which is substituted with one or more substituentsselected from -NHCN, and C1-6alkyl. In some cases, R1is selected fro, and.

[0271] In some embodiments, for a compound or salt of Formula (I), R3 is -CN, and R1 isse ecte rom , , an ; an s an opt onallysubstituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom. In some cases, R3is -CN, and R1is selected from,, and ; and B is selected from , and.In some cases, R3 is -CN, and R1 is selected from . In some cases, R3 is -CN,a In some cases, R3 is -CN, and R1 is selected from.Insc ases,Ris -CN, and R is selected from , , and ; B is anoptionally substituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom; and Y-R2is selected from -O-L-heterocycle, wherein the heterocycle portion of -O-L-heterocycle is optionally substituted with one or more R6.

[0272] In some embodiments, for a compound or salt of Formula (I), B is an optionallysubstituted 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 optionally substituted 9-membered fused c cle. 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, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. 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 selectedf. , , entsselected from halogen and C1-6 haloalkyl. In some cases, B is , which is substituted withone or more substituents selected from halogen. In some cases B is selected from ,,, , , and . In some cases, B is ,w B isselected from , and In some cases, B is , which issubstituted with one or more substituents selected from chlorine. In some cases, B is selectedfrom .

[00273] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted unsaturated 10-membered fused heterocycle. In some cases, R1is N, which is optionally substituted. In some cases, the optional one or more substituents of R1are 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle, wherein the heterocyclecontains one sulfur atom. In some cases, B is selected fro,, , , each of which is optionally substituted. In some cases, In some cases, for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -O-Cl-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, Y-R2is selected from , wherein the heterocycle portion is optionally substituted. In some cases, n is 0. In some cases, R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OH, -S(O)2(R20), -C(O)R20, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R3is selected from hydrogen, halogen, and -CN.

[0274] In some embodiments, for a compound or salt of Formula (I), R1 is selected from anoptionally substituted 11-membered fused heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 11-membered fused heterocycle. In some cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains at least onenitrogen atom. In some cases, the heterocycle contains 3 heteroatoms. In some cases, the heterocycle i , which is optionally substituted. In some cas .

[0275] Insome embodiments, for a compound or salt of Formula (I), the one or moreoptional substituents of R1are each independently selected from halogen, -CN, -NO2, =O, - N(R20)2, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents are independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl. In some cases, the optional substituents for R1are each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the optional substituents for R1are each independently selected from halogen, -CN, -OH, -NH2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6haloalkyl.. In some cases, the optional substituents for R1are each independently selected from -OH, and -NH2. In some cases, R20is selected from hydrogen and C1-3alkyl.

[0276] In some embodiments, for a compound or salt for Formula (I), n is selected from 0 to4. In some cases, n is selected from 0 to 3. In some cases, n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.

[0277] In some embodiments, for a compound or salt for Formula (I), each R4 isindependently selected from halogen, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6alkynyl, C1-6cyanoalkyl, and C1-6haloalkyl. In some cases, R4is independently selected from halogen, =O, -CN, C1-6cyanoalkyl, C2-6alkynyl, C1-6aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R4is independently selected from halogen, =O, -CN, C1-6cyanoalkyl, C2-6alkynyl, and C1-6haloalkyl. In some cases, R4is independently selected from -CN, C1-6cyanoalkyl, and C2-6alkynyl. In some cases, each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0278] In some embodiments, for a compound or salt for Formula (I), Q is a bond. In somecases, Q is a S. In some cases, Q is a O.

[0279] In some embodiments, for a compound or salt for Formula (I), each R7 isindependently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4haloalkyl, Cl-C4 hydroxyalkyl, and -N(R5)2. In some cases, each R7is independently selected from halogen, hydroxy, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 haloalkyl, and Cl-C4 hydroxyalkyl.

[0280] In some embodiments, for a compound or salt for Formula (I), each R20 isindependently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen and C1-6 alkyl. In some cases, each R20is independently selected from C1-6alkyl.

[0281] In some embodiments, for a compound or salt for Formula (I), each R21 isindependently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6 alkyl. In some cases, each R21is independently selected from C1-6alkyl.

[0282] In some embodiments, for a compound or salt for Formula (I), each R20 isindependently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen and C1-6 alkyl. In some cases, each R20is independently selected from C1-6alkyl.

[0283] In some embodiments, for a compound or salt for Formula (I), each R23 isindependently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R23is independently selected from hydrogen and C1-6alkyl. In some cases, each R23is independently selected from C1-6alkyl.

[0284] In an aspect, the present disclosure provides a compound of Formula (I-A)Formula (I-A),or a pharmaceutically acceptable salt thereof wherein: R1is selected from 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -C1-6alkyl(=NOR20), -C(O)R20=O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl-SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-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, -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, C1-6 alkyl-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 a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; Y is selected from a bond, -O-, -S-, and -N(R5)-; R2is selected from heterocycle, aryl, Cl-C6alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6 haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, 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, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6alkyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, - N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)Cl-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-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1- C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4 haloalkyl, Cl-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6alkoxy, Cl-C4hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituentsindependently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; 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-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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.

[0285] In some embodiments, Formula (I) or Formula (I-A) is represented by Formula (I-B),Formula (I-B), or a pharmaceutically acceptable salt thereof wherein:wherein R1 is selected from , , , each of which isoptionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, =O, and 5- to 12-memberedheterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; Y is -O-; R2is selected from -L-heterocycle, -L-N(R23)2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R6. B is selected from a 7- to 15-membered heterocycle, wherein the 7- to 15-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, =O, -N(R21)2, -OR21, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl; R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OR20, -C(O)R20, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; and each R20is independently selected from hydrogen; and C1-6alkyl, and C3-12carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo.

[0286] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(- , s se ec e o , , a , w e e , isoptionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -C1-6alkyl(=NOR20), -C(O)R20, =O, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*; and each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl.

[0287] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(I-B), Y is -O-.

[0288] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(I-B), R2is selected from optionally substituted -L-heterocycle, and -L-N(R23)2. In some cases, R2is selected from optionally substituted -L- 5-to 8-membered heterocycle, and -L-N(R23)2. In some cases, R2is selected from optionally substituted -L-heterocycle. In some cases, R2is selected from -L-N(R23)2. In some cases, the heterocycle contains at least one nitrogen atom. Insome cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains at least one oxygen atom. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is a saturated heterocycle. In some cases, each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl- N(R5)2, -C(O)N(R5)2, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, -O-Cl-C3alkyl. In some cases, each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, =CH2, and -O-Cl-C3 alkyl. In some cases, when R2is a heteroaryl, R6is selected from halogen and Cl-C3haloalkyl, Cl-C3alkyl. In some cases, when R2is a heteroaryl, R6is selected from a halogen. In some cases, R23is selected from hydrogen and Cl-C3 alkyl. In some cases, each R23is selected from Cl-C3 alkyl. In some cases, each R23is selected from methyl. In some cases, each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, and Cl-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or moresubstituents independently selected from halogen. In some cases, each L is selected fro,. Ins ,a ,,,, , , , , and .

[0289] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula, nd. In some cases, Y-R is selected , , and. In some cases Y-R2is selected . In some cases Y-R2i . Insome cases, Y-R2 is , , and .

[0290] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(I-B), B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-memberedheterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6alkyl. In some cases, the heterocycle of B is selected fr ,romallysubstituted with one or more substituents independently selected from halogen, -CN, -NH2, and , and.

[0291] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(I-B), R3is -CN. In some cases, R3is hydrogen. In some cases, R3is halogen. In some cases, R3is fluorine.

[0292] In some embodiments a compound or salt of Formula (I) Formula (I-A) or Formula(I B R1 i . In some cases, R1 is . In some cases, R1 is . In some cases,R1is , which is optionally substituted with one or more substituents. In some cases, theone or more optional substituents are independently selected from halogen, -S(O)2(R20), - C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20=O, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, the one or more optional substituents are independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, =O, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, the one or more optional substituents are independently selected from halogen, -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with oneor more R1*. In some cases,, which is subtituted with at least one substituent. Ins , ,and. In some cases, R1is . In some cases, each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl.

[0293] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), orFormula (I-B), does not contain an electrophile moiety.

[0294] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), orFormula (I-B), the one or more optional substituents of R1are not electrophiles.

[0295] In some embodiments, for a compound or salt of Formula (I), R1 is selected from acompound in the Examples. In some cases, B is selected from a compound in the Examples. In some cases, Y is selected from a compound in the Examples. In some cases, R2is selected from a compound in the Examples. In some cases, R3is selected from a compound in the Examples.

[0296] In some embodiments, for a compound or salt of Formula (I), each R20 is selectedfrom hydrogen and C1-3alkyl. In some cases, each R20is selected from hydrogen and C1alkyl.

[0297] In some embodiments, the compounds of Formula (I), Formula (I-A), or Formula (I-B), used in the methods include trifluoroacetic acid salts of the above compounds.

[0298] In some embodiments, the compound or salt of Formula (I) is selected fromcompounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111. In some cases, the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74. In some cases, the compound or salt of Formula (I) is compound 2. In some cases, the compound or salt of Formula (I) is compound 3. In some cases, the compound or salt of Formula (I) is compound 4. In some cases, the compound or salt of Formula (I) is compound 14. In some cases, the compound or salt of Formula (I) is compound 25. In some cases, the compound or salt of Formula (I) is compound 74.

[0299] In some embodiments, the compound or salt of Formula (I), Formula (I-A), orFormula (I-B), is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A),or Formula (I-B), is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), 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. In some embodiments, the compound or salt of 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, or 111, 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. In some embodiments, the compound or salt of 2, 3, 4, 14, 25, or 74, 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.

[0300] In some embodiments, the compound or salt of Formula (I), Formula (I-A), orFormula (I-B), 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 (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 45 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), 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.

[0301] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(I-B), is administered once daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), administered twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered 3 times daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered once weekly. In some embodiments the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered every other day. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered every 3 days.

[0302] In some embodiments, the compound or salt of Formula (I), Formula (I-A), orFormula (I-B), is administered to a subject at 10 mg to 150 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 5 mg to 75 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) 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 (I), Formula (I-A), or Formula (I-B) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 15 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) 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 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0303] In some embodiments, the compound or salt of Formula (I), Formula (I-A), orFormula (I-B), is administered to a subject at about 10 mg to about 150 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) isadministered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I- B) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 5 mg to about 75 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) 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 (I), Formula (I-A), or Formula (I-B) 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 (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 45 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) 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.

[0304] In some embodiments, the compound or salt of Formula (I), Formula (I-A), orFormula (I-B), is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 50 mg to about 100 mg, twice daily. Insome embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) 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 (I), Formula (I-A), or Formula (I-B) 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 (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 45 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) 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.

[0305] In some embodiments, a compound of Formula (I), Formula (I-A), or Formula (I-B),is administered as a capsule during the period of time. In some cases, a tablet or capsule formulation of a compound of Formula (I), Formula (I-A), or Formula (I-B), or a pharmaceutically acceptable salt of any one thereof 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 80mg, 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, about 25 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 toabout 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). In some cases, the compound or salt of Formula (I) is selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111. In some cases, the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74. In some cases, the compound or salt of Formula (I) is compound 2. In some cases, the compound or salt of Formula (I) is compound 3. In some cases, the compound or salt of Formula (I) is compound 4. In some cases, the compound or salt of Formula (I) is compound 14. In some cases, the compound or salt of Formula (I) is compound 25. In some cases, the compound or salt of Formula (I) is compound 74.

[0306] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula(I-B) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (I), Formula (I-A), or Formula (I-B), 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 toabout 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 toabout 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 toabout 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. In some cases, the compound or salt of Formula (I) is selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111. In some cases, the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74. In some cases, the compound or salt of Formula (I) is compound 2. In some cases, the compound or salt of Formula (I) is compound 3. In some cases, the compound or salt of Formula (I) is compound 4. In some cases, the compound or salt of Formula (I) is compound 14. In some cases, the compound or salt of Formula (I) is compound 25. In some cases, the compound or salt of Formula (I) is compound 74.

[0307] In some embodiments, the combination therapy comprises oral administration of acompound of Formula (I), Formula (I-A), or Formula (I-B), 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 mgto 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 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 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 toabout 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 to about 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 toabout 400 mg, about 100 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 compound or salt of Formula (I) is selected from compounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111. In some cases, the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74. In some cases, the compound or salt of Formula (I) is compound 2. In some cases, the compound or salt of Formula (I) is compound 3. In some cases, the compound or salt of Formula (I) is compound 4. In some cases, the compound or salt of Formula (I) is compound 14. In some cases, the compound or salt of Formula (I) is compound 25. In some cases, the compound or salt of Formula (I) is compound 74. In some cases, the compound and inhibitor are administered on separate days. In some cases, the compound and inhibitor are administered on the same day.

[0308] Included in the present disclosure are salts, particularly pharmaceutically acceptablesalts, 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.

[0309] Chemical entities having carbon-carbon double bonds or carbon-nitrogen doublebonds 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.

[0310] A “tautomer” refers to a molecule wherein a proton shift from one atom of amolecule 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: OH O O OH NHHO.[The compounds disclosed herein, in some embodiments, are used in differentenriched 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.

[0312] Unless otherwise stated, compounds described herein are intended to includecompounds 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.

[0313] The compounds of the present disclosure optionally contain unnatural proportions ofatomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are allcontemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0314] In certain embodiments, the compounds disclosed herein have some or all of the 1Hatoms 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.

[0315] Deuterium substituted compounds are synthesized using various methods such asdescribed 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.

[0316] Deuterated starting materials are readily available and are subjected to the syntheticmethods 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.

[0317] Compounds of the present invention also include crystalline and amorphous forms ofthose 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.

[0318] 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.

[0319] The methods and compositions described herein include the use of amorphous formsas well as crystalline forms (also known as polymorphs). The compounds described herein may be 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 wellas 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.

[0320] 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.

[0321] Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound as set forth herein are included within the scope ofthe claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0322] Prodrugs are often useful because, in some situations, they may be easier toadminister 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.

[0323] In some embodiments, the design of a prodrug increases the lipophilicity of thepharmaceutical agent. In some embodiments, the design of a prodrug increases the effectivewater 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 Association and 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.

[0324] Synthetic chemistry transformations and methodologies useful in synthesizing thecompounds 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

[0325] Provided herein, in certain embodiments, are compositions comprising atherapeutically effective amount of a compound of Formulas (I), (I-A), or (I-B); and a RTK- MAPK pathway inhibitor, an ERBB family inhibitor, a RAF-MEK-ERK pathway inhibitor, an EGFR inhibitor, a SHP-2 inhibitor, or a SOS1 inhibitor; or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”).

[0326] Pharmaceutical compositions may be formulated using one or more physiologicallyacceptable 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).

[0327] The compositions and methods of the present disclosure may be utilized to treat anindividual 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 a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution ispyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0328] A pharmaceutically acceptable excipient can contain physiologically acceptableagents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0329] A pharmaceutical composition (preparation) can be administered to a subject by anyof a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0330] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution,suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0331] Subjects may generally be monitored for therapeutic effectiveness using assays andmethods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0332] The dose of a pharmaceutical agent described herein for treating a disease or disordermay depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre- clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. Theoptimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0333] Pharmaceutical compositions comprising a pharmaceutical agent can be formulatedin a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0334] Pharmaceutical acceptable excipients are well known in the pharmaceutical art anddescribed, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0335] A pharmaceutical composition, e.g., for oral administration or for injection, infusion,subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, aliquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0336] For oral formulations, at least one of the pharmaceutical agents described herein canbe used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0337] A pharmaceutical composition comprising any one of the pharmaceutical agentsdescribed herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0338] In certain embodiments, the pharmaceutical compositions comprising apharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe- like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0339] Pharmaceutical compositions comprising a pharmaceutical agent can be formulatedas emulsions for topical application. An emulsion contains one liquid distributed in the body of asecond liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0340] Ointments and creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0341] In some embodiments, the pharmaceutical agent described herein can be formulatedas in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0342] Aerosolized formulations described herein are optionally delivered using an aerosolforming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^. Further, the formu...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof wherein: B is selected from a 7- to 15-membered heterocycle and C7-C15carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- 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, -C1-6alkyl(=NOR20), - 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, C1-6alkoxyalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, -O-, -S-, and -N(R5)-; R2is selected from heterocycle, aryl, Cl-C6 alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L- N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, 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, the aryl portion of -L- NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6alkyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, -C1-C3 alkyl-N(R5)2, - C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)Cl-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl 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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4 haloalkyl, Cl-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6alkoxy, Cl-C4hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl- N(R20)2, 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-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R23is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

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 thecombination of the RTK-MAPK pathway inhibitor and the compound or salt of Formula (I) 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 (I), or any combination thereof.

4. The method of any one of claims 1 to 3, wherein the therapeutically effectiveamount of the compound or salt of Formula (I) 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 effectiveamount of the compound or salt of Formula (I) 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 effectiveamount 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 effectiveamount 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 pathwayinhibitor and the compound or salt of Formula (I) are administered on different days.

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

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

11. The method of any one of claims 1 to 10, wherein the RTK-MAPK pathwayinhibitor 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 pathwayinhibitor is a RAF-MEK-ERK pathway inhibitor.

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

14. The method of any one of claims 1 to 13, wherein the inhibitor is selected fromthe 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 pathwayinhibitor is an epidermal growth factor receptor (EGFR) inhibitor.

17. The method of any one of claims 1 to 11, wherein the RTK-MAPK pathwayinhibitor 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 pathwayinhibitor 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 pathwayinhibitor 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 celllung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

28. The method of any one of claims 1 to26, wherein the cancer is non-small cell lungcancer.

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

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 tumorcancer.

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

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

36. The method of any one of claims 1 to 26, wherein the cancer is selected from aKRas 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 38, wherein the RTK-MAPK pathwayinhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (I).

41. The method of any one of claims 1 to 40, wherein the compound is selected fromcompounds 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutical acceptable salt thereof.

42. The method of any one of claims 1 to 40, wherein the compound is compound 2,or a pharmaceutical acceptable salt thereof.

43. The method of any one of claims 1 to 40, wherein the compound is compound 3,or a pharmaceutical acceptable salt thereof.

44. The method of any one of claims 1 to 40, wherein the compound is compound 4,or a pharmaceutical acceptable salt thereof.

45. The method of any one of claims 1 to 40, wherein the compound is compound 14,or a pharmaceutical acceptable salt thereof.

46. The method of any one of claims 1 to 40, wherein the compound is compound 25,or a pharmaceutical acceptable salt thereof.

47. The method of any one of claims 1 to 40, wherein the compound is compound 74,or a pharmaceutical acceptable salt thereof.

48. The compound or salt of any one of claim 1 to 40, wherein B is selected from anoptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle.

49. The compound or salt of any one of claim 1 to 40, or 48, wherein B is anoptionally substituted 8- to 15-membered fused heterocycle.

50. The compound or salt of any one of claim 1 to 40, or 48, wherein B is anoptionally substituted C8-C15fused carbocycle.

51. The compound or salt of any one of claims 1 to 40, or 48 to 50, wherein for B, theoptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle are each independently bicyclic or tricyclic.

52. The compound or salt of any one of claims 1 to 40, or 48 to 51, wherein theheterocycle or carbocycle of B is bicyclic.

53. The compound or salt of any one of claims 1 to 40, or 48 to 51, wherein theheterocycle or carbocycle of B is tricyclic.

54. The compound or salt of any one of claims 1 to 40, or 48 to 53, wherein for B, theoptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fy , , , , , eachof which is optionally substituted with one or more substituents.

55. The compound or salt of claim 54, wherein for B, the optionally substituted 8- to15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are selectedfrom , , , , and each of which isoptionally substituted with one or more substituents.

56. The compound or salt of any one of claim 1 to 40, or 48 to 55, wherein for B, theone or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, and C1-C3alkyl.

57. The compound or salt of any one of claim 1 to 40, or 48 to 56, wherein for B, theoptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle are selected from ,.

58. The compound or salt of any one of claims 1 to 40, or 48 to 53, wherein B isselected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15 carbocycle.

59. The compound or salt of claim 58, wherein B is selected from an optionallysubstituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle.

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

61. The compound or salt of claim 59, wherein B is an optionally substitutedunsaturated C8-C15 fused carbocycle.

62. The compound or salt of any one of claims 1 to 40, or 58 to 61, wherein for B, theheterocycle and carbocycle are each independently bicyclic or tricyclic.

63. The compound or salt of claim 62, wherein for B, the heterocycle and carbocycleare each independently bicyclic.

64. The compound or salt of claim 62, wherein for B, the heterocycle and carbocycleare each independently tricyclic.

65. The compound or salt of any one of claims 1 to 40, or 58 to 64, wherein B iss, , , , , , , , and , each ofwhich is optionally substituted with one or more substituents.,,llysubstituted with one or more substituents.

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

68. The compound or salt of any of claims 1 to 40, 58 to 67, wherein for B, the one ormore optional substituents are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

69. The compound or salt of claim 68, wherein B is selected from ,,,and .

70. The compound or salt of any of claims 1 to 40, 48 to 67, wherein for B, the one ormore 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

71. The compound or salt of claim 70, wherein for B, the one or more optionalsubstituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-Cl-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl.

72. The compound or salt of claims 70 or 71, wherein B is selected from,,,F , , , , , ,, ,73. The compound or salt of any one of claims 1 to 40, or 48 to 53, wherein B is anoptionally substituted 7- to 12-membered fused heterocycle.

74. The compound or salt of any one of claims 1 to 40, or 48 to 53, wherein B is anoptionally substituted 7- to 11-membered fused heterocycle.

75. The compound or salt of claims 73 or 74, wherein B is an optionally substituted 8-to 10-membered fused heterocycle.

76. The compound or salt of claim 75, wherein B is an optionally substituted 8- to 9-membered fused heterocycle.

77. The compound or salt of claims 73 or 74, wherein the heterocycle is anunsaturated heterocycle.

78. The compound or salt of any one of claims 1 to 40, 73 to 77, wherein B has atleast one sulfur atom.

79. The compound or salt of any one of claims 1 to 40, 73 to 78, wherein B has atleast one sulfur atom and at least one nitrogen atom.

80. The compound or salt of any one of claims 1 to 40, 73 to 78, wherein B has atleast one sulfur atom and at least one oxygen atom.

81. The compound or salt of any one of claims 1 to 40, or 73 to 78, wherein B has attwo sulfur atoms.

82. The compound or salt of any one of claims 1 to 40, or 73 to 81, wherein B iss ,,,, , , , and , eac o w c s opt ona lysubstituted.

85. The compound or salt of any one of claims 1 to 40, or 73 to 84, wherein the one ormore optional substituents of B, are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-Cl-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl.

86. The compound or salt of claim 85, wherein the one or more optional substituentsof B, are independently selected at each occurrence from halogen, C1-C3alkyl, -NH2, and -CN.

87. The compound or salt of any one of claims 1 to 40, or 73 to 83, wherein B iss ,88. The compound or salt of any one of claims 1 to 40, or 48 to 53, wherein B isselected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle.

89. The compound or salt of claim 88, wherein the heterocycle of B has at least onesulfur atom.

90. The compound or salt of claim 88 or 89, wherein the heterocycle of B has one orsulfur atoms.

91. The compound or salt of claim 90, wherein the heterocycle of B has at least onenitrogen atom.

92. The compound or salt of any one of claims 1 to 40, or 88 to 91, wherein B isselected from ,, each of which is optionally substituted.

93. The compound or salt of any one of claims 1 to 40, or 88 to 92, wherein the one ormore optional substituents of B are independently selected at each occurrence from halogen, C1- C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl.

94. The compound or salt of any one of claims 1 to 40, or 88 to 92, wherein the one ormore optional substituents of B are independently selected at each occurrence from halogen, C1- C3alkyl, -OH, -NH2, =O, and -CN.

95. The compound or salt of claim 93, wherein B is selected from ,,, , , , and .

96. The compound or salt of any one of claims 1 to 40, or 48 to 53, wherein B isselected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom.

97. The compound or salt of claim 96, wherein B is selected fro, , each of which is optionally substituted.

98. The compound or salt of claims 96 or 97, wherein the one or more optionalsubstituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, - OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

99. The compound or salt of claim 98, wherein the one or more optional substituentsof B are independently selected at each occurrence from halogen, C1-C3alkyl, -NH2, and -CN.

100. The compound or salt of any one of claims 1 to 40, or 96 to 99, wherein B issubstituted.

101. The compound or salt of any one of claims 1 to 40, or 96 to 99, wherein B issubstituted with at least one -NH2.

102. The compound or salt of any one of claims 1 to 40, or 96 to 101, wherein B isse ec e rom , , , , anNH2.

103. The compound or salt of any one of claims 1 to 40, or 96 to 101, wherein B issubstituted with at least one -NH2at least one -CN.104 The compound or salt of claim 103 wherein B is selected from ,,, and .

105. The compound or salt of any one of claims 1 to 40, or 48 to 104, wherein R3 isselected from hydrogen, halogen, -CN, -C(O)R22, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl C1-6haloalkyl and C1-6alkyl.

106. The compound or salt of claim 105, wherein R3 is selected from hydrogen,fluorine, -CN, -C(O)H, C1 hydroxyalkyl, and C1-6 alkyl.

107. The compound or salt of claims 105 or 106, wherein R3 is selected fromhydrogen, fluorine, and -CN.

108. The compound or salt of claim 107, wherein R3 is selected from fluorine.

109. The compound or salt of claim 107, wherein R3 is selected from hydrogen.

110. The compound or salt of claim 107, wherein R3 is selected from -CN.

111. The compound or salt of any one of claims 1 to 40, or 48 to 110, wherein Y is -O-.

112. The compound or salt of any one of claims 1 to 40, or 48 to 111, wherein L isselected from C1-C4alkylene.

113. The compound or salt of claim 112, wherein L is selected from unsubstituted C1-C4 alkylene.

114. The compound or salt of claim 112, wherein each L is independently selectedfrom a Cl-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl.

115. The compound or salt of claim 114, wherein the optional substituents of L areselected from Cl-C4hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

116. The compound or salt of any one of claims 1 to 40, or 111 to 115, wherein L iss ,,, , , , and .

118. The compound or salt of claim 114 or 115, wherein each L is independentlyselected from a substituted Cl-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle 3- to 5-membered heterocycle.

119. The compound or salt of claim 118, wherein each L is independently selectedfrom a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle or 4-membered heterocycle, wherein the C3carbocycle is optionally substituted with one or more substituents selected from halogen.

120. The compound or salt of claim 119, wherein each L is independently selectedf .

121. The compound or salt of claim 120, wherein each L is independently selectedf.

122. The compound or salt of claim 121, wherein each L is independently selectedf.

123. The compound or salt of claim 112, wherein each L is independently selectedfrom a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen and Cl-C4 alkyl.

124. The compound or salt of claim 123, wherein L is selected fro, ,, .

125. The compound or salt of claim 112, wherein each L is independently selectedfrom an unsubstituted Cl-C4 alkylene.

126. The compound or salt of claim 125, wherein L is selected from and.

127. The compound or salt of claim 126, wherein L is selected from .

128. The compound or salt of any one of claims 1 to 40, or 48 to 127, wherein R2 isselected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R23)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

129. The compound or salt of claim 128, wherein R2 is -L-heterocycle, wherein theheterocycle portion of R2is an optionally substituted heterocycle.

130. The compound or salt of claim 128 or 129, wherein R2 is -L-heterocycle,optionally substituted with one or more R6.

131. The compound or salt of any one of claims 1 to 40, or 48 to 130, wherein Y-R2 isselected from , wherein the heterocycle portion is optionallysubstituted with one or more R6.

132. The compound or salt of any one of claims 1 to 40, or 128 to 131, wherein theheterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, and Cl-C3 aminoalkyl.

133. The compound or salt of claim 132, wherein the heterocycle portion of R2 is aheterocycle optionally substituted with one or more substituents selected from C1-C3alkyl and halogen.

134. The compound or salt of any one of claims 1 to 40, or 48 to 133, wherein Y-R2 isselected from.

135. The compound or salt of any one of claims 1 to 40, or 48 to 131, wherein Y-R2 isselected from, wherein the heterocycle portion is optionallysubstituted with one or more R6.

136. The compound or salt of claim 135, wherein R6 of R2 is independently selected ateach occurrence from halogen, hydroxy, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, cyano, and Cl-C3 aminoalkyl.

137. The compound or salt of claim 136, wherein R6 of R2 is independently selected ateach occurrence from C1-C3alkyl and halogen.138 The compound or salt of claim 137 wherein Y-R2 is selected from, , , and .

139. The compound or salt of any one of claims 1 to 40, or 48 to 128, wherein Y-R2 iss ,ocycleportion is optionally substituted with one or more R6.

140. The compound or salt of claim 139, wherein Y-R2 selected fro,.

141. The compound or salt of claim 140, wherein Y-R2 is selected fr, wherein the heterocycle is optionally substituted.

142. The compound or salt of claim 141, wherein the heterocycle is optionallysubstituted with one or more substituents selected from halogen, hydroxy, Cl-C3alkyl, - N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3 alkyl isoptionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

143. The compound or salt of claims 1 to 40, or 48, or 141-142, wherein Y-R2 iss ,,, , , , ,,144. The compound or salt of claim 128, wherein R2 is -L-heteroaryl, wherein theheteroaryl portion is optionally substituted with one or more R7.

145. The compound or salt of claim 144, wherein each R7 is independently selectedfrom halogen, and Cl-C4 haloalkyl; 146. The compound or salt of claim 145, wherein Y-R2 is selected froman .

147. The compound or salt of claim 128, wherein R2 is -L-aryl, optionally substitutedwith one or more R7.

148. The compound or salt of claim 147, wherein Y-R2 is selected fromherein the heterocycle portion is optionally substituted with one or more R7.mpound or salt of claim 148, wherein Y-R2 is selected fromand .

150. The compound or salt of claim 128, wherein R2 is -L-heteroaryl, optionallysubstituted with one or more R7.

151. The compound or salt of claim 150, wherein Y-R2 is selected fra , wherein the heteroaryl portion is optionally substituted with one or moreR7.

152. The compound or salt of claims 150 or 151, wherein Y-R2 is selected from.

153. The compound or salt of claim 128, wherein R2 is -L-N(R23)2.

154. The compound or salt of claim 153, wherein Y-R2 is selected from.

155. The compound or salt of claim 154, wherein R2 is heterocycle, optionallysubstituted with one or more R6.

156. The compound or salt of claim 155, wherei- .

157. The compound or salt of claim 128, wherein Y-R2is .

158. The compound or salt of any one of claims 1 to 40, or 48 to 127, wherein R2 isselected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6; -L-aryl, and -L- heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and -L-N(R23)2. 159 The compound or salt of claim 158 wherein the heterocycle of R2 is selected from,, , , and , wherein the heterocycle of R2 is optionallysubstituted with one or more R6; wherein the aryl and heteroaryl of R2is selected fr ,,, and , wherein the aryl and the heteroaryl are each optionally substituted.

160. The compound or salt of claim 159, wherein the heterocycle of R2 is selected from,ndrein t, , , , and oreR; an , .

161. The compound or salt of any one of claims 158 to 160, wherein each R6 isindependently selected from halogen, hydroxy, Cl-C3alkyl, Cl-C3haloalkyl, -N(R5)S(O)2(R5), - OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3 alkyl is optionallysubstituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from Cl-C3alkyl, halogen and Cl-C3haloalkyl.

162. The compound or salt of any one of claims 158-161, wherein the heteroc cle ofR2 h l d h l f R2 d N R20 f R2 i l d f i l d f ,, , , , ,,,R2 iss ,,, ,, and , wherein the heterocycle, and the heterocycle portion of-L-heterocycle, are each optionally substituted with one or more R ,reinthe aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted witho ,164. The compound or salt of any one of claims 158-163, wherein Y-R2 is selected,,,, , , ,, , ,,, , , and .

165. The compound or salt of any one of claims 1 to 40, or 48 to 164, wherein Y-R2 is, ,.

166. The compound or salt of any one of claims 1 to 40, or 48, wherein Y is -O- and R2is selected from L-5-membered heteroaryl, wherein L is selected from an optionally substituted C1-C4alkylene, and wherein the heteroaryl is optionally substituted with one or more R7, wherein each R7is preferably selected from halogen, Cl-C4 alkyl, and Cl-C4 haloalkyl.

167. The compound or salt of any one of claims 166, wherein Y-R2 is selected from, ,,and .

168. The compound or salt of any one of claims 1 to 40, or 48 to 165, wherein R1 isselected 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl.

169. The compound or salt of claim 166, wherein R1 is 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, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl.

170. The compound or salt of any one of claims 1 to 40, or 48 to 168, wherein R1 is anoptionally substituted 5- to 12-membered heterocycle.

171. The compound or salt of claim 170, wherein the 5- to 12-membered heterocycleof R1is unsaturated.

172. The compound or salt of claim 170, wherein the 5- to 12-membered heterocycleof R1is saturated.

173. The compound or salt of claim 170, wherein the 5- to 12-membered heterocycleof R1is bridged.

174. The compound or salt of claim 170, wherein the 5- to 12-membered heterocycleof R1is a spiro heterocycle.

175. The compound or salt of claim 170, wherein the 5- to 12-membered heterocycleof R1is non-aromatic.

176. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 iss ,,,, , and , each of which is optionally substituted.

177. The compound or salt of claim 176, wherein the optional one or more substituentsare each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

178. The compound or salt of claim 177, wherein R1 is selected fr ,,each of which is optionally substitutedwith one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6 alkoxy, =O, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl.

179. The compound or salt of any one of claims 1 to 40, or 48, wherein R1 is selectedf ,,,, , , , , ,,,,,, , , , , , ,,,,,, , , ,,,,,, , ,, ,.

180. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from 6- to 8-membered heterocycle, which is optionally substituted.

181. The compound or salt of claim 180, wherein R1 is selected from 7-memberedsaturated heterocycle, 8-membered bridged heterocycle, and 6- to 7-membered unsaturated heterocycle, each of which is optionally substituted.

182. The compound or salt of claim 181, wherein R1 is selected fr,, each of which is optionally substituted.

183. The compound or salt of claim 182, wherein the one or more optional substituentsare independently selected from -OH, -CN, oxo, C1-6cyanoalkyl.

184. The compound or salt of claims 182 or 183, wherein R1 is selected from,, an .

185. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted 6- to 7-membered heterocycle.

186. The compound or salt of claim 185, wherein the 6- to 7-membered heterocyclecontains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle is optionally substituted.

187. The compound or salt of 186, wherein the 6- to 7-membered heterocycle of R1 isbound to Formula (I) via the only 1 nitrogen atom.

188. The compound or salt of any one of claims 185 to 187, wherein R1 is selectedfrom an optionally substituted unsaturated 6-membered heterocycle.

189. The compound or salt of any one of claims 185 to 187, wherein R1 is selectedfrom an optionally substituted unsaturated 7-membered heterocycle.

190. The compound or salt of any one of claims 185 to 188, wherein R1 is selectedfrom , any of which is optionallysubstituted.

191. The compound or salt of claim 185, wherein R1 is selected fr,, any of which is optionally substituted.

192. The compound or salt of claim 185 to 191, wherein the one or more optionalsubstituents of R1are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, -NHCN, and C2-6alkynyl.

193. The compound or salt of any one of claims 185 to 192, each is optionallysubstituted with one or more substituents independently selected from halogen, -OH, -NH2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

194. The compound or salt of any one of claims 185 to 193, wherein the one or moreoptional substituents of R1are each independently selected from halogen.

195. The compound or salt of any one of claims 185 to 194, wherein R1 is selectedf ,,, , , , and .196 Th m nd r lt of any one of claims 185 to 191, wherein R1 is selectedfrom , , and , wherein each is optionally substituted with one or moresubstituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl and C16 alkyl197. The compound or salt of claim 196, wherein R1 is selected fro and, wherein each is optionally substituted with one or more substituents independentlyselected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

198. The compound or salt of claim 197, wherein R1 is selected froand, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6haloalkyl.

199. The compound or salt of claim 198, wherein R1 is selected from ,, , and .

200. The compound or salt of any one of claims 182, wherein R1 is selected from, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6cyanoalkyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

201. The compound or salt of claim 200, wherein R1 is selected fro, which isoptionally substituted with one or more substituents independently selected from halogen.

202. The compound or salt of claim 201, wherein R1 is selected from.

203. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted 6- to 7-membered heterocycle.

204. The compound or salt of claim 203, wherein the 6- to 7-membered heterocyclecontains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur.

205. The compound or salt of claim 204, wherein the optionally one or more additionalheteroatoms are selected from sulfur.

206. The compound or salt of any one of claims 203 to 205, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms.

207. The compound or salt of any one of claims 203 to 206, wherein the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle.

208. The compound or salt of any one of claims 203 to 207, wherein the 6- to 7-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom.

209. The compound or salt of any one of claims 203 to 208, wherein R1 is selectedfrom,, , , , and , each of which is optionallysubstituted.

210. The compound or salt of any one of claims 203 to 209, wherein the one or moreoptional substituents of R1are each independently selected from halogen, -OH, -CN, C1-6cyanoalkyl, -NHCN, C1-6 alkyl, oxo, and C2-6 alkynyl.

211. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted 6- to 10-membered heterocycle.

212. The compound or salt of claim 211, wherein R1 is selected fr ,and, each of which is optionally substituted.

213. The compound or salt of claim 212, wherein the one or more optional substituentsare independently selected from halogen, =O, -OH, -C(O)N(R20)2, C2-6alkynyl, -NHCN, -CN, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl.

214. The compound or salt of claims 212 or 213, wherein R1 is selected from, ,d.

215. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from a 7- to 11-membered spiro heterocycle.

216. The compound or salt of claim 215, wherein R1 is selected from a 10-memberedspiro heterocycle.

217. The compound or salt of claims 215 or 216, wherein the spiro heterocycle has atleast 3 nitrogen atoms.

218. The compound or salt of claim 217, wherein R1 is selected f, and, each of which is optionally substituted.

219. The compound or salt of claim 218, wherein R1 is selected fr, and, 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, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

220. The compound or salt of claim 219, wherein R1 is selected from ,and .

221. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted unsaturated 9- to 11-membered heterocycle.

222. The compound or salt of claim 221, wherein R1 is selected from an optionallysubstituted unsaturated 10-membered heterocycle.

223. The compound or salt of claims 221 or 222, wherein R1 is, which is optionally substituted.N N 224. The compound or salt of claim 223, where, which is optionallysubstituted with one or more substituents selected from halogen, -OH, -C(O)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl.

225. The compound or salt of claim 224, wherein R1 is selected from, each of which is further optionally 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.

226. The compound or salt of any one of claims 221 to 223, wherein the one or moreoptional 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl.

227. The compound or salt of claims 223 or 226, wherein R1 is selected from,, , and , each of which is optionally substituted.

228. The compound or salt of claim 227, wherein R1 is selected from, ,, , an .

229. The compound or salt of claim 223, wherein the one or more optional substituentsof 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.

230. The compound or salt of claim 229, wherein the one or more optional substituentsof R1are independently selected from halogen, and -C(O)N(R20)2.

231. The compound or salt of claim 230, wherein R1 is selected fra .

232. The compound or salt of claim 231, where.

233. The compound or salt of claim 231, where.

234. The compound or salt of claim 223, wherein the one or more optional substituentsof R1are independently selected from halogen, C1-6 alkyl, C1-6 alkyl-N(R20)2, - C(O)NR20OR20, -C(O)N(R20)2, and -C(O)R20.

235. The compound or salt of claims 234, wherein the one or more optionals ,,, , , and .

236. The compound or salt of claim 235, wherein R1 is selected from,,, .

237. The compound or salt of any one of claims 221 to 223, wherein the one or moreoptional substituents of R1are independently selected from halogen, -N(R20)2, -CN, C1-6alkyl, C1-6 cyanoalkyl, C1-6 alkyl-N(R20)2, C1-6 alkyl-SO2-C1-6 alkyl, C2-6 alkenyl, - C(O)NR20OR20, -C(O)N(R20)2, -C(O)R20, and 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted independently with one or more R1*, wherein each R1*is independently selected from halogen, -OR20, and C1-6alkyl.

238. The compound or salt of claims 223 or 237, wherein the one or more optionals,, , , , , ,,,, , , ,,, , and.

240. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted 6- to 11-membered heterocycle, wherein the 6- to 11- membered heterocycle has at least one nitrogen atom.

241. The compound or salt of claim 240, wherein the one or more optional substituentsof R1is selected from halogen, -OR20, -C(O)N(R20)2, -C(O)R20, -S(O)2R20, =O, -C1-6 alkyl(=NOR20), =NO(R20), -CN, -NHCN, C1-6alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1*is independently selected from halogen, and C1-6 alkyl. ,, , , , ,, .ted, ,, ,, and .

244. The compound or salt of any one of claim 1 to 40, or 48, wherein R1 is selectedfrom hydrogen, , , ,,.

245. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from hydrogen and optionally substituted 5- to 15-membered heterocycle.

246. The compound or salt of claims 245, wherein R1 is selected fr ,and, each of which is optionally substituted.

247. The compound or salt of claim 246, wherein the optional one or more substituentsof R1is selected from -OH, =NO(R20), -NHCN, and C1-6 alkyl.

248. The compound or salt of any one of claims 245 to 247, wherein R1 is selectedf ,,,, , and .

249. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from hydrogen and optionally substituted 7- to 10-membered heterocycle.

250. The compound or salt of claim 249, wherein R1 is selected from hydrogenh isoptionally substituted.

251. The compound or salt of claims 249 or 250, wherein the optional one or moresubstituents of R1are independently selected from halogen, -NH2, -S(O)2(R20), -C(O)R20, - C(O)N(R20)2, =O,=NO(R20), -CN, -NHCN, C1-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1*is independently selected from halogen, and C1-6alkyl.

252. The compound or salt of any one of claims 249 to 251, wherein R1 is selectedf ,, , , , ,,253. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted 8- to 10-membered heterocycle.

254. The compound or salt of claim 253, wherein the heterocycle is bicyclic.

255. The compound or salt of claims 253 or 254, wherein the heterocycle has at leastone nitrogen atom.

256. The compound or salt of claims 253 or 254, wherein the heterocycle has at leasttwo nitrogen atoms.

257. The compound or salt of any one of claims 253 to 25, , ,, and , each of which is optionally substituted.

258. The compound or salt of any one of claims 253 or 257, wherein the optional oneor more substituents of R1are independently selected from halogen, , oxo, ,, , and 5- to 9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is substituted with at least one R1*, wherein the R1*is selected from halogen, and C1-6 alkyl.

259. The compound or salt of any one of claims 253 or 258, wherein the optional oneor more substituents of R1are independently selected from chlorin ,,, , and .

261. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 is anoptionally substituted 12- to 15-membered heterocycle.

262. The compound or salt of claim 261, wherein R1 is an optionally substituted 12-membered heterocycle.

263. The compound or salt of claim 262, wherein R1 is an optionally substituted 13-membered heterocycle.

264. The compound or salt of claim 263, wherein R1 is an optionally substituted 14-membered heterocycle.

265. The compound or salt of claim 264, wherein R1 is an optionally substituted 15-membered heterocycle.

266. The compound or salt of any one of claims 261 to 265, wherein the heterocycle ofR1is tricyclic.

267. The compound or salt of any one of claims 261 to 266, wherein the heterocycle ofR1contains a fused heterocycle.

268. The compound or salt of any one of claims 261 to 267, wherein the heterocycle ofR1contains a spiro heterocycle.

269. The compound or salt of any one of claims 261 to 268, wherein the heterocycle ofR1contains a fused and spiro-heterocycle.

270. The compound or salt of any one of claims 261 to 269, wherein the heterocycle ofR1is an unsaturated heterocycle.

271. The compound or salt of any one of claims 261 to 269, wherein the heterocycle ofR1is a non-aromatic heterocycle.

272. The compound or salt of any one of claims 261 to 271, wherein the heterocycle ofR1has at least one double bond.

273. The compound or salt of any one of claims 261 to 272, wherein the heterocycle ofR1has at least two double bonds.

274. The compound or salt of any one of claims 261 to 272, wherein the heterocycle ofR1has two double bonds.

275. The compound or salt of any one of claims 261 to 273, wherein R1 is selectedf, , , , ,, oresubstituents.

276. The compound or salt of claim 275, wherein the optional one or more substituentsare 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, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl.

277. The compound or salt of claim 276, wherein the optional one or more substituentsare selected from halogen, -OH, C1-6alkyl, and -C(O)N(R20)2.

278. The compound or salt of any one of claims 261 to 277, wherein R1 is selectedf,, , ,.

279. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected 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 C1-6 alkyl.

280. The compound or salt of claim 279, wherein R1 is selected froan .

281. The compound or salt of any one of claims 1 to 40, or 48 to 175, wherein R1 isselected from an optionally substituted bridged 8- to 9-membered heterocycle.

282. The compound or salt of claim 281, wherein the heterocycle of R1 is selected from, , and , each of which is optionally substituted.

283. The compound or salt of claims 281 or 282, wherein the one or more substituentsof R1are selected from halogen, C1-6 alkyl, -N(R20)2, and C1-6 aminoalkyl. 284 The com ound or salt of any one of claims 281 to 283, wherein R1 is selected, , and .

285. The compound or salt of claim 281, wherein R1 is selected from an optionallysubstituted bridged 8-membered heterocycle, wherein the heterocycle contains heteroatoms selected from nitrogen.

286. The compound or salt of claim 285, wherein the one or more substituents of R1are selected from C1-6 alkyl, -N(R20)2, and C1-6 aminoalkyl.

287. The compound or salt of claim 286, wherein the heterocycle of R1 is selected from, each of which is optionally substituted.

288. The compound or salt of any one of claims 285 to 287, wherein R1 is selected.

289. The compound or salt of claims 1 to 40, or 48 to 175, or 288, wherein R1 isselected from.

290. The compound or salt of any one of claims 1 to 40, or 48 to 170, wherein R1 ishydrogen.

291. The compound or salt of any one of claims 1 to 40, or 48 to 290, wherein n is 0.

292. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof wherein: R1is selected from 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6 alkyl-SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-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, -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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, and C3-C12carbocycle; B is selected from a 7- to 15-membered heterocycle and C7-C15carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; Y is selected from a bond, and -O-; R2is selected from heterocycle, aryl, Cl-C6alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, 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, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6alkyl, C2-6alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl;n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6 alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3hydroxyalkyl, Cl-C3alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, - N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, - 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(Cl-C3alkyl), -OC(O)NH(C1- C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl 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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4haloalkyl, Cl-C4hydroxyalkyl, -C1-C3alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, Cl-C4 hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle;each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle.

293. The compound or salt of claim 292, wherein Formula (I-A) is represented byFormula (I-B),w e e s se ec e o , , , eac o w ch isoptionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, =O, and 5- to 12-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, -OR20, -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; Y is -O-; R2is selected from -L-heterocycle, and -L-N(R23)2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R6. B is selected from a 7- to 15-membered heterocycle, wherein the 7- to 15-membered heterocycle is optionally substituted with one or more substituents independently selected fromhalogen, -CN, =O, -N(R21)2, -OR21, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl; R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OR20, -C(O)R20, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; and each R20is independently selected from hydrogen; and C1-6alkyl, and C3-12carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, and oxo.

294. The compound or salt of claims 292 or 293, wherein R1 is selected fro,oneor more substituents independently selected from halogen, -S(O)2(R20), -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, =O, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*; and each R1*is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl.

295. The compound or salt of any one of claims 292 to 294, wherein Y is -O-.

296. The compound or salt of any one of claims 292 to 295, wherein each L isindependently selected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from halogen, and Cl-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 4- to 6- membered heterocycle, wherein the C3-C6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen.

297. The compound or salt of any one of claims 292 to 296 wherein each L is selectedf and. -R2 is selectedfrom , ,and299. The compound or salt of any one of claims 292 to 298, wherein B is selected froman optionally substituted 8- to 10-membered heterocycle.

300. The compound or salt of claim 299, wherein the 8- to 10-membered heterocycle isoptionally substituted with one or more substituents independently selected from halogen, -CN, - NH2, and C1-6 alkyl.

301. The compound or salt of any one of claims 292 to 300, wherein the heterocycle ofBis selected from , , , , , , and .

302. The compound or salt of any one of claims 292 to 301, wherein , ,,, , , and , each of which is optionally substituted withone or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl.

303. The compound or salt of any one of claims 292 to 302, wherein B is selected from,304. The compound or salt of any one of claims 292 to 303, wherein R3 is -CN.

305. The compound or salt of any one of claims 292 to 304, wher,which is optionally substituted with one or more substituents.

306. The compound or salt of any one of claims 292 to 304, where.

307. The compound or salt of any one of claims 292 to 304, wheren s .N 308. The compound or salt of any one of claims 292 to 304, wherein R1 is .

309. The compound or salt of any one of claims 292 to 308, wherein the one or moreoptional substituents of R1are independently selected from halogen, -S(O)2(R20), -C(O)N(R20)2, - C1-6alkyl(=NOR20), -C(O)R20=O, and 5- to 9-membered heterocycle, wherein the 5- to - membered heterocycle are each optionally substituted independently with one or more R1*.

310. The compound or salt of any one of claims 292 to 308, wherein the one or moreoptional substituents of R1are independently selected from halogen, -S(O)2(R20), -C(O)N(R20)2, - C1-6alkyl(=NOR20), -C(O)R20, =O, and 5- to 9-membered heterocycle, wherein the 5- to - membered heterocycle are each optionally substituted independently with one or more R1*.

311. The compound or salt of any one of claims 292 to 308, wherein the one or moreoptional substituents of R1are independently selected from halogen, -C(O)N(R20)2, -C1-6 alkyl(=NOR20), -C(O)R20, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*.

312. The compound or salt of claim 311, wherein each R1* is independently selectedfrom halogen, C1-6haloalkyl, and C1-6alkyl.

313. The compound or salt of any one of claims 292 to 305, wher ,which is subtituted with at least one substituent.

314. The compound or salt of any one of claims 292 to 305, wherein R1 is, ,,, , and .315 The compound or salt of any one of claims 292 to 305, wherein R1 is.

316. A pharmaceutical composition comprising the compound of any one of claims 1to 315 and a pharmaceutically a t bl i i t317. A method of treating a disease or disorder, using a compound or salt of any one ofclaims 1 to 315 or a pharmaceutical composition of claim 316.

318. A method of inhibiting KRas G12D and / or other G12 mutants, using a compoundor salt of any one of claims 1 to 315 or a pharmaceutical composition of claim 316.

319. A method of inhibiting KRas G12D and / or other G12 mutants, using a compoundor salt of any one of claims 1 to 315 or a pharmaceutical composition of claim 316.

320. A method of inhibiting KRas G12D and / or other G12 alleles, using a compoundor salt of any one of claims 1 to 315 or a pharmaceutical composition of claim 316.

321. A method of inhibiting KRas G12D and / or other alleles, using a compound or saltof any one of claims 1 to 315 or a pharmaceutical composition of claim 316.

322. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of a RTK-MAPK pathway inhibitor and a compound of Formulas (I), (I-A), or (I-B)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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

323. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of a RAF-MEK-ERK pathway inhibitor and a compound of Formulas (I), (I-A), or (I-B)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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

324. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of a ERBB family inhibitor and a compound of Formulas (I), (I-A), or (I-B)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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

325. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of a EGFR inhibitor and a compound of Formulas (I), (I-A), or (I-B) 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

326. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor and a compound of Formulas (I), (I-A), or (I-B) 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

327. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of an SOS1 inhibitor and a compound of Formulas (I), (I-A), or (I-B), 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 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, 103, 104, 105, 106, 107, 108, 109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

328. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of anyone thereof.

329. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 2, or a pharmaceutically acceptable salt of thereof.

330. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 3, or a pharmaceutically acceptable salt of thereof.

331. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 4, or a pharmaceutically acceptable salt of thereof.

332. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 14, or a pharmaceutically acceptable salt of thereof.

333. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 25, or a pharmaceutically acceptable salt of thereof 334. The method of any one of claims 322 to 327, wherein the compound of Formulas(I), (I-A), or (I-B) is selected from compound 74, or a pharmaceutically acceptable salt of thereof.

335. The method of any one of claims 322 to 333, wherein the combination exhibitssynergy.

336. The method of any one of claims 322 to 325 & 328 to 333, wherein the inhibitoris selected from the group consisting of afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, and cetuximab.

337. The method of any one of claims 322 to 325 and 328 to 333, wherein the inhibitoris cetuximab.

338. The method of claim of any one of claims 322 to 337, wherein the combinationexhibits synergy.

339. The method of claims 322 or 337, wherein the therapeutically effective amount ofthe 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.

340. The method of any one of claims 322 to 339, wherein the therapeutically effectiveamount of the compound or salt of the combination is between about 0.01 to 100 mg / kg per day.

341. The method of any one of claims 322 to 340, wherein the therapeutically effectiveamount of the compound or salt in the combination is between about 0.1 to 50 mg / kg per day.

342. The method of any one of claims 322 to 341, wherein the therapeutically effectiveamount of the inhibitor of the combination is between about 0.01 to 100 mg / kg per day.

343. The method of any one of claims 322 to 342, wherein the therapeutically effectiveamount of the inhibitor of the combination is between about 0.1 to 50 mg / kg per day.

344. The method of any one of claims 322 to 343, wherein the inhibitor and thecompound or salt are administered on different days.

345. The method of any one of claims 322 to 344, wherein the compound or salt isadministered at a maximum tolerated dose.

346. The method of any one of claims 322 to 345, wherein the inhibitor is administeredat a maximum tolerated dose.

347. The method of any one of claims 322 to 346, wherein the inhibitor and thecompound or salt are each administered at a maximum tolerated dose.

348. The method of claim 322, wherein the RTK-MAPK pathway inhibitor is a RAF-MEK-ERK pathway inhibitor.

349. The method of claim 322, wherein the RTK-MAPK pathway inhibitor is a ERBBfamily inhibitor.

350. The method of claim 322 or 349, wherein the inhibitor is selected from the groupconsisting of afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, and cetuximab.

351. The method of claim 322 or 350, wherein the inhibitor is cetuximab.

352. The method of claim 322, wherein the RTK-MAPK pathway inhibitor is anepidermal growth factor receptor (EGFR) inhibitor.

353. The method of claim 322, wherein the RTK-MAPK pathway inhibitor is a SHP-2inhibitor.

354. The method of claim 353, 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).

355. The method of claim 354, wherein the SHP-2 inhibitor is RMC-4550.

356. The method of claim 354, wherein the SHP-2 inhibitor is RMC-4360.

357. The method of claim 354, wherein the SHP-2 inhibitor is TNO155.

358. The method of claim 354, wherein the SHP-2 inhibitor is SHP-099.

359. The method of claim 322, wherein the RTK-MAPK pathway inhibitor is a SOS1inhibitor.

360. The method of claim 359, wherein the SOS1 inhibitor is BI-3406.

361. The method of any one of claims 322 to 360, wherein the RTK-MAPK pathwayinhibitor is administered orally.

362. The method of any one of claims 322 to 361, 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.

363. The method of any one of claims 322 to 362, wherein the cancer is non-small celllung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

364. The method of any one of claims 322 to 362, wherein the cancer is non-small celllung cancer.

365. The method of any one of claims 322 to 362, wherein the cancer is small cell lungcancer.

366. The method of any one of claims 322 to 362, wherein the cancer is colorectalcancer.

367. The method of any one of claims 322 to 362, wherein the cancer is rectal cancer.

368. The method of any one of claims 322 to 362, wherein the cancer is pancreaticcancer.

369. The method of any one of claims 322 to 362, wherein the cancer is a solid tumorcancer.

370. The method of any one of claims 322 to 369, wherein the cancer is selected froma KRas mutant-associated cancer.

371. The method of any one of claims 322 to 369, wherein the cancer is selected froma KRas wildtype-associated cancer.

372. The method of any one of claims 322 to 369, wherein the cancer is selected froma KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype- associated cancer.

373. The method of any one of claims 322 to 369, wherein the cancer is a KRas G12D-associated cancer.

374. The method of any one of claims 322 to 369, wherein the cancer is a KRas G12V-associated cancer.

375. The method of any one of claims 322 to 369, wherein the cancer is a KRaswildtype-associated cancer.

376. The method of any one of claims 322 to 369, wherein the RTK-MAPK pathwayinhibitor synergistically increases the sensitivity of cancer cells to the compound or salt.

377. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a combination of cetuximab and a compound O N N sally acceptable salt of any one thereof.

378. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of cetuximab and a compound selected from, and , or a pharmaceutically acceptable salt of any one thereof.O N N F N 379. The method of claims 377 or 378, wherein the compou.

380. The method of claims 377 or 378, wherein the compou.

381. The method of claims 377 or 378, wherein the compound is. od of claims 377 or 378, wherein the compound is.

383. The method of claims 377 or 378, wherein the compound is .

384. The method of claims 377 or 378, wherein the compound is.

385. The method of any one of claims 377 to 384, wherein cetuximab synergisticallyincreases the sensitivity of the cancer cells to the compound.

386. The method of any one of claims 377 to 385, 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.

387. The method of any one of claims 377 to 385, wherein the cancer is non-small celllung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

388. The method of any one of claims 377 to 385, wherein the cancer is non-small celllung cancer.

389. The method of any one of claims 377 to 385, wherein the cancer is small cell lungcancer.

390. The method of any one of claims 377 to 385, wherein the cancer is colorectalcancer.

391. The method of any one of claims 377 to 385, wherein the cancer is rectal cancer.

392. The method of any one of claims 377 to 385, wherein the cancer is pancreaticcancer.

393. The method of any one of claims 377 to 385, wherein the cancer is a solid tumorcancer.

394. The method of any one of claims 377 to 393, wherein cetuximab and thecompound or salt are administered on different days.

395. The method of any one of claims 377 to 394, wherein the combination isadministered on different days.

396. A pharmaceutical composition, comprising a therapeutically effective amount of acombination of cetuximab and the compound of claim 377 to 384, and a pharmaceutically acceptable excipient.

397. A kit comprising the pharmaceutical composition of claim 394 for treating cancerin a subject.

398. A kit comprising: a) a pharmaceutical composition comprising cetuximab and b) apharmaceutical composition comprising a compound of any one of claims 377-384 for treating cancer in a subject.

399. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of an RTK-MAPK pathway inhibitor and a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein: B is selected from a 7- to 15-membered heterocycle and C7-C15carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- 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, -C1-6 alkyl(=NOR20), - 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, C1-6 alkyl-N(R20)2, C16 aminoalkyl C16 alkoxy C16 hydroxyalkyl, C1-6 cyanoalkyl,C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle 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 -N(R5)-; R2is selected from heterocycle, aryl, Cl-C6 alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L- N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, 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, the aryl portion of -L- NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6alkyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3 alkyl, Cl-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, -C1-C3 alkyl-N(R5)2, - C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4 haloalkyl, Cl-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6alkoxy, Cl-C4hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl- N(R20)2, 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-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle;each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

400. A method of treating cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of cetuximab and a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein: B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(O)R21, C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- 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, -C1-6 alkyl(=NOR20), - 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, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkoxyalkyl, 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, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; Y is selected from a bond, -O-, -S-, and -N(R5)-; R2is selected from heterocycle, aryl, Cl-C6alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Cl-C6 haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L- N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, 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, the aryl portion of -L- NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)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, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6alkyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and C1-C6 alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-Cl-C3alkyl, Cl-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, -C1-C3 alkyl-N(R5)2, - C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)Cl-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl), -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-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 selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 haloalkyl, Cl-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6alkoxy, Cl-C4hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 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 independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R23is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 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.

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