Combination therapies with KRAS modulators

Abstract

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

Description

COMBINATION THERAPIES WITH KRAS MODULATORS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 518,171 filed on August 8, 2023; the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION

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

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

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

[0005] In some embodiments, oncogenic KRas mutations create an immunosuppressive microenvironment which can result in resistance to immune checkpoint blockade (ICB) therapy, including anti-PD-1 and anti-PD-L1 inhibitors. Activated KRas has been demonstrated to repress the expression of interferon regulatory factor 2 (IRF2), which directly represses CXCL3 expression. This KRas-mediated repression of IRF2 leads to increased expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells (MDSC) promoting migration of these cells to the tumor microenvironment. In some cases, a role for KRas in modulating the immune microenvironment and primary ICB resistance in advanced colorectal cancer has been established. In colorectal cancer, anti-PD-1 resistance of KRAS-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. (e.g., see Liao et al., (2019) Cancer Cell 35:559 - 572). In addition, oncogenic KRas signaling has been shown to promote tumor immunoresistance to ICB therapy by stabilizing PD-L1 mRNA via repression of the AU- rich element-binding protein tristetraprolin (TTP), which negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA (e.g., see Coelho et al., (2017) Immunity 47(6): 1083-1099). In some cases, oncogenic KRas has also been demonstrated to impair antigen presentation by repressing MHC I expression thereby allowing tumor cells to evade cytotoxic T-lymphocytes (e.g., see El-Jawhari et al., (2014) Molecular Immunology 58(2): 160-168), and KRas activating mutations upregulate IL-8 expression in NSCLC, and IL-8 plays a role in cell growth and migration in KRas-associated NSCLC (e.g., see Sunaga et al., (2012) Int. J. Cancer 130(8):1733-1744).

[0006] Thus, activated KRas mutations or other KRas-activating generic alterations expression may modulate many aspects of the immune system and can be responsible for the immunosuppressive tumor microenvironment in KRas mutant or hyperactivated Kras wildtype- associated tumors. As such, the direct inhibition of KRas mutant or hyperactivated Kras wildtype-associated-mediated cell activity may reverse this reported immunosuppressive tumor microenvironment thereby improving the clinical activity of immune checkpoint blockade therapy, including the PD-1 / PD-L1 pathway.

[0007] As so, there is a need to develop combination therapies using KRas mutant or Kras wildtype inhibitors and ICB therapy, including anti-PD-1 and anti-PD-L1 inhibitors, for treating KRas mutant or hyperactivated Kras wildtype-associated cancers that can be resistant to ICB therapy.

[0008] Additionally, beyond the compounds described herein direct potency against tumor cells, compounds described herein may modulate the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine / chemokine release.

[0009] Additionally, beyond the compounds described herein direct potency against tumor cells, compounds described herein may reprogram the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine / chemokine release. Specifically, treatment with compounds described herein reduces immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS mutant cells. Results of our study herein (e.g., example 36) reveal a direct mechanism by which compounds described herein can modify tumor-cell-intrinsic immune signals to enhance antitumor immunity in a synergistic manner with the use of common immune checkpoint inhibitors. Our preclinical data provides strong rationale for clinical studies combining compounds described herein (e.g., compounds of Formula (II)) with, and expanding the therapeutic use of, existing checkpoint inhibitors (inhibitors targeting: cytotoxic T lymphocyte associated antigen 4 (CTLA-4), e.g. Yervoy / lpilimumab; programmed death 1 / programmed death-ligand 1 (PD-1 / PD-L1), e.g. Keytruda / pembrolizumab; and lymphocyte-activation gene 3 (LAG-3), e.g. BMS- 986016 / relatlimab) for various types of cancers harboring oncogenic KRAS.

[0010] In an aspect, the present disclosure provides combination therapies useful for treating a disease or disorder (e.g., cancer). In some cases, provided are therapeutically effective combinations of an agent that disrupts Programmed cell death protein 1 (PD-1) and Programmed death-ligand 1 (PD-L1) axis signaling (e.g., a PD-1 inhibitor, a PD-L1 inhibitor) and a compound of Formula (II), kits comprising the compositions and methods of use therefor.

[0011] 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 immunomodulator inhibitor and a compound represented by the structure of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L- N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl are optionally substituted with one or more R7; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle areoptionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, - C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3alkyl)C(=O), oxo, ( C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle;each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12- membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4.

[0012] In an aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, whereinthe C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2;each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected fromhalogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0013] 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 immunomodulator inhibitor and a compound represented by the structure of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle;Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-,(C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0014] In some embodiments, for a compound or salt of Formula (II), when M is NR3, Y is O, and R1is piperazine, the piperazine is substituted with one or more R9. In some cases, R1is not piperazine.

[0015] 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 immunomodulator inhibitor and a compound represented by the structure of Formula (III):Formula (III) or a pharmaceutically acceptable salt thereof wherein: R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; R2is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O,=S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; n is selected from 0 to 3; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2- C4 hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; Y is selected from a bond, O, S and NR5; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo;each Q is independently selected from a bond, S, and O; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and each R5is independently selected from hydrogen or C1-C6alkyl. INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0018] FIG.1 illustrates that compounds herein reduce immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS-mutant HPAC cells. DETAILED DESCRIPTION OF THE INVENTION

[0019] 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.

[0020] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0022] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). 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-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). 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-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). 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-C5alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0023] 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 from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0024] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0025] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certainembodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). 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.

[0026] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0027] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0028] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C8alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, analkylene 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).

[0029] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-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-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5alkenylene).

[0030] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons 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-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylenecomprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5alkynylene).

[0031] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0032] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like.

[0033] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rdis an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above.

[0034] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.

[0035] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0036] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0037] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0038] "Cycloalkylalkyl" refers to a radical of the formula –Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0039] "Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0040] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0041] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.

[0042] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0043] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like.

[0044] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0045] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0046] "Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.

[0047] “Heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”. In some cases, spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom. The spiro- heterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.

[0048] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group.

[0049] "Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein 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 leastone 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.

[0050] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0051] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0052] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0053] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0054] As used herein, the term “electrophile” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and / or an excess of electrons, for example an —SH group). Electrophiles typically are electron poor or comprise atoms which are electron poor. In certain embodiments, an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge. In some embodiments, an electrophile comprises a conjugated double bond, for example an α,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound.

[0055] As used herein, the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionallysubstituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0056] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0057] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0058] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0059] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0060] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each 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 as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0061] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0062] 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.

[0063] The term “G12 mutants”, as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X).

[0064] The term "KRas G12D-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12D mutation.

[0065] The term "KRas G12V-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12V mutation.

[0066] The term "KRas wildtype-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas wildtype.

[0067] The term “immunomodulator inhibitor” refers to an agent that modifies, or modulates, the immune system to help a subject respond to a disease or disorder.

[0068] The term “PD-1 inhibitor” refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-1 axis signaling activity and include agents that block PD-1.

[0069] The term “PD-L1 inhibitor” refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-L1 axis signaling activity and include agents that block PD-L1.

[0070] The term “PD-1 binding antagonist” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2.

[0071] The term “PD-L1 binding antagonist” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and / or B7-1.

[0072] The term “biosimilar” means an antibody or antigen-binding fragment that has the same primary amino acid sequence as compared to a reference antibody (e.g., nivolumab or pembrolizumab) and optionally, may have detectable differences in post-translation modifications (e.g., glycosylation and / or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).

[0073] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0074] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0075] 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 ofsomething present in addition to determining whether it is present or absent depending on the context.

[0076] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to the individual in need.

[0077] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0078] As used herein, a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.

[0079] As used herein, “synergy,” “synergetic,” “synergism,” or “synergistic effect” refer to two or more compounds or compositions, that individually produce an effect, however, together produce a combined effect that is greater than their individual effects.

[0080] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in theart. 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.

[0081] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0082] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0083] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein. COMPOSITIONS AND INHIBITORS Immunomodulator Inhibitors

[0084] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

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

[0086] In some embodiments, Formula (II) is represented by Formula (II*).

[0087] In some embodiments, the immunomodulator inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor. In some cases, the immunomodulatorinhibitor is a PD-1 inhibitor. In some cases, the immunomodulator inhibitor is a PD-L1 inhibitor. In some cases, the immunomodulator inhibitor is a CTLA-4 inhibitor.

[0088] In some embodiments, the immunomodulator inhibitor is selected from a PD-1 / PD-L1 checkpoint inhibitor.

[0089] In some embodiments, the immunomodulator inhibitor is immune checkpoint inhibitor.

[0090] In some embodiments, the immunomodulator inhibitor is pembrolizumab.

[0091] In some embodiments, the immunomodulator inhibitor is relatlimab. PD-1 / PD-L1 Inhibitors

[0092] In some embodiments, programmed death protein 1 (PD-1) is an immunoinhibitory receptor that is primarily expressed on activated T and B cells. PD-1 is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72). PD-1 contains a membrane proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal tyrosine-based switch motif (ITSM). Two ligands that bind to PD-1 have been identified, PD-L1 and PD-L2, that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192: 1027-34). PD-L1 is a ligand for PD-1 and is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med.8:787-9). In some cases, the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J. Mol. Med.81:281-7).

[0093] In some embodiments, immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-Ll, and the effect is additive when the interaction of PD-1 with PD- L2 is blocked as well. In some cases, disruption of the PD-1 / PD-L1 interaction has been shown to increase T cell proliferation and cytokine production and block progression of the cell cycle.

[0094] In some embodiments, PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system, blocking the interaction between PD-1 and PD-L1 has garnered the attention of the pharmaceutical industry leading to a new break-through class of immune checkpoint therapies for a wide range of cancers. In some cases, the PD-1 / PD-L1 pathway is a well-validated target for the development of antibody therapeutics for cancer treatment and several anti-PD-1 and anti-PD-L1 antibodies have undergone human clinical trials for a wide-variety of cancers including NSCLC, renal cell carcinoma, melanoma, head and neck squamous cancer, ureothelial cancer, hepatocellular carcinoma, and other cancers. In some cases, anti-PD-1 antibodies include nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®) and tislelizumab, and biosimilars thereof. In some cases, anti-PD-L1 antibodies includeatezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and biosimilars thereof.

[0095] In some embodiments, methods for manufacturing agents that disrupt PD-1 / PD-L1 signaling axis, including the antibodies described herein, are well known to those skilled in the art and agents that disrupt PD-1 / PD-L1 signaling axis may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or approved human clinical use. In some cases, suitable agents that disrupt PD-1 / PD-L1 signaling for use in the compositions and methods disclosed herein and methods for preparing such agents, and diagnostic and efficacy markers useful for monitoring treatment are disclosed in US Patent Application Publication Nos: 20180327848; 20180237524; 20180148790; 20180111996; 20160305947; 20160304969; 20160304606; 20150232555; 20150079109; 20140348743; 20140294852; 20140271684; 20140234296; 20130133091; 20110123550; and 20090217401. PD-1 inhibitor

[0096] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0097] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0098] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0099] In some embodiments, Formula (II) is represented by Formula (II*).

[0100] In some embodiments, a PD-1 inhibitor is selected from a PD-1 binding antagonist. In some cases, the PD-1 binding antagonist is selected from anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody.

[0101] In some embodiments, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its binding partners. In some cases, the PD-1 inhibitor inhibits the binding of PD-1 to PD-L1 and / or PD-L2. In some cases, PD-1 inhibitors include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In some cases, a PD-1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less non- dysfunctional. In some cases, the PD-1 inhibitor is an anti-PD-1 antibody. In some cases, the PD- 1 antibody is pembrolizumab, or a biosimilar thereof. In some cases, the PD-1 antibody is cemiplimab, or a biosimilar thereof. In some cases, the PD-1 antibody is tislelizumab, or a biosimilar thereof. PD-L1 Inhibitors

[0102] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0103] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0104] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0105] In some embodiments, Formula (II) is represented by Formula (II*).

[0106] In some embodiments, a PD-L1 inhibitor is selected from a PD-L1 binding antagonist. In some cases, the PD-L1 binding antagonist is selected from an anti-PD-L1 antibody, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody.

[0107] In some embodiments, a PD-L1 inhibitor is a molecule that inhibits the binding of PD- L1 to its binding partners. In some cases, the PD-L1 inhibitor inhibits binding of PD-L1 to PD-1 and / or B7-1. In some cases, the PD-L1 inhibitors include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In some cases, a PD-L1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as render a dysfunctional T-cell less non-dysfunctional. In some cases, a PD-L1 inhibitor is an anti-PD-L1 antibody. In some cases, an anti- PD-L1 antibody is avelumab or a biosimilar thereof. In some cases, an anti-PD-L1 antibody is atezolizumab or a biosimilar thereof. In some cases, an anti-PD- L1 antibody is durvalumab or a biosimilar thereof. In some cases, an anti-PD-L1 antibody is BMS-936559 (MDX-1105) or a biosimilar thereof. CTLA-4 inhibitor

[0108] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0109] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0110] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (II), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0111] In some embodiments, Formula (II) is represented by Formula (II*).

[0112] In some embodiments, the CTLA-4 inhibitor is selected from lpilimumab. KRAS Inhibitors

[0113] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. The compounds and salts (e.g., a compound of Formula (I), Formula (II), Formula (II*), or Formula (III)) may be used in combination with at least one other inhibitor (e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor). The compounds and salts (e.g., a compound of Formula (I), Formula (II), Formula (II*), or Formula (III)) may be used in combination with one other inhibitor (e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor). In some cases, a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof, may be used in the methods of the disclosure. In some cases, a compound of Formula (I), Formula (II), Formula (III), or sub Formulas thereof, may be referred to as a KRAS inhibitor. In some cases, a compound of Formula (I), Formula (II), Formula (III), or Formula (II*), may be referred to as a KRAS inhibitor.

[0114] In some embodiments, a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein:R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from hydrogen, -N(R21)2, -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R21)2, -L-NHC(=NH)NH2, -L- C(O)N(R21)2, -L-C1-C6haloalkyl, -L-OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L- S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L-OC(O)N(R21)2, or -LC(=O)OC1-C6alkyl, wherein the heterocycle and the aryl portion of -L-NR5C(O)-aryl and the heterocycle portion of -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are optionally substituted with one or more R6, and wherein the aryl or heteroaryl of the -L-aryl and the -L-heteroaryl are optionally substituted with one or more R7; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl;each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -CN, -NO2, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R5is independently selected from hydrogen and C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are optionally substituted with one or more substituents independently selected from halogen,cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12- membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and wherein B forms a spirocycle with Ring A; and Ring A is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents selected from R4.

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

[0116] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a heterocycle wherein the heterocycle is optionally substituted with one or more substituents selected from R4. In some cases, Ring A includes at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some cases, the heteroatom of Ring A is nitrogen, wherein the nitrogen is optionally substituted with R3, wherein R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, the heteroatom of Ring A is sulfur, wherein the sulfur is optionally substituted with 1 or 2 oxygen atoms. In some cases, the heteroatom of Ring A is oxygen.

[0117] In some embodiments, for a compound or salt of Formula (I), Ring A is selected from a carbocycle, wherein the carbocycle is optionally substituted with one or more substituents selected from R4.

[0118] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2.

[0119] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2.

[0120] In some embodiments, for a compound or salt of Formula (I), each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected fromhalogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, and oxo. In some cases, each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6alkyl.

[0121] In some embodiments, for a compound or salt of Formula (I), R2is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6.

[0122] In some embodiments, for a compound or salt of Formula (I), R2is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

[0123] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from an optionally substituted C1-C4alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0124] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0125] In some embodiments, for a compound or salt of Formula (I), wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle. In some cases, each L is independently selected from.

[0126] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocyclehas 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.

[0127] In some embodiments, for a compound or salt of Formula (I), R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0128] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0129] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0130] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected fromand, wherein the heterocycle portion is optionally substituted with one or more R6.

[0131] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom.the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In somecases, Y-R2is selected fromcases, Y-R2is selected from

[0132] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, C1-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1- C3 alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0133] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

[0134] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, Cl- C3 hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3alkyl, C1-C3alkoxy, and -N(R5)2.

[0135] In some embodiments, for a compound or salt of Formula (I), R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3alkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0136] In some embodiments, for a compound or salt of Formula (I), R2is selected from

[0137] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0138] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0139] In some embodiments, for a compound or salt of Formula (I), Y-R2is.

[0140] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from , and.

[0141] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15carbocycle.

[0142] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle.

[0143] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionallysubstituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic.

[0144] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0145] In some embodiments, for a compound or salt of Formula (I), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0146] In some embodiments, for a compound or salt of Formula (I), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, each of which is optionally substituted with one or more substituents.

[0147] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from , , , , , and , each of which is optionally substituted with one or more substituents.

[0148] In some embodiments, for a compound or salt of Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, , and , each of which is optionally substituted with one or more substituents.

[0149] In some embodiments, for a compound or salt of Formula (I), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at eachoccurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, - CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0150] In some embodiments, for a compound or salt of Formula (I), B is selected from ,

[0151] In some embodiments, for a compound or salt of Formula (I), for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, CN, halogen, C1-C3alkyl.

[0152] In some embodiments, for a compound or salt of Formula (I), B is selected from

[0153] In some embodiments, for a compound or salt of Formula (I), each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4is independently selected from C1-6alkyl, oxo, and halogen.

[0154] In some embodiments, for a compound or salt of Formula (I), n is selected from 1 and 2. In some cases, n is 0.

[0155] In some embodiments, for a compound or salt of Formula (I), Y is O.

[0156] In some embodiments, for a compound or salt of Formula (I), R1is selected from optionally substituted 5- to 12-membered heterocycle.

[0157] In some embodiments, for a compound or salt of Formula (I), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6 alkyl, C2-6alkenyl, and C2-6alkynyl.

[0158] In some embodiments, for a compound or salt of Formula (I), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -S(O)2N(R20)2, -NR20S(O)2R20,-N(R20)C(O)R20, - N(R20)C(O)N(R20)2, N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, OC(O)N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl

[0159] In some embodiments, for a compound or salt of Formula (I), R1is selected from C3- C12carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2.

[0160] In some embodiments, for a compound or salt of Formula (I), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0161] In some embodiments, for a compound or salt of Formula (I), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0162] In some embodiments, for a compound or salt of Formula (I), R20of R1is selected from hydrogen and C1-3 alkyl.

[0163] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0164] In some embodiments, for a compound or salt of Formula (I), the 5- to 12-membered heterocycle of R1is a saturated heterocycle.

[0165] In some embodiments, for a compound or salt of Formula (I), 5- to 12-membered heterocycle of R1is a bridged heterocycle.

[0166] In some embodiments, for a compound or salt of Formula (I), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0167] In some embodiments, for a compound or salt of Formula (I), R1is selected fromsubstituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0168] In some embodiments, for a compound or salt of Formula (I), R1is selected from

[0169] In some embodiments, for a compound or salt of Formula (I), L is selected from C1-C4 alkylene.

[0170] In some embodiments, for a compound or salt of Formula (I), L is selected from unsubstituted C1-C4alkylene.

[0171] In some embodiments, for a compound or salt of Formula (I), R2is -L-heterocycle, optionally substituted with one or more R6, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom.

[0172] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0173] In some embodiments, for a compound or salt of Formula (I), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

[0174] In some embodiments, for a compound or salt of Formula (I), R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

[0175] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0176] In some embodiments, a compound is represented by the structure of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- OR21, -L-NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L-OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L-NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, - N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0177] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2.

[0178] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2.

[0179] In some embodiments, for a compound or salt of Formula (II), each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O- C1-10alkyl, and oxo. In some cases, each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6alkyl.

[0180] In some embodiments, for a compound or salt of Formula (II), R3is selected from hydrogen and C1-6alkyl.

[0181] In some embodiments, for a compound or salt of Formula (II), M is selected from O, NH, and NMe. In some cases, M is O. In some cases, M is selected from NH and NMe.

[0182] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15 carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted 8- to 15- membered heterocycle. In some cases, B is an optionally substituted C8-C15 carbocycle.

[0183] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle.

[0184] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle are each bicyclic or tricyclic.

[0185] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most onenitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.

[0186] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0187] In some embodiments, for a compound or salt of Formula (II), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0188] In some embodiments, for a compound or salt of Formula (II), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, each of which is optionally substituted with one or more substituents.

[0189] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from,each of which is optionally substituted with one or more substituents.

[0190] In some embodiments, for a compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from,, each of which is optionally substituted with one or more substituents.

[0191] In some embodiments, for a compound or salt of Formula (II), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, - CN, C1-6alkoxy, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0192] In some embodiments, for a compound or salt of Formula (II), B is selected from

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

[0194] In some embodiments, for a compound or salt of Formula (II), each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4is independently selected from C1-6alkyl, oxo, and halogen.

[0195] In some embodiments, for a compound or salt of Formula (II), n is selected from 1 and 2. In some cases, n is 0.

[0196] In some embodiments, for a compound or salt of Formula (II), Y is O.

[0197] In some embodiments, for a compound or salt of Formula (II), R1is selected from optionally substituted 5- to 12-membered heterocycle.

[0198] In some embodiments, for a compound or salt of Formula (II), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0199] In some embodiments, for a compound or salt of Formula (II), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O,=NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0200] In some embodiments, for a compound or salt of Formula (II), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2.

[0201] In some embodiments, for a compound or salt of Formula (II), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0202] In some embodiments, for a compound or salt of Formula (II), R20of R1is selected from hydrogen and C1-3alkyl.

[0203] In some embodiments, for a compound or salt of Formula (II), the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0204] In some embodiments, for a compound or salt of Formula (II), the 5- to 12-membered heterocycle of R1is a saturated heterocycle.

[0205] In some embodiments, for a compound or salt of Formula (II), 5- to 12-membered heterocycle of R1is a bridged heterocycle.

[0206] In some embodiments, for a compound or salt of Formula (II), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl. In some embodiments, for a compound or salt of Formula (II), R1is selected from,one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0207] In some embodiments, for a compound or salt of Formula (II), R1is selected from

[0208] In some embodiments, for a compound or salt of Formula (II), R1is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1is selected from, which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from, which is substituted with one or more substituents selectedfrom -NHCN, and C1-6alkyl. In some cases, R1is selected from.

[0209] In some embodiments, for a compound or salt of Formula (II), R1is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -OH, -C(O)NH2, - NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl; Y is O; R2is selected from -L- heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4alkylene. In some cases,, .

[0210] In some embodiments, for a compound or salt of Formula (II), each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl. In some cases, each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - NR20S(O)2R20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN. In some cases, each R9is independently selected from halogen, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -N(R20)2, -NO2, =O, and =NO(R20). In some cases, each R9is independently selected from halogen, and -N(R20)2.

[0211] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from an optionally substituted C1-C4alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0212] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0213] In some embodiments, for a compound or salt of Formula (II), wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from.

[0214] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0215] In some embodiments, for a compound or salt of Formula (II), R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0216] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0217] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0218] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected fromand, wherein the heterocycle portion is optionally substituted with one or more R6.

[0219] In some embodiments, for a compound or salt of Formula (II), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In somecases, Y-R2is selected fromcases, Y-R2is selected from

[0220] In some embodiments, for a compound or salt of Formula (II), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, C1-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1- C3 alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0221] In some embodiments, for a compound or salt of Formula (II), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

[0222] In some embodiments, for a compound or salt of Formula (II), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, Cl- C3 hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3alkyl, C1-C3alkoxy, and -N(R5)2.

[0223] In some embodiments, for a compound or salt of Formula (II), R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3alkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0224] In some embodiments, for a compound or salt of Formula (II), R2is selected from

[0225] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from

[0226] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from

[0227] In some embodiments, for a compound or salt of Formula (II), Y-R2is.

[0228] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from , and.

[0229] In some embodiments, for a compound or salt of Formula (II), L is selected from C1- C4 alkylene.

[0230] In some embodiments, for a compound or salt of Formula (II), L is selected from unsubstituted C1-C4alkylene.

[0231] In some embodiments, for a compound or salt of Formula (II), R2is -L-heterocycle, optionally substituted with one or more R6, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom.

[0232] In some embodiments, for a compound or salt of Formula (II), R2is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6.

[0233] In some embodiments, for a compound or salt of Formula (II), R2is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

[0234] In some embodiments, for a compound or salt of Formula (II), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0235] In some embodiments, for a compound or salt of Formula (II), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl. In some cases, R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen. In some cases, Y-R2is

[0236] In some embodiments, for a compound or salt of Formula (II), M is selected from NR3. In some cases, M is selected from NH and NMe. In some cases, M is selected from NMe and NCH2CH3. In some cases, M is NMe. In some cases, M is selected from C1-6cyanoalkyl. In some cases, M is selected from C2cyanoalkyl. In some cases, M is selected from NH. In some cases, R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from hydrogen, C1-6alkyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6alkyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C2-6alkyl, C1-6alkyl- N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6 haloalkyl. In some cases, R3is selected from C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1- 6 hydroxyalkyl, C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6cyanoalkyl, C1-6alkoxyalkyl, and C1-6haloalkyl. In some cases, R3is selected from hydrogen, C1-6alkyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6haloalkyl. In some cases, R3is selected from C1-6alkoxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, R3is. In some cases, R3is selected from C2-6alkyl.

[0237] In some embodiments, for a compound or salt of Formula (II), M is NR3, B is selected from, each of which is optionally substituted; n is 0; Y is O; R2is selected from L-heterocycle, wherein the heterocycle is optionally substituted with one or more R6; R1is, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases,. some cases,. In some cases,heterocycle of L-heterocycle is bicyclic. In some cases, the heterocycle of L-heterocycle is monocyclic. In some cases, L is selected from an C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, Y-R2is selected from,, which is substituted with one or more substituents. In some cases,, which is substituted with one or more substituents. In some cases, B is selected from, which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, - C(O)NH2, -NH2, =O, -CN, -O-C1-C3haloalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some-O-C1-C3haloalkyl, and C1-6haloalkyl. In some cases,, which is substituted with oneor more substituents selected from halogen. In some cases, B is selected from,, which is substituted with one or more substituents selected from fluorine. In some cases, B issubstituted with one or more substituents selected from chlorine. In some cases, B is selected from. some cases, R3is selected from hydrogen and C1-6alkyl. In some cases, R3is selected from C1-6alkyl. In some cases, R3is methyl. In some cases, each R6is selected from halogen, oxo, and C1-6alkyl. In some cases, each R6is selected from halogen, and C1-6alkyl. In some cases, each R6is selected from halogen. In some cases, R1is selected from.

[0238] In some embodiments, a compound is represented by the structure of Formula (III):Formula (III) or a pharmaceutically acceptable salt thereof wherein:R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; R2is selected from -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and L-bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; n is selected from 0 to 3; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano,hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2- C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; Y is selected from a bond, O, S and NR5; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1- C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and each R5is independently selected from hydrogen or C1-C6alkyl.

[0239] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted withone or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =NO(R20), -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0240] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- NR21S(O)2(R21) and -L-S(O)2N(R21)2.

[0241] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- N(R21)C(O)(OR21), and -L-OC(O)N(R21)2.

[0242] In some embodiments, for a compound or salt of Formula (III), each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O- C1-10alkyl, and oxo. In some cases, each R21is independently selected from hydrogen; C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6alkyl.

[0243] In some embodiments, for a compound or salt of Formula (III), R2is selected from L- bicyclic heterocycle, wherein the bicyclic heterocycle is optionally substituted with one or more R6.

[0244] In some embodiments, for a compound or salt of Formula (III), R2is selected from L- pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6.

[0245] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 5- to 15-membered heterocycle or optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C15carbocycle. In some cases, B is an optionally substituted C8-C15carbocycle.

[0246] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C15 fused carbocycle.

[0247] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most onenitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.

[0248] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15- membered fused heterocycle are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle are each bicyclic or tricyclic.

[0249] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0250] In some embodiments, for a compound or salt of Formula (III), B the heterocycle or carbocycle are each independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0251] In some embodiments, for a compound or salt of Formula (III), B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15 fused carbocycle is selected from, each of which is optionally substituted with one or more substituents.

[0252] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from,

[0253] In some embodiments, for a compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C15fused carbocycle is selected from,, each of which is optionally substituted with one or more substituents.

[0254] In some embodiments, for a compound or salt of Formula (III), for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OR20)2, -OH, -C(O)N(R20)2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from oxo, -NH2, -CN, halogen, C1-C3alkyl. In some cases, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0255] In some embodiments, for a compound or salt of Formula (III), B is selected from, , , , , ,

[0256] In some embodiments, for a compound or salt of Formula (III), for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH2, halogen, C1-C3alkyl.

[0257] In some embodiments, for a compound or salt of Formula (III), B is selected from.

[0258] In some embodiments, for a compound or salt of Formula (III), each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen. Ins some cases, each R4is independently selected from C1-6alkyl, oxo, and halogen.

[0259] In some embodiments, for a compound or salt of Formula (III), n is selected from 1 and 2. In some cases, n is 0.

[0260] In some embodiments, for a compound or salt of Formula (III), Y is O.

[0261] In some embodiments, for a compound or salt of Formula (III), R1is selected from optionally substituted 5- to 12-membered heterocycle.

[0262] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O,=NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0263] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20,-N(R20)2, -C(O)R20, C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =NO(R20), CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0264] In some embodiments, for a compound or salt of Formula (III), R1is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -N(R20)C(O)OR20, and -OC(O)N(R20)2.

[0265] In some embodiments, for a compound or salt of Formula (III), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0266] In some embodiments, for a compound or salt of Formula (III), R1is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0267] In some embodiments, for a compound or salt of Formula (III), R20of R1is selected from hydrogen and C1-3alkyl.

[0268] In some embodiments, for a compound or salt of Formula (III), the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0269] In some embodiments, for a compound or salt of Formula (III), the 5- to 12-membered heterocycle of R1is a saturated heterocycle.

[0270] In some embodiments, for a compound or salt of Formula (III), 5- to 12-membered heterocycle of R1is a bridged heterocycle.

[0271] In some embodiments, for a compound or salt of Formula (III), R1is selected from,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0272] In some embodiments, for a compound or salt of Formula (III), R1is selected fromf which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, - NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

[0273] In some embodiments, for a compound or salt of Formula (III), R1is selected from

[0274] In some embodiments, for a compound or salt of Formula (III), R1is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1is selected from, which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In somecases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from , which is substituted with one or more substituents selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from, and.

[0275] In some embodiments, for a compound or salt of Formula (III), R1is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally one or more C1-6alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -OH, -C(O)NH2, - NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl; Y is O; R2is selected from -L- bicyclic heterocycle, wherein the bicyclic heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4alkylene. In somes, .

[0276] In some embodiments, for a compound or salt of Formula (III), L is selected from C1- C4 alkylene.

[0277] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from an optionally substituted C1-C4alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0278] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from a substituted C1-C4alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

[0279] In some embodiments, for a compound or salt of Formula (III), wherein each L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from.

[0280] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocyclehas 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.

[0281] In some embodiments, for a compound or salt of Formula (III), R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

[0282] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0283] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from, , wherein the heterocycle portion is optionally substituted with one or more R6.

[0284] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from

[0285] In some embodiments, for a compound or salt of Formula (III), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2is selected from, , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and oxo. In somecases, Y-R2is selected fromcases, Y-R2is selected from

[0286] In some embodiments, for a compound or salt of Formula (III), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, C1-C3aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1- C3 alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0287] In some embodiments, for a compound or salt of Formula (III), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl.

[0288] In some embodiments, for a compound or salt of Formula (III), each R6is independently selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, Cl- C3 hydroxyalkyl, C1-C3alkyl, C1-C3aminoalkyl, C1-C3alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3alkyl, C1-C3alkoxy, and -N(R5)2.

[0289] In some embodiments, for a compound or salt of Formula (III), R6is selected from halogen, -OH, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, -CN, and C1-C3aminoalkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is halogen. In some cases, R6is C1-C3alkyl. In some cases, R6is selected from halogen and C1-C3alkyl. In some cases, R6is selected from methyl and fluorine.

[0290] In some embodiments, for a compound or salt of Formula (III), R2is selected from

[0291] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from

[0292] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from

[0293] In some embodiments, for a compound or salt of Formula (III), Y-R2is.

[0294] In some embodiments, for a compound or salt of Formula (III), L is selected from unsubstituted C1-C4 alkylene.

[0295] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from, wherein the heterocycle portion is optionally substituted with one or more R6.

[0296] In some embodiments, for a compound or salt of Formula (III), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl.

[0297] In some embodiments, for a compound or salt of Formula (III), R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

[0298] In some embodiments, for a compound or salt of Formula (III), Y-R2is selected from.

[0299] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the carbocycle of R1is selected from C3-C12carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8carbocycle, or C3-C6carbocycle. In some cases, the carbocycle of R1is selected from C3-C12carbocycle, C4-C12carbocycle, C5-C12carbocycle, C6-C12carbocycle, C7-C12carbocycle, C8-C12 carbocycle, or C9-C12 carbocycle.

[0300] In some embodiments, for a compound of Formula (I), the heterocycle of R1is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8-to 12-membered heterocycle. In some cases, the heterocycle of R1is a 5- to 11-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, the heterocycle of R1is saturated. The heterocycle may be optionally substituted as described elsewhere herein.

[0301] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1is saturated. The monocyclic heterocycle may be optionally substituted as described elsewhere herein.

[0302] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12-membered bridged heterocycle, or 8- to 12-membered bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 11-membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8- membered bridged heterocycle. In some cases, the heterocycle of R1is a 6- to 11-membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9-membered bridged heterocycle, or 6- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a bridged 7- to 11-membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9- membered bridged heterocycle, or 7- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered bridged heterocycle or 5- to 9-membered bridgedheterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered bridged heterocycle. In some embodiments, the heterocycle of R1is saturated. The bridged heterocycle may be optionally substituted as described elsewhere herein.

[0303] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is a 5- to 9-membered heterocycle, the 5- to 9- membered heterocycle contains at most 1 nitrogen atom. In some embodiments, R1is selected from optionally substituted 5- to 9- membered heterocycle, each of which is optionally substituted.

[0304] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the heterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R1contains at most 1 heteroatom atom. In some embodiments, the heterocycle of R1contains at most 2 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is selected from. In some cases, the heterocycle is selected from, , , , and. In some cases, the bridged heterocycle is selected from, , . The heterocycle may be optionally substituted as described elsewhere herein.

[0305] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the spiroheterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the spiroheterocycle of R1contains at most 2 heteroatom atoms. In some embodiments, the spiroheterocycle of R1contains at most 3 heteroatom atoms. In some embodiments, the spiroheterocycle of R1contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R1contains at least 2 heteroatom atoms. In some cases, the spiroheterocycle of R1contains at least 3 heteroatom atoms. In some cases, the spiroheterocycle of R1contains at least 4 heteroatom atoms. In some cases, the spiroheterocycle of R1contains at least 2 nitrogen atoms. In some embodiments, the spiroheterocycle of R1contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R1contains at most 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the spiroheterocycle of R1issome embodiments, the spiroheterocycle of R1is selected fromThe spiroheterocycle may be optionally substituted as described elsewhere herein.

[0306] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from optionally substituted 7- to 8-membered spiroheterocycle. In some cases, R1is selected from optionally substituted 7-membered spiroheterocycle. In some cases, R1is selected from optionally substituted 8-membered spiroheterocycle.

[0307] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 7- to 11- membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6- membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein.

[0308] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1is selected from a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is selected from a 9- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is selected from a 10- to 12- membered fused heterocycle. The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6aminoalkyl,C1-6alkoxy,C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy,C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0309] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the fused heterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the fused heterocycle of R1contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle i. fused heterocycle may be optionally substituted as described elsewhere herein.

[0310] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted.

[0311] In some embodiments, for a compound of Formula (I), R1is selected from C6-C7 carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12- membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, C1-6aminoalkyl, C1-6alkoxy,C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0312] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C6-C7carbocycle, 5- to 10-membered heterocycle, 7- to 8-membered spiroheterocycle, and 6-, 8- to 12-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0313] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), for R1, R20of -OR20and -N(R20)2, is selected hydrogen and C1-6alkyl.

[0314] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C6-C7carbocycle and 5- to 10-membered heterocycle, each of which is optionally substituted. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, R1is selected from C6-C7carbocycle, each of which is optionally substituted.

[0315] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, - N(R20)C(O)N(R20)2, and C1-6alkyl.

[0316] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), one or more optional substituents of R1are independently selected from halogen, -OR20, - N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, the one or more optional substituents of R1are independently selected from -OR20, - N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6alkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, C1-6aminoalkyl, and C1-6hydroxyalkyl. In some cases, the one or more optional substituents of R1 are independently selected from -OR20, -N(R20)2, C1-6aminoalkyl, C1-6alkyl, and C1-6hydroxyalkyl. In some cases, the one or more optional substituents of R1are independently selected from -OR20, -N(R20)2, and C1-6alkyl. In some cases, the one or more optional substituents of R1are independently selected from -N(R20)C(O)N(R20)2.

[0317] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R1is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, - OR20, -SR20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =N(R20), -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0318] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R1is further selected from 7-, 8-, 10, 11-membered spiro heterocycle and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle wherein the C3-C12carbocycle, 5- to 12-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, - OR20, -SR20, -N(R20) S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0319] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, - N(R20)2, C1-6alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl.

[0320] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, - N(R20)2, C1-6alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl. In ,substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6alkyl, -OR20, -N(R20)C(O)N(R20)2, -B(OR20)2, C1-6cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl. In some cases, ,, , , , , , ,

[0321] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - OR20, -N(R20)2, C1-6alkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, -N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2. In some cases, R1is selected from , , ,, each of which is optionally substituted with one or more substituents independently selected from -OR20, -N(R20)2, C1-6alkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, - N(R20)C(O)N(R20)2, -N(R20)C(O)R20, and -B(OR20)2.

[0322] In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III),

[0323] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from - N(R20)2, -OR20, and C1-6alkyl. In some cases, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20, and C1-6alkyl. In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from -OR20, and C1-6alkyl. In some cases, R1is selected

[0324] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula, each of which are optionally substituted.

[0325] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, each of which is optionally substituted with one or more substituents independently selected from -OH, -CN, oxo, C1-6cyanoalkyl.

[0326] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula

[0327] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, , , each of which are optionally substituted.

[0328] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected fromeach of which are optionally substituted.

[0329] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula, each of which are optionally substituted.

[0330] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is which is optionally substituted.

[0331] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula

[0332] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula

[0333] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), wherein the 5- to 12-membered heterocycle of R1is unsaturated and a bridged heterocycle. In some cases, R1is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. In some cases, R1is selected from .

[0334] In some embodiments, for a compound of Formula (I) or Formula (II), R1is selected from 5- to 10-membered heterocycle, 7-, 8-, 10-, 11-membered spiro heterocycle, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, and wherein each are optionally substituted with one or more substituents independently selected from halogen, -N(R20)2, C1-6alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20)2,C1-6cyanoalkyl, -N(R20)C(O)N(R20)2, =O, C1-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and C1-6aminoalkyl; R3is naphthalene, wherein naphthalene is optionally substituted with one or more substituents independently selected fromhalogen, -OH, -NH2, -NO2, =O, C1-6alkyl, C2-6alkynyl, C1-6aminoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl; R4is selected from hydrogen, halogen or C1-C3alkyl; Y is O; L is independently a C1-C4alkylene; R2is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2. In some cases, Y-R2is selected fromwherein the heterocycle portion is optionally substituted.

[0335] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom.

[0336] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 6- to 7-membered heterocycle. In some cases, R1is selected from 7- membered heterocycle. In some cases, R1is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7- membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R1is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- to 7-membered heterocycle of R1is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R1is selected from, each of which is substituted. In some cases, R1is selected from,, ,, each of which is substituted. In some cases, thesubstituents of R1are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, - NO2, =O, -CN, C1-6fluoroalkyl, and C2-6alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkenyl. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =O, -CN, and C2-6alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the substituents of R1are each selected from one or more halogen, -OH, -NHCN, =O, -CN, and C2-6alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6alkyl.,, each of which is optionally substituted. In some cases, R1is selected from, each of which is optionally substituted. In some cases, R1is selected from , , , , each of which is optionally substituted. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)-(C1-6alkoxy), -NH-C(O)-(C1-6hydroxyalkyl), -NH2, -NH(CN), =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OH, -CN, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6cyanoalkyl, C1-6alkyl, oxo, and C2-6alkynyl. In some cases, the one ormore optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6,

[0337] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds. In some cases, R1is selected fromwherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1iswherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1isselected fromwherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is. , . , ,, wherein each is substituted with one or more substituents independently selected from halogen.

[0338] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6-to 7-membered heterocycle is substituted with one or more substituents selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R1is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen. In some cases, R1is selected from an unsaturated 7-membered heterocycle,

[0339] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. Insome cases, R1is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, - NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, R1is selected from

[0340] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 6-membered heterocycle. In some cases, the 6- membered heterocycle contains only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R1is bound to Formula (II) via the only 1 nitrogen atom. In some cases, the 6- membered heterocycle of R1is bound to Formula (III) via the only 1 nitrogen atom. In some cases, R1is selected from, any of which is optionally substituted. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OR20, - N(R20)2, =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, - NH2, -NH(CN), =O, -CN, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6alkyl, and C2-6alkynyl. In 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. In some cases, R1is selected from

[0341] In some embodiments, for a compound of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted 6-membered unsaturated heterocycle and 6- membered saturated heterocycle.

[0342] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0343] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6haloalkyl.

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

[0345] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

[0346] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from, wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6haloalkyl. In some cases, R1is.

[0347] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, the 6- to 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, R1is, each of which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each 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. In some cases, R1is selected from

[0348] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1is selected from an optionally substituted 10-membered heterocycle. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiro heterocycle. In some cases, the 10-membered heterocycle is a fused heterocycle. In some cases, the 10-membered heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom. In some cases, R1is selected from, each of which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R20)2, -C(O)NR20OR20, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, R1is selected from,some cases, R1is selected from. some cases, R1is selected from, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -N(R20)2, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

[0349] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 10- membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 10-membered fused heterocycle. In some cases,, which is optionally substituted. In some cases, the one or more optional substituents are selected from halogen, -OH, -C(O)N(R20)2, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, R1is, optionally substituted with one or more substituents selected from - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and C3-12carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0350] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from a 7- to 11-membered spiro heterocycle. In some cases, R1is selected from a 10-membered spiro heterocycle. In some cases, the spiro heterocycle has at least 3 nitrogen atoms. In some cases, the spiro heterocycle has at least 1 sulfur atom. In some cases, R1is selected from, each of which is optionally substituted. In some cases, the one or more optional substituents are independently selected from halogen, -OH, - N(R20)2, -NO2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, R1is selectedsome cases, R1is. some cases, M is selected from O, and NR3. In some cases, M is selected from O. In some cases, M is selected from NR3. In some cases, R3is selected from C1-6alkyl. In some cases, R3is selected from C1-2 alkyl. In some cases, R3is selected from methyl.

[0351] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1is selected from an optionally substituted 8- to 10-membered fused heterocycle.In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10- membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10- membered heterocycle is a non-aromatic heterocycle. In some cases, R1is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 9- membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1is selected from, each of which is optionally substituted with one or more substituents. In some cases, R1is, which is optionally substituted with one or more substituents. In some cases, R1is, which is optionally substituted with one or more substituents. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(=NR20)N(R20)2, -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, and 5- to 12-memberedheterocycle, 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, C1-6alkyl- 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, C1-6alkyl-N(R20)2, -S(O)2(R20), - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from halogen, =O, -S(O)2(R20), -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20). In some cases, the optional one or more substituents are independently selected from -S(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from S(O)2(R20). In some cases, the optional one or more substituents are independently selected from S(O)R20(=NR20). In some cases, the optional one or more substituents are independently selected from -C(O)R20. In some cases, the optional one or more substituents are independently selected from -C(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from - C(O)NR20OR20. In some cases, R1is selected from, ,,, each of which is further optionally substituted. In some cases, the further one or more optional substituents are selected from halogen, -OH, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6alkyl. In some cases, the further one or more optional substituents are selected from halogen, and C1-6alkyl. In some cases, the further one or more optional substituents are selected from halogen. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12- membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12-membered saturated heterocycle. In some cases, each R20is independently selected from 5- to 6-membered saturated heterocycle. In some cases, the heterocycle of R20has at least one nitrogen atom. In some cases, the heterocycle of R20has at least one sulfur atom. In some cases, the heterocycle of R20has at least one oxygen atom. In some cases, the heterocycle of R20contains only 1 heteroatom. In some cases, the heterocycle of R20has at least two heteroatoms. In some cases, the heterocycle of R20contains only 2 heteroatoms. In some cases, the optional one or more substituents of R1are independentlyoptional one or more substituents of R1are independently selected from halogen,,,some cases, the optional one or more substituents of R1areor more substituents of R1are independently selected from,more substituents of R1are independently selected from halogen, and C1-6alkyl-N(R20)2. In some cases, the optional one or more substituents of R1are independently selected from halogen,. , ydrogen, C1-6alkyl, and C3-6carbocycle. In some cases, R1is selected,some cases, R1is selectedselected 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 selectedfrom , which is optionally substituted with one more substituents independentlyselected from halogen and C1-6alkyl. In some cases, R1is selected from.

[0352] In some embodiments, for a compound or salt of Formula (I), Formula (II), orselected from a 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and RBis selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, and -CN. In some cases, RBis selected from hydrogen, and halogen. In some cases, RBis chloride. In some cases, RBis hydrogen. In some cases,, 2, 3, or 4 heteroatoms. In some cases,has at least 1, 2, 3, or 4 nitrogen atoms. In some cases,has at least 1 oxygen atom. In some cases,is a monocyclic heterocycle. In some cases,is a bicyclic heterocycle. In some cases,is selected from an optionally substituted 5-membered heterocycle. In some cases,is selected from an optionallysubstituted with one or more R1*. In some cases,, ,is optionally substituted with one or more R1*. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, and C1-6alkyl. In some cases,, , ,

[0353] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), when R1is substituted with -C(O)R20, R20is selected from a 5- to 12- membered heterocycle, which is optionally substituted. In some cases, R1is substituted with - C(O)R20. In some cases, R20is selected from a 5- to 12-membered unsubstituted heterocycle. In some cases, R20is selected from a 5- to 6-membered heterocycle, which is optionally substituted. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has two heteroatoms. In some cases, the heterocycle of R20is selected, each of which is optionally substituted. In some cases, R20is selected fromsome cases, the optional substituents are selected from C1-10alkyl, oxo, and =NH.

[0354] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with oneor more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH.

[0355] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is an optionally substituted 12- to 15-membered heterocycle. In some cases, R1is an optionally substituted 12-membered heterocycle. In some cases, R1is an optionally substituted 13-membered heterocycle. In some cases, R1is an optionally substituted 14- membered heterocycle. In some cases, R1is an optionally substituted 15-membered heterocycle. In some cases, the heterocycle of R1is tricyclic. In some cases, the heterocycle of R1contains a fused heterocycle. In some cases, the heterocycle of R1contains a spiro-heterocycle. In some cases, the heterocycle of R1contains a fused and spiro-heterocycle. In some cases, the heterocycle of R1is an unsaturated heterocycle. In some cases, the heterocycle of R1is a non- aromatic heterocycle. In some cases, the heterocycle of R1has at least one double bond. In some cases, the heterocycle of R1has at least two double bonds. In some cases, the heterocycle of R1has at least 2 heteroatoms. In some cases, the heterocycle of R1has at least 3 heteroatoms. In some cases, the heterocycle of R1has at least 4 heteroatoms. In some cases, the heterocycle of R1has at least 5 heteroatoms. In some cases, the heterocycle of R1has at least 6 heteroatoms. 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 cases, the heteroatoms are selected from nitrogen and oxygen. In,, each of which is optionally substituted with one or more substituents. In some cases, R1is, , , , ,, each of which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, =NH, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, C1-6alkyl, and -C(O)N(R20)2. In some cases, R1is selected from,

[0356] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is an optionally substituted 12- to 15-membered heterocycle. In some cases, R1, wherein Ring W is an optionally substituted heterocycle and Ring P is an optionally substituted carbocycle or optionally substituted heterocycle, wherein Ring P forms a spirocycle with Ring W. In some cases, Ring W is an optionally substituted fused heterocycle. In some cases, Ring P and Ring W combine to form a heterocycle having at least 12 atoms and most 15 atoms. In some cases, Ring P and Ring W have in total at least 12 atoms and most 15 atoms. In some cases, Ring W is an optionally substituted 10-membered fused heterocycle. Insome cases,, wherein Ring P is an optionally substituted carbocycle or optionally substituted heterocycle. In some cases,. some cases, Ring P is an optionally substituted carbocycle. In some cases, Ring P is an optionally substituted heterocycle. In some cases, Ring P forms an optionally substituted C3-C6carbocycle or optionally substituted 4-to 6-membered heterocycle. In some cases, Ring P forms an optionally substituted C3 carbocycle. In some cases, Ring P forms an optionally substituted C4 carbocycle. In some cases, Ring P forms an optionally substituted C5 carbocycle. In some cases, Ring P forms an optionally substituted 4-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P has at least 1, 2, or 3 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, Ring P has 1 sulfur atom. In some cases, Ring P has 1 nitrogen atom. In some cases, Ring P has 1 oxygen atom. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, -NHCN, =O, =NR20, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, =O, =NH, -CN, and C1-6alkyl. In some cases, the one or more optional substituents of Ring W are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, and C2-6alkynyl. In some cases, the one or more optional substituents of Ring W are independently selected 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.

[0357] In some embodiments, for a compound or salt of Formula (I), Formula (II), or, each of which is optionally substituted with one or more substituents. In some cases, the one or more of the optional substituents are independently selected from halogen, -OH, -N(R20)2, -B(OH)2, -C(O)N(R20)2, -NHCN, -NO2, C1-6alkoxy, =O, -CN, C1-6alkyl, C2-6alkenyl, C1-6aminoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl. In some cases, R1is selected from,,,,.

[0358] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2is selected fromsubstituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3alkyl, - N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-C1-C3alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2,and -O-C1-C3alkyl, wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some

[0359] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2is selected from -L-N(R21)2. In some cases, each R21is selected from hydrogen and C1-6alkyl. In some cases, each R21is selected from C1-6alkyl. In some cases, L is independently selected from a substituted C1-C4alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle, wherein the C3-C6carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases,. In some cases, R2is. In some cases, Y-R2is.

[0360] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),each R21is independently selected from hydrogen. In some cases, each R21is independently selected from hydrogen and C1-6alkyl. In some cases, each R21is independently selected from C1-6alkyl. In some cases, each R21is independently selected from hydrogen; and C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo.

[0361] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III),R1is selected from an optionally substituted 8- to 10-membered fused heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R1is selected from an optionally substituted 9-membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the 10-membered fused heterocycleis 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 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10- membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1is selected from, which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents are independently selected from halogen, =O, -OH, -CN, -NHCN, - C(O)R20, -C(O)N(R20)2, -C(O)NR20OR20, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =O, -C(O)R20, -C(O)N(R20)2, and -C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20, -C(O)N(R20)2, and - C(O)NR20OR20. In some cases, the optional one or more substituents are independently selected from -C(O)R20. In some cases, the optional one or more substituents are independently selected from -C(O)N(R20)2. In some cases, the optional one or more substituents are independently selected from -C(O)NR20OR20. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20isindependently selected from hydrogen; and C1-6alkyl, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, and 3- to 12- membered saturated heterocycle. In some cases, the optional one or more substituents of R1are

[0362] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R1is selected from , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6cyanoalkyl, and C1-6alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from , which is substituted with one or more substituents selected from -NHCN, and C1-6alkyl. In some cases, R1is selected from, and.

[0363] In some embodiments, for a compound or salt of Formula (I), R1is selected from a substituted saturated 6-membered heterocycle, wherein the saturated 6-membered heterocycle issubstituted with at least one -NHCN, and optionally one or more C1-6alkyl; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl; Ring A is selected from an optionally substituted heterocycle; Y is O; R2is selected from -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; and L is selected from C1-C4alkylene. In some cases, R1is selected from, and

[0364] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), B is an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10-membered fused carbocycle. In some cases, B is an unsubstituted 8- to 10- membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9-membered fused carbocycle. In some cases, B is , which is optionally substituted with one or more substituents. In some cases, B is, which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selectedselected from halogen and C1-6haloalkyl. In some cases,, which is substituted with one or more substituents selected from halogen. In some cases, B is selected from,, which is substituted with one or more substituents selected from fluorine. In some cases, B issubstituted with one or more substituents selected from chlorine. In some cases, B is selected from. some cases, B is a substituted 10-membered fused carbocycle. In some cases, for the 10-membered fused carbocycle of B, the one or more substituents are independently selected from halogen, -NH2, C1-C3alkyl, -B(OH)2, -OH, - C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B isIn some cases, for the 10-membered fused carbocycle of B, is substituted with at least one,. some cases, B is an unsubstituted 9- to 10-membered fused carbocycle. Insome cases, B is selected, each of which is unsubstituted. In some cases,. , .

[0365] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1are independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl.

[0366] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formulathe one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, -CN, C2-6alkynyl, - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from -C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from optionally substituted 5- to 12-memberedheterocycle. 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 more optional substituents of R1is selected from,optionally substituted with one or more R1*. In some cases, the heterocycle of the one or more optional substituents of R1is selected from, which is optionally substituted with one or more R1*. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, and C1-6alkyl. In some cases, each R1*is independentlyselected from halogen. In some cases, each R1*is independently selected from C1-6alkyl. In some cases, each R1*is independently selected from -OR20. In some cases, each R1*is independently selected from -OH. In some cases, each R1*is independently selected from -OMe. In some cases, the heterocycle of the one or more optional substituents of R1is selected from

[0367] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the one or more optional substituents of R1are independently selected from - C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from optionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle is selected from,, each of which is optionally substituted with one or more R1*. In some cases, the one or more

[0368] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. Insome cases, each R1*is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, each R1*is independently selected from halogen, and C1-6alkyl. In some cases, each R1*is independently selected from halogen. In some cases, each R1*is independently selected from C1-6alkyl.

[0369] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, oxo, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -SO2R20, -NHCN, C1-6cyanoalkyl, C1-6alkyl, C1-6alkyl-N(R20)2, C2-6alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 9- membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1isselected , , , , and , each of which is optionally substituted. In somecases, R1is selected , which is optionally substituted. In some cases, R1is selected,

[0370] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -NHCN, C1-6cyanoalkyl, C1-6alkyl, C2-6alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, C1-6haloalkyl, and C1-6alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1is selected, , , each of which isoptionally substituted. In some cases, R1is selected , which is optionally substituted. Insome cases, M is selected from O, and NMe. In some cases, M is O. In some cases, M is NMe. In some cases, R2is selected from -L-N(R21)2and -L-heterocycle, optionally substituted with one or more R6. In some cases, Y-R2is selected from, ,some cases, B is selected from an optionally substituted carbocycle. In some cases, B is selected fromsubstituted. In some cases, B is selected from,. , .

[0371] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is selected from a compound in the Examples section. In some cases, Y is selected from a compound in the Examples section. In some cases, L is selected from a compound in the Examples section. In some cases, R2is selected from a compound in the Examples section. In some cases, B is selected from a compound in the Examples section.. In some cases, M is selected from a compound in the Examples section. In some cases, the optional substituents of the heterocycle for R1is selected from a compound in the Examples section.

[0372] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R2is -L-N(R21)2. In some cases, R2is -L-OR21. In some cases, R2is heterocycle. In some cases, R2is C1-C6alkyl. In some cases, R2is -L-heterocycle. In some cases, R2is -L-aryl. In some cases, R2is -L-heteroaryl. In some cases, R2is -L-cycloalkyl. In some cases, R2is -L-N(R21)2. In some cases, R2is -L-NHC(=NH)NH2. In some cases, R2is -L-C(O)N(R21)2. In some cases, R2is -L-C1-C6haloalkyl. In some cases, R2is -L-OR21. In some cases, R2is -L-NR21C(O)-aryl. In some cases, R2is -L-COOH. In some cases, R2is -L-NR21S(O)2(R21). In some cases, R2is -L- S(O)2N(R21)2. In some cases, R2is -L-N(R21)C(O)(OR21). In some cases, R2is -L-OC(O)N(R21)2. In some cases, R2is or -LC(=O)OC1-C6alkyl. In some cases, the heterocycle, the aryl portion of - L-NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7. In some cases, when Y is a bond, O, or S, R2is further selected from hydrogen

[0373] In some embodiments, Formula (I) or Formula (II) is represented by Formula (II*):Formula (II*) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3is selected from hydrogen, C1-6alkyl, and C1-6cyanoalkyl; R1is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1- 6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; B is selected from C6-C15 carbocycle, wherein the C6-C15 carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkyl, - B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; R2is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4alkylene, wherein the C1-C4alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0374] In some embodiments, for a compound or salt of Formula (II*), R1is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, the heterocycle of R1has at least one nitrogen atom. In some cases, the at least one nitrogen at of the heterocycle of R1is bound to Formula (II*). In some cases, R1is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted withone or more substituents selected from halogen, and C1-6alkyl. In some cases, R1is selected from, which is substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl- N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle is optionally substituted with one or more substituents selected fromsome cases, M is selected from O. In some cases, M is NCH2CH3. In some cases, M is NMe. In some cases, the heterocycle of R2is a saturated heterocycle. In some cases, R6of R2is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl. In some cases, L of R2is selected from C1-C4alkylene and . In some cases, R2is selected from,some cases, B is selected from an optionally substituted C9-C10fused carbocycle. In some cases, B is selected from, each of which is optionally substituted. In some cases, B is optionally substituted with one or more substituentsindependently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-C1-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is optionally substituted with one or more substituents independently selected from halogen. In some cases,. some cases,. some cases, B is unsubstituted. In some cases, B is substituted.

[0375] In some embodiments, for a compound or salt of Formula (II*), R1is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10- membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, R1is selected from an optionally substituted 10-membered spiro heterocycle. In some cases, R1is selected from an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of R1has at least 3 heteroatoms. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)N(R20)2, - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, - C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl. Insome cases, R1is selected from , which is substituted with one or more substituents independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =O, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and C1-6alkyl. In some cases, R1is selected from,cases, M is selected from O. In some cases, M is NMe. In some cases, the heterocycle of R2is a saturated heterocycle. In some cases, R6of R2is independently selected at each occurrence from halogen, =CH2, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, cyano, and C1-C3aminoalkyl. In some cases, L of R2is selected from C1-C4 alkylene.is optionally substituted. In some cases, B is optionally substituted with one or more substituents independently selected from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-C1-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is optionally substituted with one or more substituents independently selected from halogen. Insome cases,. some cases,. some cases, B is unsubstituted. In some cases, B is substituted.

[0376] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl. In some embodiments, for a compound or salt of Formula (I), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl. In some embodiments, for a compound or salt of Formula (II), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl. In some embodiments, for a compound or salt of Formula (III), the heterocycle or carbocycle of R1is not substituted by C1-6cyanoalkyl.

[0377] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), each R20is independently selected from hydrogen; and C1-6alkyl.

[0378] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), is not substituted by C1-6cyanoalkyl.

[0379] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1is not a piperazine. In some cases, R1is not a substituted piperazine.

[0380] In some embodiments, for a compound of Formula (I), wherein the compound is not a Michael acceptor.

[0381] In some embodiments, for a compound of Formula (I), the compound or salt does not include an electrophilic substituent.

[0382] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), does not contain an electrophile moiety.

[0383] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), does not contain a covalent modifier.

[0384] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (II*), or Formula (III), the one or more optional substituents of R1are not electrophiles.

[0385] In some embodiments, the compounds of Formula (I), (II), (II*), (III), or subformulas used in the methods include trifluoroacetic acid salts of the above compounds.

[0386] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (II) of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 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 Formula (II) is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0387] In some embodiments, a compound or salt of Formula (II) is administered once daily. In some embodiments, the compound or salt of Formula (II) is administered twice daily. In some embodiments, the compound or salt of Formula (II) is administered 3 times daily. In some embodiments, the compound or salt of Formula (II) is administered once weekly. In some embodiments, the compound or salt of Formula (II) is administered every other day. In some embodiments, the compound or salt of Formula (II) is administered every 3 days.

[0388] In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 150 mg. In some embodiments, the compound or salt of Formula (II) or a salt thereof is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 5 mg to 75 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 15 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (II) is administered to a subject at 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0389] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (II) is administered once daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In someembodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0390] In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 50 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 45 mg, twice daily. In some embodiments, the compound or salt of Formula (II) is administered to a subject at about 60 mg, twice daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0391] In some embodiments, a compound of Formula (II) is administered as a capsule during the period of time. In some cases, a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg toabout 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, 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 to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of a compound of Formula (II) (e.g., compound 53, 61, 63, 64, 69, and 96), or a pharmaceutically acceptable salt thereof.

[0392] In some embodiments, a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg,about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg,about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg,about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg), during a period of time.

[0393] In some embodiments, the combination therapy comprises oral administration of a compound of Formula (II) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg,about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 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 to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg toabout 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 to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg), and oral administration of an inhibitor selected from: 1) immunomodulator inhibitor; 2) PD-1 inhibitor; 3) PD-L1 inhibitor; and 4) CTLA-4 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 immunomodulator inhibitor. In some cases, the inhibitor is an PD-1 inhibitor. In some cases, the inhibitor is an PD-L1 inhibitor. In some cases, the inhibitor isan CTLA-4 inhibitor. In some cases, the compound of Formula (II) is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is selected compound 53, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 61 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 63 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 64 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 69 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 96, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is orally administered once daily. In one embodiment, the compound of Formula (II) is orally administered twice daily.

[0394] In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as a tablet or capsule. In one embodiment, a tablet or capsule formulation of a compound of Formula (II) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, 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 45mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg, about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some cases, a compound is selected form In some embodiments, a compound of Formula (II) is orally administered once a day (QD) on a daily basis during a period of time. In some embodiments, a compound of Formula (II) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (II) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about440 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, and i.v. administration of an inhibitor, wherein the inhibitor is selected from: 1) immunomodulator inhibitor; 2) PD-1 inhibitor; 3) PD-L1 inhibitor; and 4) CTLA-4 inhibitor; wherein the inhibitor is administered, for example, once a week, once every two weeks, once every three weeks, or once every four weeks, depending on the dosage. In some cases, the compound of Formula (II) is selected compound 53, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 61 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 63 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 64 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 69 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (II) is compound 96, or a pharmaceutically acceptable salt of any one thereof.

[0395] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0396] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0397] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:.

[0398] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0399] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0400] The compounds of the present disclosure optionally contain unnatural proportions of atomic 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 all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0401] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0402] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0403] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0404] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0405] 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.

[0406] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein 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 well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0407] 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 carboxylicacid 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.

[0408] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0409] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prod...

Claims

CLAIMS WHAT IS CLAIMED IS:

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

2. The method of claim 1, wherein the immunomodulator inhibitor is a PD-1 inhibitor.

3. The method of claim 2, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment.

4. The method of claim 2, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof.

5. The method of claim 2, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.

6. The method of claims 4 or 5, wherein the therapeutically effective amount of nivolumab or biosimilar thereof in the combination is about 240 mg administered every two weeks.

7. The method of claims 4 or 5, wherein the therapeutically effective amount of nivolumab, or biosimilar thereof, in the combination is about 480 mg administered every four weeks.

8. The method of claim 4, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.

9. The method of claim 4, wherein the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 200 mg administered every three weeks.

10. The method of claim 4, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof.

11. The method of claim 1, wherein the immunomodulator inhibitor is a PD-L1 inhibitor.

12. The method of claim 11, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof.

13. The method of claim 12, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.

14. The method of claim 1, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor.

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

16. The method of any one of claims 1 to 15, 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.

17. The method of any one of claims 1 to 16, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

18. The method of any one of claims 1 to 16, wherein the cancer is non-small cell lung cancer.

19. The method of any one of claims 1 to 16, wherein the cancer is small cell lung cancer.

20. The method of any one of claims 1 to 16, wherein the cancer is colorectal cancer.

21. The method of any one of claims 1 to 16, wherein the cancer is rectal cancer.

22. The method of any one of claims 1 to 16, wherein the cancer is pancreatic cancer.

23. The method of any one of claims 1 to 16, wherein the cancer is a solid tumor cancer.

24. The method of any one of claims 1 to 16, wherein the cancer is selected from a KRas mutant-associated cancer.

25. The method of any one of claims 1 to 16, wherein the cancer is selected from a KRas wildtype-associated cancer.

26. The method of any one of claims 1 to 16, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer.

27. The method of any one of claims 1 to 16, wherein the cancer is a KRas G12D-associated cancer.

28. The method of any one of claims 1 to 16, wherein the cancer is a KRas G12V-associated cancer.

29. The method of any one of claims 25 to 26, wherein the KRas wildtype is hyperactivated.

30. The method of any one of claims 1 to 29, wherein the immunomodulator inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (II).

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

32. The method of any one of claims 1 to 31, wherein the therapeutically effective amount of the combination of the immunomodulator inhibitor and the compound or salt of Formula (II) results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition, an increased duration of stable disease in the subjects relative to treatment with only the compound or salt of Formula (II), or any combination thereof.

33. The method of any one of claims 1 to 32, wherein the therapeutically effective amount of the compound or salt of Formula (II) of the combination is between about 0.01 to 100 mg / kg per day.

34. The method of any one of claims 1 to 33, wherein the therapeutically effective amount of the compound or salt of Formula (II) in the combination is between about 0.1 to 50 mg / kg per day.

35. The method of any one of claims 1 to 34, wherein the therapeutically effective amount of the immunomodulator inhibitor of the combination is between about 0.01 to 100 mg / kg per day.

36. The method of any one of claims 1 to 35, wherein the therapeutically effective amount of the immunomodulator inhibitor of the combination is between about 0.1 to 50 mg / kg per day.

37. The method of any one of claims 1 to 36, wherein the immunomodulator inhibitor and the compound or salt of Formula (II) are administered on different days.

38. The method of any one of claims 1 to 37, wherein the compound or salt of Formula (II) is administered at a maximum tolerated dose.

39. The method of any one of claims 1 to 38, wherein the immunomodulator inhibitor is administered at a maximum tolerated dose.

40. The method of any one of claims 1 to 39, wherein the immunomodulator inhibitor and the compound or salt of Formula (II) are each administered at a maximum tolerated dose.

41. The method of any one of claims 1 to 40, wherein when M is NR3, Y is O, and R1is piperazine, the piperazine is substituted with one or more R9, wherein each R9is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -NO2, =O, =NO(R20), -CN, - NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl.

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

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

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

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

46. The method of any one of claims 1 to 41, wherein the compound is selected from ,47. The method of any one of claims 1 to 41, wherein the compound is selected from.

49. The method of any one of claims 1 to 41, wherein the compound is selected fromsalt of any one thereof.

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

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

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

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

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

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

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

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

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

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

61. The method of claim 60, wherein B is an optionally substituted unsaturated C8-C15 fused carbocycle.

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

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

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

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

66. The method of claim 65, wherein B is selected from,one or more substituents.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

84. The method of any one of claims 77 to 83, wherein R1is selected from,85. The method of claim 84, wherein the optional one or more substituents are each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

107. The method of claim 106, wherein R1is selected from, , ,108. The method of any one of claims 93 to 101, wherein R1is selected from , which is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl, and C1-6alkyl.

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

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

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

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

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

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

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

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

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

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

120. The method of claim 119, wherein R1is selected from,optionally substituted.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

144. The method of claims 143, wherein the one or more optional substituents of R1are selected from chlorine, -NH2, -CN, C1alkyl, C2alkenyl,, , ,. . The method of claim 144, wherein R1is selected from,,146. The method of any one of claims 1 to 76, wherein R1is an optionally substituted 12- to 15-membered heterocycle.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

169. The method of claim 168, wherein R1is selected from,171. The method of any one of claims 1 to 170, wherein Y is O.

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

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

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

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

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

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

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

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

180. The method of claim 177 to 179, wherein Y-R2is selected from,optionally substituted with one or more R6.

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

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

184. The method of claim 183, wherein Y-R2is selected from, ,186. The method of claim 1 to 171, wherein R2is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6.

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

188. The method of claim 187, wherein each L is independently selected from a substituted C1- C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle.

189. The method of claim 188, wherein each L is independently selected from a substituted C3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle.

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

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

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

193. The method of claim 192, wherein the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2,=CH2, oxo, =NO-C1-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3alkyl, wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

195. The method of any one of claims 1 to 176 or 186 to 190, wherein R2is selected from -L- N(R21)2.

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

197. The method t of claims 1, 195 or 196, wherein L isF.

198. The method of any one of claims 1, or 195 to 197, wherein R2is.,,thereof.

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

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

203. The method of any one of claims 201 to 202, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15 carbocycle.

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

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

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

207. The method of any one of claim 203 to 206, wherein for B the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle are each bicyclic and tricyclic.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

230. The method of claims 201 to 226, wherein the 5- to 12-membered heterocycle of R1is a spiro heterocycle.

231. The method of claims 201 to 230, wherein R1is selected from, ,,, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

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

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

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

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

236. The method of claim 235, wherein L is selected from unsubstituted C1-C4 alkylene.

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

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

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

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

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

242. The method of claim 241, wherein B is selected from an optionally substituted 5- to 15- membered heterocycle and optionally substituted C3-C15 carbocycle.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

264. The method of any one of claims 245 to 260, wherein R1is selected from ,independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6aminoalkyl, C1-6alkoxy, =O, -CN, C1-6hydroxyalkyl, and C1-6haloalkyl.

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

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

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

268. The method of any one of claims 241 to 267, wherein L is selected from C1-C4 alkylene.

269. The method of claims 267 or 268, wherein L is selected from unsubstituted C1-C4 alkylene.

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

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

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

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

274. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound of Formula (II*):Formula (II*) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR3; R3is selected from hydrogen, C1-6alkyl, and C1-6cyanoalkyl; R1is selected from a 7- to 10-membered heterocycle, wherein the 7- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; B is selected from C6-C15 carbocycle, wherein the C6-C15 carbocycle is optionally substituted with one or more substituents independently selected from halogen, C1-C3alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl; R2is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is optionally substituted with one or more R6; L is independently selected from a C1-C4alkylene, wherein the C1-C4alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle; each R20is independently selected from hydrogen; and C1-6alkyl, C3-6carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle.

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

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

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

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

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

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

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

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

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

285. The method of claim 278, wherein.

286. The method of claim 274, wherein M is selected from O.

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

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

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

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

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

292. The method of claim 291, wherein L of R2is selected from C1-C4 alkylene and294. The method of any one of claims 274 to 293, wherein B is selected from an optionally substituted C9-C10fused carbocycle.

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

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

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

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

299. The method of claim 298, wherein.

300. The method of claim 298, wherein.

301. The method of claim 274, wherein B is unsubstituted.

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

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

304. The method of claim 303, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

305. The method of claims 274 or 303, wherein the immunomodulator inhibitor is a PD-1 inhibitor.

306. The method of claim 305, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment.

307. The method of claim 305, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof.

308. The method of claim 305, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.

309. The method of claims 307 or 308, wherein the therapeutically effective amount of nivolumab or biosimilar thereof in the combination is about 240 mg administered every two weeks.

310. The method of claims 307 or 308, wherein the therapeutically effective amount of nivolumab, or biosimilar thereof, in the combination is about 480 mg administered every four weeks.

311. The method of claim 307, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.

312. The method of claim 311, wherein the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 200 mg administered every three weeks.

313. The method of claim 307, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof.

314. The method of claims 274 or 303, wherein the immunomodulator inhibitor is a PD-L1 inhibitor.

315. The method of claim 314, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof.

316. The method of claim 315, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.

317. The method of claims 274 or 303, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor.

318. The method of any one of claims 274 to 317, wherein the immunomodulator inhibitor is administered orally.

319. The method of any one of claims 274 to 318, 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), multiplemyeloma, 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.

320. The method of any one of claims 274 to 319, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

321. The method of any one of claims 274 to 320, wherein the cancer is non-small cell lung cancer.

322. The method of any one of claims 274 to 320, wherein the cancer is small cell lung cancer.

323. The method of any one of claims 274 to 320, wherein the cancer is colorectal cancer.

324. The method of any one of claims 274 to 320, wherein the cancer is rectal cancer.

325. The method of any one of claims 274 to 320, wherein the cancer is pancreatic cancer.

326. The method of any one of claims 274 to 320, wherein the cancer is a solid tumor cancer.

327. The method of any one of claims 274 to 326, wherein the cancer is selected from a KRas mutant-associated cancer.

328. The method of any one of claims 274 to 326, wherein the cancer is selected from a KRas wildtype-associated cancer.

329. The method of any one of claims 274 to 326, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype-associated cancer.

330. The method of any one of claims 274 to 326, wherein the cancer is a KRas G12D- associated cancer.

331. The method of any one of claims 274 to 326, wherein the cancer is a KRas G12V- associated cancer.

332. The method of any one of claims 328 to 329, wherein the KRas wildtype is hyperactivated.

333. The method of any one of claims 274 to 332, wherein the immunomodulator inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (II).

334. The method of any one of claims 1 to 40, wherein the compound is selected from,,335. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof wherein: M is selected from O, S, SO, SO2, and NR3; R1is selected from C3-C12carbocycle and 5- to 15-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl-SO2R20, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-C12carbocycle; Y is selected from a bond, O, S and NR5; R2is selected from -L-N(R21)2, -L-OR21, heterocycle, C1-C6alkyl, -L-heterocycle, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R21)2, -L-C1-C6haloalkyl, -L- NR21C(O)-aryl, -L-COOH, -L-NR21S(O)2(R21), -L-S(O)2N(R21)2, -L-N(R21)C(O)(OR21), -L- OC(O)N(R21)2, and -LC(=O)OC1-C6alkyl, wherein the heterocycle, the aryl portion of -L- NR21C(O)-aryl, the heterocycle portion of -L-heterocycle, the cycloalkyl portion of the -L- cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of the -L- aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7, and wherein when Y is a bond, O, or S, R2is further selected from hydrogen; each L is independently selected from a C1-C4alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4hydroxyalkyl, C1-C4alkyl, C3-C6carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycleare optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; R3is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkoxyalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; each R4is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, oxo, hydroxyl, halogen, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C1-C6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from cyano, halogen, —OR5, and —N(R5)2; each R5is independently selected from hydrogen or C1-C6alkyl; each R6is independently selected from halogen, hydroxy, C1-C3hydroxyalkyl, C1-C3alkyl, oxo, C1-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-C1-C3alkyl, C1-C3aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3alkoxy)C1-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)C1-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3alkyl)O(C1-C3alkyl), -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C1-C3alkyl)phenyl are each optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O;each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, or -N(R5)2; each R20is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, =NH, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; and B is selected from a heterocycle and carbocycle, wherein the heterocycle and carbocycle are each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4alkyl, C1-6aminoalkyl, -S-C1-C3alkyl, C2-C4alkenyl, C2-C4alkynyl, C2-C4hydroxyalkynyl, C1-C3cyanoalkyl, triazolyl, C1-C3haloalkyl, -O-C1-C3haloalkyl, -S-C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4alkynyl(NR5)2, -N(R5)2, (C1-C3alkoxy)haloC1-C3alkyl-, C1-6alkyl-N(R20)2, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, -NH2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

336. The method of claim 335, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

337. The method of claim 335, wherein the compound is selected from compound 53.

338. The method of claim 335, wherein the compound is selected from compound 61.

339. The method of claim 335, wherein the compound is selected from compound 63.

340. The method of claim 335, wherein the compound is selected from compound 64.

341. The method of claim 335, wherein the compound is selected from compound 69.

342. The method of claim 335, wherein the compound is selected from compound 96.

343. The method of any one of claims 334 to 342, wherein the immunomodulator is selected from a checkpoint inhibitor.

344. The method of any one of claims 334 to 342, wherein the immunomodulator is selected from a PD-1 / PD-L1 pathway inhibitor.

345. A method of treating a KRAS associated cancer in a subject in need thereof, wherein the KRAS associated cancer is resistant to treatment with an immunomodulator, comprising administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

346. The method of claim 345, wherein the KRas associated cancer is a KRas G12D- associated cancer.

347. The method of claim 345, wherein the KRas associated cancer is a KRas G12V- associated cancer.

348. The method of claim 345, wherein the KRas associated cancer is a KRas wildtype- associated cancer.

349. The method of claim 345, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

350. The method of any one of claims 345 to 349, wherein the immunomodulator is selected from a checkpoint inhibitor.

351. The method of any one of claims 345 to 349, wherein the immunomodulator is selected from a PD-1 / PD-L1 pathway inhibitor.

352. A method of suppressing resistance to treatment with an immunomodulator in a subject having a KRas associated cancer that include administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

353. The method of claim 352, wherein the KRas associated cancer is a KRas G12D- associated cancer.

354. The method of claim 352, wherein the KRas associated cancer is a KRas G12V- associated cancer.

355. The method of claim 352, wherein the KRas associated cancer is a KRas wildtype- associated cancer.

356. The method of claim 352, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

357. The method of any one of claims 352 to 356, wherein the immunomodulator is selected from a checkpoint inhibitor.

358. The method of any one of claims 352 to 356, wherein the immunomodulator is selected from a PD-1 / PD-L1 pathway inhibitor.

359. A method of treating a subject identified or diagnosed as having a KRas associated cancer that include (a) detecting resistance of the KRas associated cancer in the subject to treatment with an immunomodulator that was previously administered to the subject; and (b) after (a), administering to the subject a combination of an immunomodulator and, a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

360. The method of claim 359, wherein the KRas associated cancer is a KRas G12D- associated cancer.

361. The method of claim 359, wherein the KRas associated cancer is a KRas G12V- associated cancer.

362. The method of claim 359, wherein the KRas associated cancer is a KRas wildtype- associated cancer.

363. The method of claim 359, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

364. The method of any one of claims 359 to 363, wherein the immunomodulator is selected from a checkpoint inhibitor.

365. The method of any one of claims 359 to 363, wherein the immunomodulator is selected from a PD-1 / PD-L1 pathway inhibitor.

366. A method of treating a subject identified or diagnosed as having a KRas associated cancer and determined to have previously developed resistance to treatment with a KRas associated inhibitor that include administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

367. The method of claim 366, wherein the KRas associated cancer is a KRas G12D- associated cancer.

368. The method of claim 366, wherein the KRas associated cancer is a KRas G12V- associated cancer.

369. The method of claim 366, wherein the KRas associated cancer is a KRas wildtype- associated cancer.

370. The method of claim 366, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

371. The method of any one of claims 366 to 370, wherein the immunomodulator is selected from a checkpoint inhibitor.

372. The method of any one of claims 366 to 370, wherein the immunomodulator is selected from a PD-1 / PD-L1 pathway inhibitor.

373. A method of treating a subject identified or diagnosed as having a KRas associated cancer, comprising (a) administering a KRas inhibitor as a monotherapy until disease progression, and (b) after (a), administering to the subject a combination of an immunomodulator, or a pharmaceutical composition thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

374. The method of claim 373, wherein the KRas associated cancer is a KRas G12D- associated cancer.

375. The method of claim 373, wherein the KRas associated cancer is a KRas G12V- associated cancer.

376. The method of claim 373, wherein the KRas associated cancer is a KRas wildtype- associated cancer.

377. The method of claim 373, wherein the compound is selected from compound 53, 61, 63, 64, 69, and 96, or a pharmaceutically acceptable salt of anyone thereof.

378. The method of any one of claims 373 to 377, wherein the immunomodulator is selected from a checkpoint inhibitor.

379. The method of any one of claims 373 to 377, wherein the immunomodulator is selected from a PD-1 / PD-L1 pathway inhibitor.

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

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

382. The method of claim 381, wherein the compound is compound 53.

383. The method of claim 381, wherein the compound is compound 61.

384. The method of claim 381, wherein the compound is compound 63.

385. The method of claim 381, wherein the compound is compound 64.

386. The method of claim 381, wherein the compound is compound 65.

387. The method of claim 381, wherein the compound is compound 69.

388. The method of claim 381, wherein the compound is compound 96.

389. The method of any one of claims 381 to 388, wherein the immunomodulator inhibitor is a PD-1 inhibitor.

390. The method of claim 389, wherein the PD-1 inhibitor is an antibody or antigen-binding fragment.

391. The method of claim 389, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof.

392. The method of claim 389, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.

393. The method of claim 389, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.

394. The method of claim 389, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof.

395. The method of any one of claims 381 to 388, wherein the immunomodulator inhibitor is a PD-L1 inhibitor.

396. The method of claim 395, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof.

397. The method of claim 396, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.

398. The method of any one of claims 381 to 388, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor.

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