Combination therapies with a KRAS modulator and an immunomodulator inhibitor

Abstract

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

Description

COMBINATION THERAPIES WITH A KRAS MODULATOR AND AN IMMUNOMODULATOR INHIBITORCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 600,221 filed on November 17, 2023, the entire content of which is incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, Snapshot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 el). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras- driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP -bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.

[0003] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, Snapshot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 el). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP -bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium.Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.

[0004] 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.

[0005] 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

[0006] 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-Ll 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 theimmune 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).

[0007] 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.

[0008] 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-Ll inhibitors, for treating KRas mutant or hyperactivated Kras wildtype-associated cancers that can be resistant to ICB therapy.

[0009] Additionally, 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.

[0010] Additionally, 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 14) 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 providesstrong rationale for clinical studies combining compounds described herein (e.g., compounds of Formula (I)) 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.

[0011] 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-Ll inhibitor) and a compound of Formula (I), kits comprising the compositions and methods of use thereof. 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:B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C1-6 alkyl(=NOR20), - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(0)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, -N02, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl-SO2R20, Ci-6 alkoxyalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C 12 carbocycle and 5- to 12- membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(0)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, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C 12 carbocycle;Y is selected from a bond, -0-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Ci-Ce haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-C00H, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, C 1-6 alkyl -N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, NMO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSCLF, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCFB-, -N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(0)Ci-Ce alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, - OC(O)heterocycle, -O-Ci-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, and -CHJieterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(Ci- C3alkyl)(Ci-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Ci-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -Ci-C3alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-Ce carbocycle, and 3- to 8-membered heterocycle, wherein the C3-Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, Ci-ehydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-Ce carbocycle or 3- to 8-membered heterocycle, wherein the C3-Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12-membered heterocycle; and each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2,-NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0012] 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 ofFormula (Formula (I- A), or a pharmaceutically acceptable salt thereof wherein:R1is selected from 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -Ci-6alkyl(=NOR20), -C(O)R20, =0, -CN, -NHCN, C1-6 alkyl-N(R20)2, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C 2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(0)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, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci- 6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle;B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;Y is selected from a bond, and -O-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, - L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Ci-Ce haloalkyl, -L-OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L- N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR23C(O)- aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L- heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-Ci2carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 cyanoalkyl, Ci-e hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, NMO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)Ci-Ce alkyl, -CH2(pyrazolyl), -CH2NHSO2Ci-Ce alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -0C(0)NH(CI-C3alkyl)O(Ci-C3alkyl), -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(Ci- C3 alkyl)(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(0)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=0)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2;each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3- Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[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 ofFormulaFormula (I-B), or a pharmaceutically acceptable salt thereof wherein:optionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -CI-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -OR20, -N(R20)2, -N02, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl;Y is -0-;R2is selected from -L-heterocycle, and -L-N(R23)2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R6.B is selected from a 7- to 15-membered heterocycle, wherein the 7- to 15-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, =0, -N(R21)2, -OR21, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, and C2-e alkynyl;R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OR20, -C(O)R20, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl; and each R20is independently selected from hydrogen; and Ci-6 alkyl, and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(CI-6 alkyl)2, Cnio alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, and oxo.

[0014] A method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof; and a compound selectedpharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.INCORPORATION BY REFERENCE

[0015] 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

[0016] 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:

[0017] FIG. 1 illustrates that compounds herein reduce immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS-mutant HP AC cells.DETAILED DESCRIPTION OF THE INVENTION

[0018] 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.

[0019] 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

[0020] 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.

[0021] "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 tofifteen carbon atoms (z.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (z.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (z.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (z.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (z.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (z.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (z.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (z.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (z.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (z.e., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (z.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (z.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (z.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0022] 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 “Ci-ealkyl” 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 -Ci-ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0023] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above.

[0024] "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 certain embodiments, 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-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0025] "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, andpreferably having from two to twelve carbon atoms (z.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (z.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (z.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (z.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0026] 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-ealkenylene- 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-ealkenylene- 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.

[0027] "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, ^-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., Ci-Cs alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).

[0028] "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-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). 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., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0029] "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-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0030] "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 inaccordance with the Hiickel 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.

[0031] "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.

[0032] "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.

[0033] “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.

[0034] 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.

[0035] "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), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0036] "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 ofmonocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0037] "Cycloalkylalkyl" refers to a radical of the formula -Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0038] "Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0039] Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0040] 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, di chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-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., tri chloromethane, 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., l-chloro,2-fluoroethane.

[0041] "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, l-fluoromethyl-2-fluoroethyl, and the like.

[0042] "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-di amine, pentane- 1,2,4- triamine and the like.

[0043] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-l-ol, butane- 1,4-diol, pentane- 1, 2, 4-triol, and the like.

[0044] "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.

[0045] "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.

[0046] “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 spiroheterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.

[0047] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group.

[0048] "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 least one of the rings in the ring system is aromatic, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. 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.

[0049] 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.

[0050] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles includedihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0051] 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, z.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.

[0052] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N-NH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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 (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N- NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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 (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -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)O Ra, -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 or2), -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.

[0053] 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 a,P-unsaturated carbonyl or a,P-unsaturated thiocarbonyl compound.

[0054] 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, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0055] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0056] 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, / ?-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.

[0057] 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.

[0058] 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.

[0059] 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 com 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, com 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.

[0060] 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 theonset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0061] 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.

[0062] The term “G12 mutants”, as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X).

[0063] The term "KRas G12D-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12D mutation.

[0064] The term "KRas G12V-associated cancer" as used herein refers to cancers associated with or mediated by or having a KRas G12V mutation.

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

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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-translationmodifications (e.g., glycosylation and / or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).

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

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

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

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

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

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

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

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

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

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

[0082] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.COMPOSITIONS AND INHIBITORSImmunomodulator Inhibitors

[0083] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination ofi) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0084] In an aspect, provided herein are methods of treating cancer in a subject in 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 (I), 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 (I- A), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

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

[0087] 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: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0088] In some embodiments, the immunomodulator inhibitor is selected from a PD-1 inhibitor, a PD-Ll inhibitor, and a CTLA-4 inhibitor. In some cases, the immunomodulator inhibitor 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. 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-L1, 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-Ll 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-Ll antibodies include atezolizumab (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 (I), 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 (I), 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0099] 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 (I-A), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0100] 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 (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0101] 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: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0102] In 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.

[0103] 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

[0104] 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0105] 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0106] 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 (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0107] 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 (I- A), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0108] 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 (I-B), 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: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0110] 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-Ll antibody, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides. In some cases, the PD-L1 binding antagonist is an anti-PD-Ll antibody.

[0111] 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-Ll 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-Ll antibody. In some cases, an anti- PD-L1 antibody is avelumab or a biosimilar thereof. In some cases, an anti-PD-Ll antibody is atezolizumab or a biosimilar thereof. In some cases, an anti-PD- Ll antibody is durvalumab or a biosimilar thereof. In some cases, an anti-PD-Ll antibody is BMS-936559 (MDX-1105) or a biosimilar thereof.CTLA-4 inhibitor

[0112] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0113] 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 (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0114] 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: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0115] 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 (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0116] 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 (I- A), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0117] 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 (I-B), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0118] In some embodiments, the CTLA-4 inhibitor is selected from Ipilimumab.KRAS Inhibitors

[0119] 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), (I- A), or (I-B)) 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), (I- A), or (I-B)) 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), (LA), or (LB), may be used in the methods of the disclosure. In some cases, a compound of Formula (I), (LA), or (LB), may be referred to as a KRAS inhibitor. In some cases, a compound of Formula (I), (LA), or (LB), may be referred to as a KRAS inhibitor.

[0120] In some embodiments, a compound represented by the structure of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein:B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C1-6 alkyl(=NOR20), - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(0)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, Ci-6alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, Ci-e alkyl- SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C 12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(0)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, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C3-C 12 carbocycle;Y is selected from a bond, -0-, -S-, and -N(R5)-;R2is selected from heterocycle, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-CI-C6haloalkyl, -L-OR23, - L-NR23C(O)-aryl, -L-C00H, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L- OC(O)N(R23)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, C 1-6 alkyl -N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, C 1-6 cyanoalkyl, Ci-6 hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, NMO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSCLF, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCFB-, -N(R5)2, (C1-C3 alkoxy)Ci-C3 alkyl-, (Ci- C3alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2,OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-Ci-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(CI-C3alkyl)(Ci-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Ci-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-Ce carbocycle, and 3- to 8-membered heterocycle, wherein the C3-Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, Ci-ehydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-Ce carbocycle or 3- to 8-membered heterocycle, wherein the C3-Ce carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6alkyl)2, Ci-io alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0121] In some embodiments, for a compound or salt for Formula (I), B is selected from an optionally substituted 7- to 15-membered fused heterocycle and optionally substituted C7-C15 fused carbocycle. In some cases, and optionally substituted C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 7- to 15-membered fused heteroaryl and optionally substituted C7-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 7- to 15- membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0122] In some embodiments, for a compound or salt for Formula (I), B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle. In some cases, and optionally substituted Cs-Cis fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 8- to 15-membered fused heteroaryl and optionally substituted Cs-Cis fused aryl. In some cases, B is an optionally substituted unsaturated Cs-Cis fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 8- to 15- membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0123] In some embodiments, for a compound or salt for Formula (I), B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining three rings (e.g., tricyclic). In some cases, B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining two rings (e.g., bicyclic). In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are each independently bicyclic or tricyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is bicyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is tricyclic.

[0124] In some embodiments, for a compound or salt for Formula (I), the heterocycle or carbocycle of B is bicyclic. In some cases, the heterocycle or carbocycle of B is tricyclic. In some cases, the tricyclic heterocycle contains three interconnected rings of atoms.

[0125] In some embodiments, for a compound or salt for Formula (I), for B, the heterocycle and carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently bicyclic.

[0126] In some embodiments, for a compound or salt for Formula (I), for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected from, each of which is optionally substituted with one or more substituents. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected from, each of which is optionally substituted with one or more substituents In some cases, B, each of which is optionally substituted with one or more substituents. In some cases,B is selected fromeach of which is optionally substituted with one or more substituents.

[0127] In some embodiments, for a compound or salt for Formula (I), B is selected fromsubstituents.

[0128] In some embodiments, for a compound or salt for Formula (I), for B, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, - CN, -NO2, =0, -N(R21)2, -B(OR21)2, -OR21, -SR21, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OH, -SR21, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-e alkynyl. In some cases, for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(0H)2, -OH, -O-C1-C3 haloalkyl, -C(0)NH2, -NH2, =0, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-e alkynyl. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, =0, -NH2, -N(CI-6 alkyl)H -N(CI-6 alkyl)2, -OH, C1-6 aminoalkyl, Ci- 6 alkoxy, C1-6 alkoxyalkyl, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, C1-C3 alkyl. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally

[0129] In some embodiments, for a compound or salt for Formula (I), B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle. In some cases, the heterocycle of B has at least one sulfur atom. In some cases, the heterocycle of B has one or sulfur atoms. In some cases, the heterocycle of B has at least onesubstituted. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =0, - CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, -NH2, =0, and -

[0130] In some embodiments, for a compound or salt for Formula (I), B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. Inis optionally substituted. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR20, -C(O)N(R20)2, - N(R20)2, =0, -CN, -NHCN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted. In some cases, B is substituted with at least one -NH2. In some cases, B is selected fromsome cases, B is substituted with at least one -NH2 at least one -CN. In some cases, B is selected

[0131] In some embodiments, for a compound or salt for Formula (I), B is an optionally substituted 7- to 11 -membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, B is an optionally substituted 7-membered fused heterocycle. In some cases, B is an optionally substituted 8-membered fused heterocycle. In some cases, B is an optionally substituted 9-membered fused heterocycle. In some cases, B is an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of B is anunsaturated heterocycle. In some cases, the heterocycle of B is a non-aromatic heterocycle. In some cases, B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases,B has at least 2 heteroatoms. In some cases, B is selected fromeach of which is optionally substituted. In some cases, B is selected fromeach of which is optionally substituted. In some cases, B is selected from, each of which is optionally substituted. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -B(0H)2, -OH, -O-C1-C3 haloalkyl, -C(0)NH2, -NH2, =0, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least three substituents. In some cases, B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from -CN. In some cases, B is selected from,

[0132] In some embodiments, for a compound or salt for Formula (I), R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl. In some cases, R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -C(O)N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, Ci-6hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl. In some cases, R3is selected from hydrogen, halogen, -CN, -NO2, -NH2, -N(CI-6 alkyl)H -N(CI-6 alkyl)2,-OH, - C(O)N(R20)2, -C(O) R20, -C(O)OR20, -OC(O) R20, CI-6 aminoalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl,C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-e alkynyl. In some cases, R3is selected from hydrogen, -CN, -C(O)R20, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, -CN, -C(O)R20, Ci-6 hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, fluorine, and -CN. In some cases, R3is selected from fluorine. In some cases, R3is selected from hydrogen. In some cases, R3is selected from -CN.

[0133] In some embodiments, for a compound or salt for Formula (I), Y is -O-. In some cases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R5)-.

[0134] In some embodiments, for a compound or salt for Formula (I), L is selected from Ci- C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene. In some cases, two substituents on the same carbonatom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some embodiments, for a compound or salt for Formula (I), L is selected from Ci- C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected fromcases, 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-C6 carbocycle 3- to 5- membered heterocycle. In some cases, each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each L is independently selectedcases, each L is independently selected from -k . In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen and C1-C4 alkyl. In some cases, L is selected from

[0135] In some embodiments, for a compound or salt for Formula (I), each L is independently selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from^^^ and.

[0136] In some embodiments, for a compound or salt for Formula (I), R2is selected from heterocycle, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, -L-heteroaryl, -L- cycloalkyl, -L-N(R23)2, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-CI-C6haloalkyl, -L-OR23, -L- NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L- OC(O)N(R23)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of - L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

[0137] In some embodiments, for a compound or salt for Formula (I), R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R23)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

[0138] In some embodiments, for a compound or salt for Formula (I), R2is -L-heterocycle, wherein the heterocycle portion is optionally substituted. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle. In some cases, R2is selected from a - L-5- to 10-membered heterocycle. In some cases, R2is selected from a -(C1-C2 alkylene)-5- to 10-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered saturated heterocycle. In some cases, R2is a -L-5-membered heterocycle. In some cases, R2is a -L-8-membered heterocycle. In some cases, the heterocycle contains at least 1 nitrogen atom. In some cases, the heterocycle containsat most 1 nitrogen atom. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. In some cases, the bicyclic heterocycle contains 1 nitrogen atom. In some cases, Y-R2is selected fromwherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen. Insome cases, Y-R2is selected fromIn some cases, Y-R2is

[0139] In some embodiments, for a compound or salt of Formula (I), 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 from, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected fromwherein the heterocycle portion is optionally substituted. In somecases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-CI-C3 alkyl, -CH2OC(O)heterocycle, -QHfcheterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, the heterocycle is substituted with at least one halogen. In some cases, the heterocycle is substituted with at least one =CH2. In some

[0140] In some embodiments, for a compound or salt of Formula (I), R2is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5- to 6-membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5- membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has two nitrogen atoms. In some cases, the heteroaryl has three nitrogen atoms. In some cases, theheteroaryl is selected fromwhich is optionally substituted. In some cases, the heteroaryl iswhich is optionally substituted. In some cases, Y-R2is selected from, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, each R7is independently selected from C1-C4 alkyl, halogen,

[0141] In some embodiments, for a compound or salt of Formula (I), R2is -L-aryl, optionally substituted with one or more R7. In some cases, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R7. In some cases, Y-R2is selected from

[0142] In some embodiments, for a compound or salt of Formula (I), R2is -L-N(R23)2. In some cases, selected fromIn some embodiments, for a compound or salt of Formula (I), R2is heterocycle, optionally substituted with one or more R6. In some cases, the heterocyclewhich is optionally substituted. In some cases, the heterocyclesome cases, Y-R2is

[0143] In some embodiments, for a compound or salt of Formula (I), R2is selected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L- heterocycle, are each optionally substituted with one or more R6; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and -L-N(R23)2. In some cases, the heterocycle of R2is selected fromwherein the heterocycle of R2is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected fromfrom, , wherein the aryl and the heteroaryl are each optionally substituted with one or more R7; and, In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-CI-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from C1-C3 alkyl, halogen and C1-C3 haloalkyl. In some cases, the heterocycle of R2, the aryl and heteroaryl of R2, and -, wherein the heterocycle, and the heterocycle portion of-L-heterocycle, are each optionally substituted with one or more R6;the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with

[0144] In some embodiments, for a compound or salt of Formula (I), L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, C1-C4 hydroxy alkyl and C1-C4 alkyl. In some cases, L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from C1-C4 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2 alkylene. In some cases, L isIn some

[0145] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from an optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =0, =S, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, Ci-e haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and Ci-6 haloalkyl.

[0146] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 haloalkyl.

[0147] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from a substituted C1-C4 alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from

[0148] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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 moreR6.

[0153] In some embodiments, for a compound or salt of Formula (I), R2is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom.In some cases, Y-R2is selected fromwherein 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-C3 alkyl and oxo. In some cases, Y-R2is selected fromcases, Y-R2is selected from

[0154] In some embodiments, for a compound or salt of Formula (I), Y is a bond. In some cases, R2is selected from an optionally substituted heteroaryl and optionally substituted aryl. In some cases, R2is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl only contain nitrogen atom(s). In some cases, the heteroaryl is a 6- membered heteroaryl. In some cases, the heteroaryl is a 5-membered heteroaryl. In some cases, the heteroaryl is selected fromeach of which is optionally substituted.In some cases, the heteroaryl is selected fromeach of which is optionally substituted. In some cases, R2is selected from an optionally substituted aryl. In some cases, the aryl is a phenyl. In some cases, the heteroaryl is optionally substituted with one or moreR6, wherein each R6is selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -CHJieterocycle, -C1-C3 alkyl-N(R5)2, and -C(O)N(R5)2. In some cases, R6is selected from C1-C3 alkyl, -CH2heterocycle, and -C(O)N(R5)2. In some cases, the aryl is optionally substituted with one or more R7. In some cases, Y-R2is selected from

[0155] In some embodiments, for a compound or salt of Formula (I), Y is -O- and R2is selected from L-5-membered heteroaryl. In some cases, the heteroaryl has at least 1 nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl has 3 nitrogen atoms. In some cases, L is selected from an optionally substituted C1-C4 alkylene. In some cases, L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen,-OH, -NO2, =0, =S, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, L is selected fromIn some cases, L is selected from. In some cases, the heteroaryl is optionally substituted with one or more R7. In some cases, each R7is selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In some cases, Y-R2is selected from

[0156] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)Ci-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(Ci- C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(CI-C3 alkyl)(Ci-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0157] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, each R6is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0158] In some embodiments, for a compound or salt of Formula (I), each R6is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, Ci- C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, -N(R5)S(O)2(R5), - OC(O)N(R5)2, =CH2, OXO, =NO-CI-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, - CH2OC(O)N(R5)2, and-O-Ci-Cs alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from C1-C3 alkyl, halogen and C1-C3 haloalkyl.

[0159] In some embodiments, for a compound or salt of Formula (I), R6is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6is selected from halogen and C1-C3 alkyl. In some cases, R6ishalogen. In some cases, R6is C1-C3 alkyl. In some cases, R6is selected from halogen and C1-C3 alkyl. In some cases, R6is selected from methyl and fluorine.

[0160] In some embodiments, for a compound or salt of Formula (I), R2is selected from

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

[0162] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0163] In some embodiments, for a compound or salt of Formula (I), Y-R2is

[0164] In some embodiments, for a compound or salt of Formula (I), L is selected from unsubstituted C1-C4 alkylene. 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.

[0166] In some embodiments, for a compound or salt of Formula (I), R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl.

[0167] In some embodiments, for a compound or salt of Formula (I), R6of R2is independently selected at each occurrence from C1-C3 alkyl and halogen.

[0168] In some embodiments, for a compound or salt of Formula (I), Y-R2is selected from

[0169] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally sub stituted 5- to 12-membered heterocycle. In some cases, the heterocycle of R1isselected from a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12- membered heterocycle, and 8- to 12-membered heterocycle. In some cases, the heterocycle of R1is selected from a 5- to 11 -membered heterocycle, 5- to 10-membered heterocycle, 5- to 9- membered heterocycle, and 5- to 8-membered heterocycle. In some cases, the heterocycle of R1is selected from a 6- to 11 -membered heterocycle, 6- to 10-membered heterocycle, 6- to 9- membered heterocycle, and 6- to 8-membered heterocycle. In some cases, the heterocycle of R1is selected from a 7- to 11 -membered heterocycle, 7- to 10-membered heterocycle, 7- to 9- membered heterocycle, and 7- to 8-membered heterocycle. In some cases, the heterocycle of R1is selected from a 5- to 6-membered heterocycle and 5- to 9-membered heterocycle. In some cases, the heterocycle of R1is selected from an 8- to 9-membered heterocycle. In some cases, R1is selected from an optionally substituted 5- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted 6- to 7-membered heterocycle. In some cases, R1is selected from an optionally substituted 7-membered heterocycle. In cases, the 5- to 12- membered heterocycle of R1is a bridged heterocycle. In cases, the 5- to 12-membered heterocycle of R1is not a bridged heterocycle. In some cases, the heterocycle of R1is saturated. In some cases, the heterocycle of R1is unsaturated. In some cases, the heterocycle of R1is an unbridged heterocycle. The heterocycle of R1is optionally substituted as described elsewhere herein.

[0170] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R1contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle of R1contains at most 2 heteroatom atoms. In some cases, the heterocycle of R1contains 1 nitrogen atom. In some cases, the heterocycle of R1contains only 1 nitrogen atom. In some cases, the heterocycle of R1contains only 1 nitrogen atom and no other heteroatoms.

[0171] 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, =0, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and Ci-e haloalkyl. In some cases, the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R1is selected from a saturated heterocycle and unsaturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R1is a saturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R1is an unsaturated heterocycle.

[0172] In some embodiments, for a compound or salt of Formula (I), R1is selected from 5- to 15-membered heterocycle, wherein the 5- to 15-membered heterocycle is optionallysubstituted. In some cases, R1is selected from an optionally substituted 6- to 15-membered heterocycle. In some cases, the heterocycle is a spiro heterocycle. In some cases, the heterocycle is a fused heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is an unsaturated heterocycle.

[0173] In some embodiments, for a compound or salt of Formula (I), R1is a 6- to 12- membered fused heterocycle, which is optionally substituted.

[0174] In some embodiments, for a compound or salt of Formula (I), R1is a 6- to 12- membered spiroheterocycle, which is optionally substituted. In some cases, R1is selected from optionally substituted 7- to 8-membered spiroheterocycle.

[0175] In some embodiments, for a compound or salt 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 is optionally substituted as described elsewhere herein.

[0176] In some embodiments, for a compound or salt of Formula (I), R1is a 5- to 12- membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 11 -membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 6- to 11 -membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a monocyclic 7- to 11 -membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered monocyclicheterocycle. In some cases, the heterocycle of R1is saturated. The monocyclic heterocycle is optionally substituted as described elsewhere herein.

[0177] In some embodiments, for a compound or salt of Formula (I), R1is a bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12-membered bridged heterocycle, or 8- to 12- membered bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 11 -membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a 6- to 11 -membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9- membered bridged heterocycle, or 6- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a bridged 7- to 11 -membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9-membered bridged heterocycle, or 7- to 8-membered bridged heterocycle. In some cases, the heterocycle of R1is a 5- to 6-membered bridged heterocycle or 5- to 9- membered bridged heterocycle. In some cases, the heterocycle of R1is an 8- to 9-membered bridged heterocycle. In some cases, the heterocycle of R1is saturated. In some cases, the bridged heterocycle is selected fromIn some cases, the bridged heterocycle is selected from. Each bridged heterocycle is optionally substituted as described elsewhere herein.

[0178] In some embodiments, for a compound or salt of Formula (I), R1is a spiro heterocycle. The spiro heterocycle of R1is a 7- to 12-membered spiro heterocycle, 7- to 12- membered spiro heterocycle, or 8- to 12-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7- to 11 -membered spiro heterocycle, 7- to 10-membered spiro heterocycle, 7- to 9-membered spiro heterocycle, or 7- to 8-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7- to 11 -membered spiro heterocycle, 7- to 10-membered spiro heterocycle, 7- to 9-membered spiro heterocycle, or 7- to 8-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7- to 11 -membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 7-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is an 8-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 9-membered spiro heterocycle. In some cases, the spiro heterocycle of R1is a 10-membered spiro heterocycle. In some cases, the spiro heterocycle of R1contains at most 1 nitrogen atom. In some cases, the spiro heterocycle of R1contains only 1 nitrogen atom. In some cases, the spiroheterocycle of R1contains at most 2 heteroatom atoms. In some cases, the spiro heterocycleof R1contains at least 2 heteroatom atoms. In some cases, the spiro heterocycle of R1contains at least 3 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the spiroheterocycle of R1is bound to the Formula via the nitrogen atom.heterocycle of R1is selected from. Each spiro heterocycle is optionally substituted as described elsewhere herein.

[0179] In some embodiments, for a compound or salt of Formula (I), R1is a fused heterocycle. In some cases, the fused heterocycle of R1is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6- to 11- membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 7- to 11 -membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R1is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 9-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 10-membered fused heterocycle. In some cases, the fused heterocycle of R1is an 11 -membered fused heterocycle. In some cases, the fused heterocycle of R1is a 6-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 7-membered fused heterocycle. In some cases, the fused heterocycle of R1is a 10-membered fused heterocycle. In some cases, the fusedheterocycle is selected fromEach fused heterocycle is optionally substituted as described elsewhere herein.

[0180] In some embodiments, for a compound or salt of Formula (I), 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,which is optionally substitutedwith one or more substituents. In some cases,, which is optionally substituted with one or more substituents. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(=NR20)N(R20)2, -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2,=0, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci-6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =0, -CN, C1-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, Ci-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents are independently selected from halogen, =0, -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, CI-6 alkyl -N(R20)2, CI-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =0, Ci-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, =0, -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 fromeach of which is further optionally substituted. In some cases, the further one or more optional substituents are selected from halogen, -OH, =0, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen, and C1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered saturated heterocycle. In some cases, each R20is independently selected from 5- to 6-membered saturated heterocycle. In some cases, the heterocycle of R20has at least one nitrogen atom. In some cases, the heterocycle of R20has at least one sulfur atom. In some cases, the heterocycle of R20has at least one oxygen atom. In some cases, the heterocycle of R20contains only 1 heteroatom. In some cases, the heterocycle of R20has at least two heteroatoms. In some cases, the heterocycle of R20contains only 2 heteroatoms. In some cases, the optional one or more substituents of R1are independently selected from halogen, -CN, C2 alkenyl,some cases, the optional one or more substituents of R1are independently selected from halogen,more substituents of R1are independently selected from halogen, and Ci-6 alkyl-N(R20)2. In some cases, the optional one or more substituents of R1are independently selected from halogen,, hydrogen, Ci-6 alkyl, and C3-6 carbocycle. In some cases, R1is selectedsome cases, R1is selectedindependently 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, =0, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-e alkynyl, 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 C1-6 alkyl. In some cases, R1is selected which is optionally substituted with one more substituents independentlyselected from halogen and Ci-6 alkyl. In some cases, R1is selected from

[0181] In some embodiments, for a compound or salt of Formula (I), R1is selected from a( B ), wherein is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1* ; and RBis selected from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkynyl, and -CN. In some cases, RBis selected from hydrogen, and halogen. In some cases, RBis chloride. In some cases, RBis hydrogen. In some cases,has at least 1, 2, 3, or 4 heteroatoms. In some cases, 2, 3, or 4 nitrogen atoms. In some cases,has at least 1 oxygen atom., is a monocyclic heterocycle. In some cases,is a bicyclic heterocycle. In some cases,is selected from an optionally substituted 5-membered heterocycle. In some cases,is selected from an optionally substituted 9-membered heterocycle. In some cases,is selected from, each of which is optionally substituted with one or more R1*.each of which is optionally substituted with one or more R1*. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, and Ci-6 alkyl. In some cases,is selected from

[0182] In some embodiments, for a compound or salt of Formula (I), 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 fromand, each of which is optionally substituted. In some cases, R20is selected fromsome cases, the optional substituents are selected from Ci-io alkyl, oxo, and =NH.

[0183] In some embodiments, for a compound or salt of Formula (I), each R20is independently selected from hydrogen; and Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, and =NH.

[0184] In some embodiments, for a compound or salt of Formula (I), each R21is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, oxo, and =NH. In some cases, each R21is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, and =NH.

[0185] In some embodiments, for a compound or salt of Formula (I), each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, and =NH.

[0186] In some embodiments, for a compound or salt of Formula (I), each R23is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted withone or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, oxo, and =NH.

[0187] In some embodiments, for a compound or salt for 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. In some cases, the one or more optional substituents are independently selected from halogen, -CN, -NO2, =0, -N(R20)2, -B(OR20)2, -OR20, -SR20, - S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 aminoalkyl, Ci-6alkoxy, C1-6 alkoxyalkyl, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents are independently selected from halogen, -OH, -N(R20)2, -NO2, =0, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the one or more optional substituents are independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R20is selected from hydrogen and C1-3 alkyl.

[0188] In some embodiments, for a compound or salt for Formula (I), R1is selected from a saturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents. In some cases, the 5- to 12-membered heterocycle of R1is bridged. In some cases, the 5- to 12-membered heterocycle of R1is not bridged. In some cases, the 5- to 12-memberedsubstituents.

[0189] 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. 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, CI-6 alkoxy, =0, -CN, Ci-6alkyl, C2.6alkenyl, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, and Ci-e haloalkyl. In some cases, R1is

[0190] In some embodiments, for a compound or salt of Formula (I), 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.

[0191] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1contains only 1 nitrogen atom and optionally one or more heteroatoms selected from oxygen, and sulfur. In some cases, the heterocycle is a fused heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle.In some cases, the heterocycle is selected fromheter0CyCiejsoptionally substituted as described elsewhere herein.

[0192] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1has at most 1 nitrogen atom. In some cases, the heterocycle of R1has only 1 nitrogen atom and optionally one or more other heteroatoms selected from oxygen and sulfur. In some cases, the heterocycle of R1has only 1 nitrogen atom and no other heteroatoms.

[0193] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted 5- to 12-membered saturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has only one nitrogen atom and 0-2 other heteroatoms selected from nitrogen, oxygen, and sulfur. In some cases, the 5- to 12-membered unsaturated heterocycle has only one nitrogen atom and no further heteroatoms. In some cases, the 5- to 12-membered unsaturated heterocycle has three nitrogen atoms and no further heteroatoms.

[0194] In some embodiments, for a compound or salt of Formula (I), 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 only one nitrogen atom and no further heteroatoms.

[0195] In some embodiments, for a compound or salt of Formula (I), 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 ofR1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R1is selectedwhich is substituted. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, -NO2, =0, -CN, C 1-6 fluoroalkyl, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =0, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the substituents of R1are each selected from one or more halogen, -OH, -NHCN, =0, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. In some cases, R1is selected fromselected fromeach of which is optionally substituted. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -C(0)NH2, -NH-C(0)-(CI-6 alkoxy), -NH-C(0)-(CI-6 hydroxyalkyl), -NH2, - NH(CN), =0, -CN, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl. In some cases, the one or more optionalsubstituents of R1are each independently selected from fluorine, -OH, -CN, C 1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, R1is selected fromof which is optionally substituted with one or more substituents. In some cases, the one or moreof the optional substituents are independently selected from halogen, -OH, -N(R20)2, -B(0H)2, - C(O)N(R20)2, -NHCN, -NO2, C1-6 alkoxy, =0, -CN, C1-6 alkyl, C2-6 alkenyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and Ci-e haloalkyl. In some cases, R1is selected

[0197] In some embodiments, for a compound or salt of Formula (I), 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, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1is selected fromwherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1is selected frommore substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R1is selected from, wherein each is substituted with one or more substituents independently selected from halogen.

[0198] In some embodiments, for a compound or salt of Formula (I), 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 unsaturated6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R1is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen. In some cases, R1is selected from an unsaturated 7-membered heterocycle, substituted with at least one halogen. In some cases, R1is selected from. In some cases, R1is selected fromsome cases, R1is

[0199] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, Ci-e haloalkyl, and C1-6 alkyl. In some cases, R4S selected from

[0200] In some embodiments, for a compound or salt of Formula (I), 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 toFormula (I) via the only 1 nitrogen atom. In some cases, R1is selected from of which is optionally substituted. In some cases, the one or more optionaleach independently selected from halogen, -OR20, -N(R20)2, =0, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -NH2, -NH(CN), =0, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -NH2, -NH(CN), =0, -CN, C1-6 hydroxyalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the 6-membered heterocycle is a partiallyunsaturated 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

[0201] In some embodiments, for a compound of Formula (I), R1is selected from an optionally substituted 6-membered unsaturated heterocycle and 6-membered saturated heterocycle.

[0202] In some embodiments, for a compound or salt of Formula (I), R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

[0203] In some embodiments, for a compound or salt of Formula (I), R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, and Ci-e haloalkyl.

[0204] In some embodiments, for a compound or salt of Formula (I), R1is selected from

[0205] In some embodiments, for a compound or salt of Formula (I), R1is selected from, wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

[0206] In some embodiments, for a compound or salt of Formula (I), R1is selected from, wherein each is optionally substituted with two substituents independently selected from halogen, and Ci-6 haloalkyl. In some cases,

[0207] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, the 6- to 10-memberedheterocycle contains at least 1 nitrogen atom. In some cases, R1is selected from “-I— ,optionally substituted with one or more substituents independently selected from halogen, =0, - OH, -CN, -NHCN, -C(O)N(R20)2, C1-6 aminoalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, and C1-6 alkyl. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R1is selected from

[0208] In some embodiments, for a compound or salt of Formula (I), 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 ofR1is bound to Formula (I) via the only 1 nitrogen atom. In some cases, R1is selected from -™L~-cases, R1is selected fromeach of which is substituted. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, -NO2, =0, -CN, C 1-6 fluoroalkyl, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, CI-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 alkyl, and C2-6 alkenyl. In some cases, the substituents of R1are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =0, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6cyanoalkyl, and C1-6 alkyl. In some cases, the substituents of R1are each selected from one or more halogen, -OH, -NHCN, =0, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. In some cases, R1is selected fromselected fromeach of which is optionally substituted. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -C(0)NH2, -NH-C(0)-(CI-6 alkoxy), -NH-C(0)-(CI-6 hydroxyalkyl), -NH2, -NH(CN), =0, -CN, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl. In some cases, the one or more optional substituents of R1are each independently selected from fluorine, -OH, -CN, C 1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, R1is selected from

[0209] In some embodiments, for a compound or salt of Formula (I), 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, R1

[0210] In some embodiments, for a compound or salt of Formula (I), 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, Ci-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20X CI-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =0, Ci-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and Ci-6 aminoalkyl. In some cases, R1is selectedmore substituents independently selected from halogen, -N(R20)2, Ci-6 alkyl, -OR20, - N(R20)C(O)N(R20)2, -B(OR20X CI-6 cyanoalkyl, -N(R20)C(O)N(R20)2, =0, Ci-6hydroxyalkyl, halogen, -N(R20)C(O)R20, -N(R20) S(O)2(R20), and Ci-6 aminoalkyl. In some cases, R1is selected

[0211] In some embodiments, for a compound or salt of Formula (I), 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 frommore substituents independently selected from halogen, =0, -OH, -CN, -NHCN, -C(O)N(R20)2, - C(O)NR20OR20, C I-6 aminoalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, and Ci-6 alkyl. In someR1is selected fromsome cases, R1is selected fromsome cases, R1is selected from, which is optionally substituted with one or more substituents independently selected from halogen, -OR20, -SR20, - N(R20)2, -NO2, =0, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-e alkynyl.

[0212] In some embodiments, for a compound or salt of Formula (I), 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,C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases,optionally substituted with one or more substituents selected from -N(R20)2, -C(O)R20, -NO2, =0, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, and C2-e alkynyl. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected fromhalogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0213] In some embodiments, for a compound or salt of Formula (I), 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, =0, -CN, -NHCN,C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R1is selected fromsome cases,

[0214] In some embodiments, for a compound or salt of Formula (I), 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 10- membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In somecases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1is selected from, each of which is optionally substituted with one or more substituents. In some cases, R1is selected fromhich is optionally substituted with one or more substituents. In some, , which is optionally substituted with one or more substituents. In some cases, the one or more optional substituents of R1are independently selected from halogen, -OH,-S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, - N(R20)2, -C(O)R20, -N02, =0, -CN, Ci-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents are independently selected from halogen, =0, -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, C 1-6 alkyl -N(R20)2, CI-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =0, Ci-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, =0, -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, theoptional 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, =0, -CN, C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, and C2-6 alkynyl. In some cases, the further one or more optional substituents are selected from halogen and C1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen. In some cases, each R20is independently selected from hydrogen; and Cn 6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered saturated heterocycle. In some cases, each R20is independently selected from 5- to 6- membered saturated heterocycle. In some cases, the heterocycle of R20has at least one nitrogen atom. In some cases, the heterocycle of R20has at least one sulfur atom. In some cases, the heterocycle of R20has at least one oxygen atom. In some cases, the heterocycle of R20contains only 1 heteroatom. In some cases, the heterocycle of R20has at least two heteroatoms. In some cases, the heterocycle of R20contains only 2 heteroatoms. In some cases, the optional one or more substituents of R1are independently selected from halogen,. In some cases, the optional one or more substituents of R1are independentlyindependently selected from halogen, and Ci-6 alkyl-N(R20)2. In some cases, the optional one or more substituents of R1are independently selected from halogen,, , and. In some cases, R1is selected from. In some cases, each R20is independently selected from hydrogen, Ci-6 alkyl, and C3-6 carbocycle. In some cases, R1is

[0215] In some embodiments, for a compound or salt of Formula (I), when R1is substituted with -C(O)R20, R20is selected from a 5- to 12-membered heterocycle.

[0216] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), orFormulathe 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, =0, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-e alkynyl, 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, =0, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-e alkynyl, and optionally substituted 5- to 12- membered heterocycle. In some cases, the one or more optional substituents of R1areindependently selected from halogen, -CN, C2-6 alkynyl, -C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from halogen, -C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from -C(=NR20)N(R20)2, and optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from optionally substituted 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R1are independently selected from a 5-membered heterocycle and 9-membered heterocycle, each of which is optionally substituted independently with one or more R1*. In some cases, R1is substituted with at least one halogen atom and optionally substituted with one or more substituents are independently selected from -CN, C2-6 alkynyl, - 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, each of which is optionally substituted with one or more R1*. In some cases, the heterocycle of the one or more optional substituents of R1is selected fromwhich 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, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -N02, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen. In some cases, each R1* is independently selected from Ci-6 alkyl. In some cases, each R1* is independently selected from -OR20. In some cases, each R1* is independently selected from -OH. In some cases, each R1* is independently selected from -OMe. In some cases,

[0217] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), 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-is optionally substituted with one or more R1*. In some cases, the one or more optional

[0218] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), 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(0)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, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R1* is independently selected from halogen, -OR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(0)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, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci- 6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen, and C1-6 alkyl. In some cases, each R1* is independently selected from halogen. In some cases, each R1* is independently selected from C1-6 alkyl.

[0219] In some embodiments, for a compound or salt of Formula (I), 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, C 1-6 cyanoalkyl, Ci-6alkyl, Ci-6alkyl-N(R20)2, C2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 9-membered heterocycle), wherein the 5- to 12- membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R1is selected, , , each of whichis optionally substituted. In some cases, R1is selected -1- , which is optionally substituted. InIn some cases,some cases, R1is selected.

[0220] In some embodiments, for a compound or salt of Formula (I), R1is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10- membered heterocycle or preferably 8-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -NHCN, C I-6 cyanoalkyl, Ci-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 ormore R1*; each R1* is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-memberedheterocycle is substituted. In some cases, R is selected -1- , ~L , and -1- , each of which isoptionally substituted. In some cases, R is selected -1- , which is optionally substituted. In

[0221] In some embodiments, for a compound or salt of Formula (I), R1is selected from

[0222] In some embodiments, for a compound or salt of Formula (I), 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 (I). In some cases, R1is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, -N(R20)2, -C(O)R20, -N02, =0, -CN, Ci-6 alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkynyl, 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents selected from halogen, and Ci-6 alkyl. 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, =0, -CN, Ci-6alkyl- N(R20)2, CI-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle is optionally substituted with one or more substituents selected from

[0223] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted 6- to 11 -membered heterocycle, wherein the 6- to 11 -membered heterocycle has at least one nitrogen atom. In some cases, the one or more optional substituents of R1is selected from halogen, -OR20, -C(O)N(R20)2, -C(O)R20, -S(O)2R20, =0, -Ci-6alkyl(=NOR20), =NO(R20), -CN, -NHCN, Ci-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1* is independently selected from halogen, and Ci-6 alkyl. In some embodiments, R1is selected from

[0224] In some embodiments, for a compound or salt of Formula (I), R1is selected from hydrogen and optionally substituted 5- to 15-membered heterocycle. In some cases, R1is selectedof which is optionally substituted. In some cases, the optional one or more substituents of R1is selected from -OH, =NO(R20), -NHCN, and Ci-6 alkyl. In some cases, R1is selected from

[0225] In some embodiments, for a compound or salt of Formula (I), R1is selected from hydrogen and optionally substituted 7- to 10-membered heterocycle. In some cases, R1is selectedof which is optionally substituted. In some cases, the optional one or more substituents of R1are independently selected from halogen, -NH2, -S(O)2(R20), -C(O)R20, -C(O)N(R20)2, =O,=NO(R20),-CN, -NHCN, C1-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1* is independently selected from halogen, and C1-6 alkyl. In some cases, R1is selected from hydrogen,

[0226] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted 8- to 10-membered heterocycle. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle haswhich is optionally substituted. In some cases, the optional one or more substituents of R1are independently selected from halogen,9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is substituted with at least one R1*, wherein the R1* is selected from halogen, and Ci-6 alkyl. In some cases, the optional one or more substituents of R1are independently selected from chlorine,

[0227] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted bridged 8- to 9-membered heterocycle. In some cases, the heterocycle of R1is selected frommore substituents of R1are selected from halogen, Ci-6 alkyl, -N(R20)2, and Ci-6 aminoalkyl. In

[0228] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted bridged 8-membered heterocycle, wherein the heterocycle contains heteroatoms selected from nitrogen. In some cases, the one or more substituents of R1are selectedfrom C i-6 alkyl, -N(R20)2, and Ci-6 aminoalkyl. In some cases, the heterocycle of R1is selected fromeach of which is optionally substituted. In some cases,, ,

[0229] In some embodiments, for a compound or salt of Formula (I), R1is hydrogen.

[0230] In some embodiments, for a compound or salt of Formula (I), 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 some cases, R1is selected fromeach of which is optionally substituted with one or more substituents. In some cases, R1is selected fromsubstituted 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, =0, =NH, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, -NHCN, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -C(O)N(R20)2, -C(O)NHOR20, -N(R20)2, -C(O)R20, -NO2, =0, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the optional one or more substituents of R1are independently selected from halogen, -OH, C1-6 alkyl, and -C(O)N(R20)2. In some cases, R1is selected from

[0231] In some embodiments, for a compound or salt of Formula (I), R1is an optionally substituted 12- to 15-membered heterocycle. In some cases,whereinRing W is an optionally substituted heterocycle and Ring P is an optionally substituted carbocycle or optionally substituted heterocycle, wherein Ring P forms a spirocycle with Ring W. In some cases, Ring W is an optionally substituted fused heterocycle. In some cases, Ring P and Ring W combine to form a heterocycle having at least 12 atoms and most 15 atoms. In some cases, Ring P and Ring W have in total at least 12 atoms and most 15 atoms. In some cases, RingW is an optionally substituted 10-membered fused heterocycle. In some cases, R1is, wherein Ring P is an optionally substituted carbocycle or optionally 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-C6 carbocycle or optionally substituted 4-to 6- membered heterocycle. In some cases, Ring P forms an optionally substituted C3 carbocycle. In some cases, Ring P forms an optionally substituted 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, =0, =NR20, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of Ring P are independently selected from halogen, -OH, =0, =NH, -CN, and C1-6 alkyl. 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, -N02, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of Ring 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 C1-6 alkyl. 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.

[0232] In some embodiments, for a compound or salt for Formula (I), R1is selected from a 5- to 12-membered bridged heterocycle, which is optionally substituted with one or more substituents. In some cases, R1is selected from an 8-membered bridged heterocycle, which isoptionally substituted with one or more substituents. In some cases, the bridged heterocycle has at least 1 heteroatom. In some cases, the bridged heterocycle has at least 2 heteroatoms. In some cases, the bridged heterocycle has at least 1 nitrogen atom. In some cases, the bridged heterocycle has at least 2 nitrogen atoms. In some cases, the bridged heterocycle has 2 nitrogen atoms. In some cases, R1is selected fromR1is selected from — I— , which is optionally substituted with one or more substituents.

[0233] In some embodiments, for a compound or salt for Formula (I), R1is selected from an unsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents. In some cases, the unsaturated 5- to 12-membered heterocycle is selected fromeach of which is optionally substituted with one or more substituents.

[0234] In some embodiments, for a compound or salt of Formula (I), wherein the 5- to 12- membered heterocycle of R1is unsaturated and a bridged heterocycle. In some cases, R1is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. Insome cases, R1is selected from -J— .

[0235] In some embodiments, for a compound or salt of Formula (I), 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 fromeach of which is optionally substituted with one or more substituents independently selected from halogen, =0, -OH, -CN, -NHCN, -C(O)N(R20)2, - C(O)NR20OR20, C 1-6 aminoalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, and Ci-6 alkyl. In somesome cases, R1is selected fromsubstituted with one or more substituents independently selected from halogen, -OR20, -SR20, - N(R20)2, -NO2, =0, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, and C2-e alkynyl.

[0236] In some embodiments, for a compound or salt of Formula (I), 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-memberedfused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R1is selected from an optionally substituted 10- membered fused heterocycle. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R1is, each of which is optionally substituted with one or more substituents. In some cases,, which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents are independently selected from halogen, =0, -OH, -CN, -NHCN, -C(O)R20, -C(O)N(R20)2, -C(O)NR20OR20, Ci-6aminoalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from halogen, =0, -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 Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered saturated heterocycle. In some cases, the optional one or more substituents of R1are independently selected from

[0237] 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—I— , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and Ci-6 alkyl. Insome cases, R1is selected from — i— , which is substituted with one or more substituents selected from -NHCN, and Ci-6 alkyl. In some cases, R1is selected from, and

[0238] In some embodiments, for a compound or salt of Formula (I), R3is -CN, and R1issubstituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom. In some cases, R3is -CN, and R1is selected from. In some cases, R3is -CN, and R1is selected from . In some cases, R3is -CN,O and R1is selected from. In some cases, R3is -CN, and R1is selected fromsome cases,selected fromoptionally substituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom; and Y-R2is selected from -O-L-heterocycle, wherein the heterocycle portion of -O-L-heterocycle is optionally substituted with one or more R6.

[0239] In some embodiments, for a compound or salt of Formula (I), 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 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-C3 alkyl, -B(OH)2, -OH, -C(0)NH2, -NH2, =0, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-e alkynyl. In some cases,B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selectedselected from halogen and Ci-e haloalkyl. In some cases,which is substituted with one or more substituents selected from halogen. In some cases, B is selected fromwhich 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

[0240] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted unsaturated 10-membered fused heterocycle. In some cases, R1is, which is optionally substituted. In some cases, the optional one or more substituents of R1are independently selected from halogen, =0, -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, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle, wherein the heterocycleeach of which is optionally substituted. In some cases, In some cases, for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =0, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, Y-R2is selected from, wherein the heterocycle portion is optionally substituted. In some cases, n is 0. In some cases, R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OH, -S(O)2(R20), -C(O)R20, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, and Ci-6 alkyl. In some cases, R3is selected from hydrogen, halogen, and -CN.

[0241] In some embodiments, for a compound or salt of Formula (I), R1is selected from an optionally substituted 11 -membered fused heterocycle. In some cases, R1is selected from an optionally substituted unsaturated 11 -membered fused heterocycle. In some cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains 3 heteroatoms. In some cases, theheterocycle is — L~ , which is optionally substituted. In some cases, R1is — L~

[0242] In some embodiments, for a compound or salt of Formula (I), the one or more optional substituents of R1are each independently selected from halogen, -CN, -NO2, =0, - N(R20)2, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -NR20S(O)2R20, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents are independently selected from halogen, -OH, -N(R20)2, -NO2, =0, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the optional substituents for R1are each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the optional substituents for R1are each independently selected from halogen, -CN, -OH, -NH2, C 1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 haloalkyl. . In some cases, the optional substituents for R1are each independently selected from -OH, and -NH2. In some cases, R20is selected from hydrogen and C1-3 alkyl.

[0243] In some embodiments, for a compound or salt for Formula (I), n is selected from 0 to 4. In some cases, n is selected from 0 to 3. In some cases, n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is

[0244] In some embodiments, for a compound or salt for Formula (I), each R4is independently selected from halogen, -NO2, =0, =S, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkynyl, C1-6 cyanoalkyl, and C 1-6 haloalkyl. In some cases, R4is independently selected from halogen, =0, -CN, C1-6 cyanoalkyl, C2-6 alkynyl, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R4is independently selected from halogen, =0, -CN, C1-6 cyanoalkyl, C2-6 alkynyl, and C 1-6 haloalkyl. In some cases, R4is independently selected from -CN, C1-6 cyanoalkyl, and C2-6 alkynyl. In some cases, each R4is independently selected from halogen, -NO2, =0, =S, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C 1-6 hydroxyalkyl, and C1-6 haloalkyl.

[0245] In some embodiments, for a compound or salt for Formula (I), Q is a bond. In some cases, Q is a S. In some cases, Q is a O.

[0246] In some embodiments, for a compound or salt for Formula (I), each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2. In some cases, each R7is independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 hydroxyalkyl.

[0247] In some embodiments, for a compound or salt for Formula (I), each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen and C1-6 alkyl. In some cases, each R20is independently selected from C1-6 alkyl.

[0248] In some embodiments, for a compound or salt for Formula (I), each R21is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen and C1-6 alkyl. In some cases, each R21is independently selected from C1-6 alkyl.

[0249] In some embodiments, for a compound or salt for Formula (I), each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R20is independently selected from hydrogen and C1-6 alkyl. In some cases, each R20is independently selected from C1-6 alkyl.

[0250] In some embodiments, for a compound or salt for Formula (I), each R23is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R23is independently selected from hydrogen and C1-6 alkyl. In some cases, each R23is independently selected from C1-6 alkyl.

[0251] . In an aspect, the present disclosure provides a compound of Formula (I- A)Formula (LA), or a pharmaceutically acceptable salt thereof wherein:R1is selected from 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -Ci-6alkyl(=NOR20), -C(O)R20=0, -CN, -NHCN, Ci- 6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Cn 6 alkyl-SO2R20, Ci-6 alkoxyalkyl, Ci-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -N02, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Cs-Ci2carbocycle;B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -N02, =0, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle;Y is selected from a bond, -0-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Ci-Ce haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-C00H, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C 1-6 alkyl -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C 1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, NMO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSChF, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCFh-, - N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, - CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, - CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -0C(0)NH(Ci- C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CFhheterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(CI-C3 alkyl)(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(0)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=0)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituentsindependently selected from halogen, -OH, -N02, =0, =S, -CN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-ehydroxyalkyl, Ci-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -N02, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0252] In some embodiments, Formula (I) or Formula (I-A) is represented by Formula (I-B),Formula (I-B), or a pharmaceutically acceptable salt thereof wherein: wherein R1is selected fromeach of which is optionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -CI-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 12-memberedheterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C 1-6 haloalkyl, and C1-6 alkyl;Y is -O-;R2is selected from -L-heterocycle, -L-N(R23)2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R6.B is selected from a 7- to 15-membered heterocycle, wherein the 7- to 15-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, =0, -N(R21)2, -OR21, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, and C2-e alkynyl;R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OR20, -C(O)R20, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; and each R20is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, and oxo.

[0253] In some embodiments, a compound or salt of Formula (I), Formula (LA), or Formulaoptionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -CI-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*; and each R1* is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl.

[0254] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), Y is -O-.

[0255] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), R2is selected from optionally substituted -L-heterocycle, and -L-N(R23)2. In some cases, R2is selected from optionally substituted -L- 5-to 8-membered heterocycle, and -L-N(R23)2. In some cases, R2is selected from optionally substituted -L-heterocycle. In some cases, R2is selected from -L-N(R23)2. In some cases, the heterocycle contains at least one nitrogen atom. Insome cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains at least one oxygen atom. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is a saturated heterocycle. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-CI-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl- N(R5)2, -C(O)N(R5)2, -N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, -O-C1-C3 alkyl. In some cases, each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, =CH2, and -O-C1-C3 alkyl. In some cases, when R2is a heteroaryl, R6is selected from halogen and C1-C3 haloalkyl, C1-C3 alkyl. In some cases, when R2is a heteroaryl, R6is selected from a halogen. In some cases, R23is selected from hydrogen and C1-C3 alkyl. In some cases, each R23is selected from C1-C3 alkyl. In some cases, each R23is selected from methyl. In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, andC1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or moresubstituents independently selected from halogen. In some cases, each L is selected from ' »

[0256] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula

[0257] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-memberedheterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl. In some cases, the heterocycle of B is selected fromsubstituted with one or more substituents independently selected from halogen, -CN, -NH2, and

[0258] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), R3is -CN. In some cases, R3is hydrogen. In some cases, R3is halogen. In some cases, R3is fluorine.

[0259] In some embodiments, a compound or salt of Formula (I), Formula (I-A), or Formulawhich is optionally substituted with one or more substituents. In some cases, theone or more optional substituents are independently selected from halogen, -S(O)2(R20), - C(O)N(R20)2, -CI-6 alkyl(=NOR20), -C(O)R20=0, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, the one or more optional substituents are independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -CI-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, the one or more optional substituents are independently selected from halogen, -C(O)N(R20)2, -Ci-6 alkyl(=NOR20), -C(O)R20, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*. In some cases,which is subtituted with at least one substituent. Inindependently selected from halogen, Ci-e haloalkyl, and Ci-6 alkyl.

[0260] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), does not contain an electrophile moiety.

[0261] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), the one or more optional substituents of R1are not electrophiles.

[0262] In some embodiments, for a compound or salt of Formula (I), R1is selected from a compound in the Examples. In some cases, B is selected from a compound in the Examples. In some cases, Y is selected from a compound in the Examples. In some cases, R2is selected from a compound in the Examples. In some cases, R3is selected from a compound in the Examples.

[0263] In some embodiments, for a compound or salt of Formula (I), each R20is selected from hydrogen and C1-3 alkyl. In some cases, each R20is selected from hydrogen and Ci alkyl.

[0264] In some embodiments, the compounds of Formula (I), (I-A), or (I-B) used in the methods include trifluoroacetic acid salts of the above compounds.

[0265] In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 45 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 yearsold. 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.

[0266] In some embodiments, a compound or salt of Formula (I), (I- A), or (I-B) is administered once daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I- B) is administered twice daily. In some embodiments, the compound or salt of Formula (I), (I- A), or (I-B) is administered 3 times daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered once weekly. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered every other day. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered every 3 days.

[0267] In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 10 mg to 150 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) or a salt thereof is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 5 mg to 75 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the compound or salt of Formula (I) is administered to a subject at 15 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0268] In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 150 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B)is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 5 mg to about 75 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 45 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered once daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0269] In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 50 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, twice daily. In some cases, the compound is selected from compounds 2, 3, 4, 14, 25, and 74.

[0270] In some embodiments, the compound or salt of Formula (I), (I- A), or (I-B) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I- A), or (I-B) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 45 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 60 mg, twice daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.

[0271] In some embodiments, a compound of Formula (I), (I-A), or (I-B) is administered as a capsule during the period of time. In some cases, a tablet or capsule formulation of a compound of Formula (I), (I-A), or (I-B) 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 75mg, 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 mgto 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 (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof. In some cases, the compound is selected from compounds 2, 3, 4, 14, 25, and 74.

[0272] In some embodiments, a compound of Formula (I), (I- A), or (I-B) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula (I), (I- A), or (I-B) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (I), (I- A), or (I-B) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg 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 toabout 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 toabout 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 toabout 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg), during a period of time. In some cases, the compound is selected from compounds 2, 3, 4, 14, 25, and 74.

[0273] In some embodiments, the combination therapy comprises oral administration of a compound of Formula (I), (I- A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 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 320mg, 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 to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 400 mg,about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg 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; and4) 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 is an CTLA-4 inhibitor. In some cases, the compound of Formula (I), (I-A), or (I-B) is selected from compounds 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B)is selected compound2, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 4, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74 or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B) is orally administered once daily. In one embodiment, the compound of Formula (I), (I-A), or (I-B) is orally administered twice daily.

[0274] In some embodiments, a compound of Formula (I), (I-A), or (I-B), 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 (I), (I- A), or (I-B) 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 60mg, 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 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 toabout 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 from compounds 2, 3, 4, 14, 25, and 74. In some embodiments, a compound of Formula (I), (I-A), or (I-B) is orally administered once a day (QD) on a daily basis during a period of time. In some embodiments, a compound of Formula (I), (I-A), or (I-B) is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment, a compound of Formula (I), (I-A), or (I-B) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg 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 160mg, 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 about100 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 aboutmg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about500 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; and4) 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 (I), (I- A), or (I-B) is selected compound 2, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 3, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B)is compound 4, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B)is compound 25, or a pharmaceutically acceptable salt of any one thereof. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74 or a pharmaceutically acceptable salt of any one thereof. 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.

[0275] 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.

[0276] 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:

[0277] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,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.

[0278] 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.

[0279] 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,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,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.

[0280] In certain embodiments, the compounds disclosed herein have some or all of theJH 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0287] 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.

[0288] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0289] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques.Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0290] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).Pharmaceutical Formulations

[0291] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”).

[0292] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0293] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, forexample, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0294] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0295] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0296] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0297] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0298] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre- clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg,e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0299] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0300] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0301] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment oftonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0302] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0303] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0304] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringelike applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodiumpropionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0305] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0306] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0307] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0308] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0309] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0310] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0311] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a crosslinked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.

[0312] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water-soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0313] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.

[0314] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell.Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0315] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.KITS AND PRODUCTSImmunomodulator inhibitor combination Kit

[0316] Some embodiments relate to kits and products that include the compound or salt of Formula (I), (I-A), or (I-B) and / or an immunomodulator inhibitor. For example, the kit or product can include a package or container with a compound of Formula (I), (I-A), or (I-B) or pharmaceutically acceptable salt. Such kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I-A), or (I-B) in combination with an immunomodulatorinhibitor that is separately provided....

Claims

CLAIMSWHAT 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 (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein:B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C1-6 alkyl(=NOR20), - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(0)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, -N02, =0, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl-SO2R20, C1-6 alkoxyalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(0)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, =0, =N(R20), =NO(R20), -CN, - NHCN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and Cs-Ci2carbocycle;Y is selected from a bond, -O-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Ci-Ce haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-COOH, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L- N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCI-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, Ci-6 alkyl, C2-6 alkynyl, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 cyanoalkyl, Ci-e hydroxyalkyl, and Ci-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-CI-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, -C1-C3 alkyl-N(R5)2, - C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Ci-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2Ci-Ce alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - 0C(0)NH(CI-C3alkyl)O(Ci-C3alkyl), -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(CI-C3 alkyl)(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -N02, =0, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

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 antigenbinding 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; andAdrenal 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 (I).

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 (I) results in an increased duration of overall survival, an increased duration ofprogression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition, an increased duration of stable disease in the subjects relative to treatment with only the compound or salt of Formula (I), or any combination thereof.

33. The method of any one of claims 1 to 32, wherein the therapeutically effective amount of the compound or salt of Formula (I) 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 (I) 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 (I) are administered on different days.

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

41. The compound or salt of any one of claims 1 to 40, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle.

42. The compound or salt of any one of claims 1 to 41, wherein B is an optionally substituted 8- to 15-membered fused heterocycle.

43. The compound or salt of any one of claims 1 to 42, wherein B is an optionally substituted Cs-Cis fused carbocycle.

44. The compound or salt of any one of claims 1 to 43, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are each independently bicyclic or tricyclic.

45. The compound or salt of any one of claims 1 to 44, wherein the heterocycle or carbocycle of B is bicyclic.

46. The compound or salt of any one of claims 1 to 45, wherein the heterocycle or carbocycle of B is tricyclic.

47. The compound or salt of any one of claims 1 to 46, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fusedwhich is optionally substituted with one or more substituents.

48. The compound or salt of claim 47, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selectedoptionally substituted with one or more substituents.

49. The compound or salt of any one of claims 1 to 48, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, and C1-C3 alkyl.

50. The compound or salt of any one of claims 1 to 49, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected from51. The compound or salt of any one of claims 1 to 46, wherein B is selected from an optionally substituted 5- to 15-membered heterocycle and optionally substituted C3-C15 carbocycle.

52. The compound or salt of claim 51, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle.

53. The compound or salt of claim 52, wherein B is an optionally substituted 8- to 15- membered fused heterocycle.

54. The compound or salt of claim 52, wherein B is an optionally substituted unsaturated Cs-Cis fused carbocycle.

55. The compound or salt of any one of claims 51 to 54, wherein for B, the heterocycle and carbocycle are each independently bicyclic or tricyclic.

56. The compound or salt of claim 55, wherein for B, the heterocycle and carbocycle are each independently bicyclic.

57. The compound or salt of claim 55, wherein for B, the heterocycle and carbocycle are each independently tricyclic.

58. The compound or salt of any one of claims 51 to 55, wherein B is selected fromoptionally substituted with one or more substituents.

59. The compound or salt of claim 58, wherein B is selected fromeach of which is optionally substituted with one or more substituents.

60. The compound or salt of claim 59, wherein B is selected from, and, each of which is optionally substituted with one or more substituents.

61. The compound or salt of any of claims 51 to 60, wherein for B, the one or more optional substituents are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

62. The compound or salt of claim 61, wherein B is selected from,63. The compound or salt of any of claims 1 to 60, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, - NHCN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.

64. The compound or salt of claim 63, 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-C3 alkyl, -B(0H)2, -OH, -O-C1-C3 haloalkyl, -C(0)NH2, -NH2, =0, -CN, C1-6 alkoxy, Ci-e hydroxyalkyl, and C2-6 alkynyl.

65. The compound or salt of claims 63 or 64, wherein B is selected from66. The compound or salt of any one of claims 1 to 46, wherein B is an optionally substituted 7- to 12-membered fused heterocycle.

67. The compound or salt of any one of claims 1 to 46, wherein B is an optionally substituted 7- to 11 -membered fused heterocycle.

68. The compound or salt of claims 66 or 67, wherein B is an optionally substituted8- to 10-membered fused heterocycle.

69. The compound or salt of claim 68, wherein B is an optionally substituted 8- to 9- membered fused heterocycle.

70. The compound or salt of claims 66 or 67, wherein the heterocycle is an unsaturated heterocycle.

71. The compound or salt of any one of claims 66 to 70, wherein B has at least one sulfur atom.

72. The compound or salt of any one of claims 66 to 71, wherein B has at least one sulfur atom and at least one nitrogen atom.

73. The compound or salt of any one of claims 66 to 71, wherein B has at least one sulfur atom and at least one oxygen atom.

74. The compound or salt of any one of claims 66 to 71, wherein B has at two sulfur atoms.

75. The compound or salt of any one of claims 66 to 74, wherein B is selected fromsubstituted.

78. The compound or salt of any one of claims 66 to 77, wherein the one or more optional substituents of B, are independently selected at each occurrence from halogen, oxo, - NH2, C1-C3 alkyl, -B(OH)2, -OH, -O-C1-C3 haloalkyl, -C(O)NH2, -NH2, =0, -CN, Ci-6alkoxy,C1-6 hydroxyalkyl, and C2-e alkynyl.

79. The compound or salt of claim 78, wherein the one or more optional substituents of B, are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN.

80. The compound or salt of any one of claims 66 to 76, wherein B is selected from81. The compound or salt of any one of claims 1 to 46, wherein B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle.

82. The compound or salt of claim 81, wherein the heterocycle of B has at least one sulfur atom.

83. The compound or salt of claim 81 or 82, wherein the heterocycle of B has one or sulfur atoms.

84. The compound or salt of claim 83, wherein the heterocycle of B has at least one nitrogen atom.

85. The compound or salt of any one of claims 81 to 84, wherein B is selected from86. The compound or salt of any one of claims 81 to 85, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, -NHCN, Ci-6aminoalkyl, Ci-6alkoxy,C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-e alkynyl.

87. The compound or salt of any one of claims 81 to 85, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, -NH2, =0, and -CN.

88. The compound or salt of claim 87, wherein B is selected from89. The compound or salt of any one of claims 1 to 46, wherein B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom.

90. The compound or salt of claim 89, wherein B is selected fromeach of which is optionally substituted.

91. The compound or salt of claims 89 or 90, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, - OR20, -C(O)N(R20)2, -N(R20)2, =0, -CN, -NHCN, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-e alkynyl.

92. The compound or salt of claim 91, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN.

93. The compound or salt of any one of claims 89 to 92, wherein B is substituted.

94. The compound or salt of any one of claims 89 to 92, wherein B is substituted with at least one -NH2.

95. The compound or salt of any one of claims 89 to 94, wherein B is selected from96. The compound or salt of any one of claims 89 to 94, wherein B is substituted with at least one -NH2 at least one -CN.

97. The compound or salt of claim 96, wherein B is selected from,98. The compound or salt of any one of claims 1 to 97, wherein R3is selected from hydrogen, halogen, -CN, -C(O)R22, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, and Ci-6 alkyl.

99. The compound or salt of claim 98, wherein R3is selected from hydrogen, fluorine, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-6 alkyl.

100. The compound or salt of claims 98 or 99, wherein R3is selected from hydrogen, fluorine, and -CN.

101. The compound or salt of claim 100, wherein R3is selected from fluorine.

102. The compound or salt of claim 100, wherein R3is selected from hydrogen.

103. The compound or salt of claim 100, wherein R3is selected from -CN.

104. The compound or salt of any one of claims 1 to 103, wherein Y is -O-.

105. The compound or salt of any one of claims 1 to 104, wherein L is selected fromC1-C4 alkylene.

106. The compound or salt of claim 105, wherein L is selected from unsubstituted Ci- C4 alkylene.

107. The compound or salt of claim 105, wherein each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 haloalky 1.

108. The compound or salt of claim 107, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and Ci-e haloalkyl.

109. The compound or salt of any one of claims 104 to 108, wherein L is selected from110. The compound or salt of claim 109, wherein L is selected from111. The compound or salt of claim 107 or 108, 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-C6 carbocycle 3- to 5-membered heterocycle.

112. The compound or salt of claim 111, wherein each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen.

113. The compound or salt of claim 112, wherein each L is independently selected114. The compound or salt of claim 113, wherein each L is independently selected115. The compound or salt of claim 114, wherein each L is independently selected116. The compound or salt of claim 105, wherein each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen and C1-C4 alkyl.

117. The compound or salt of claim 116, wherein L is selected from118. The compound or salt of claim 105, wherein each L is independently selected from an unsubstituted C1-C4 alkylene.

119. The compound or salt of claim 118, wherein L is selected from120. The compound or salt of claim 119, wherein L is selected from121. The compound or salt of any one of claims 1 to 120, wherein R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R23)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

122. The compound or salt of claim 121, wherein R2is -L-heterocycle, wherein the heterocycle portion of R2is an optionally substituted heterocycle.

123. The compound or salt of claim 121 or 122, wherein R2is -L-heterocycle, optionally substituted with one or more R6.

124. The compound or salt of any one of claims 1 to 123, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

125. The compound or salt of any one of claims 121 to 124, wherein the heterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and Ci- C3 aminoalkyl.

126. The compound or salt of claim 125, wherein the heterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen.

127. The compound or salt of any one of claims 1 to 126, wherein Y-R2is selected128. The compound or salt of any one of claims 1 to 124, wherein Y-R2is selected fromwherein the heterocycle portion is optionally substituted with one or more R6.

129. The compound or salt of claim 128, wherein R6of R2is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl.

130. The compound or salt of claim 129, wherein R6of R2is independently selected at each occurrence from C1-C3 alkyl and halogen.

131. The compound or salt of claim 130, wherein Y-R2is selected from132. The compound or salt of any one of claims 1 to 121, wherein Y-R2is selected, eterocycle portion is optionally substituted with one or more R6.

133. The compound or salt of claim 132, wherein Y-R2selected from O134. The compound or salt of claim 133, wherein Y-R2is selected from, wherein the heterocycle is optionally substituted.

135. The compound or salt of claim 134, wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 alkyl, - N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, OXO, =NO-CI-C3alkyl, -CH2OC(O)heterocycle, - CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

136. The compound or salt of claims 1 or 134-135, wherein Y-R2is selected from137. The compound or salt of claim 121, wherein R2is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7.

138. The compound or salt of claim 137, wherein each R7is independently selected from halogen, and C1-C4 haloalkyl;139. The compound or salt of claim 138, wherein Y-R2is selected from140. The compound or salt of claim 121, wherein R2is -L-aryl, optionally substituted with one or more R7.

141. The compound or salt of claim 140, wherein Y-R2is selected from erein the heterocycle portion is optionally substituted with one or more R7. mpound or salt of claim 141, wherein Y-R2is selected from143. The compound or salt of claim 121, wherein R2is -L-heteroaryl, optionally substituted with one or more R7.O'144. The compound or salt of claim 143, wherein Y-R2is selected from HN-^ , wherein the heteroaryl portion is optionally substituted with one or more145. The compound or salt of claims 143 or 144, wherein Y-R2is selected from146. The compound or salt of claim 121, wherein R2is -L-N(R23)2.

147. The compound or salt of claim 146, wherein Y-R2is selected from148. The compound or salt of claim 147, wherein R2is heterocycle, optionally substituted with one or more R6.

149. The compound or salt of claim 148, wherein150. The compound or salt of claim 121, wherein Y-R2is151. The compound or salt of any one of claims 1 to 120, wherein R2is selected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L- heterocycle, are each optionally substituted with one or more R6; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; and -L-N(R23)2.

152. The compound or salt of claim 151, wherein the heterocycle of R2is selectedwherein the heterocycle of R2is optionallysubstituted with one or more R6; wherein the aryl and heteroaryl of R2is selected from, wherein the aryl and the heteroaryl are each optionally substituted with one or more153. The compound or salt of claim 152, wherein the heterocycle of R2is selected, wherein the heterocycle is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected from154. The compound or salt of any one of claims 151 to 153, wherein each R6is independently selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, -N(R5)S(O)2(R5), - OC(O)N(R5)2, =CH2, OXO, =N0-CI-C3 alkyl, -CH2OC(O)heterocycle, -Ckhheterocycle, - CH2OC(O)N(R5)2, and -O-Ci-Cs alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from C1-C3 alkyl, halogen and C1-C3 haloalkyl.

155. The compound or salt of any one of claims 151-154, wherein the heterocycle ofR2, the aryl and heteroaryl of R2, and -N(R20)2 of R2is selected from is selected from-L-heterocycle, are each optionally substituted with one or more R6;the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with157. The compound or salt of any one of claims 151-156, wherein Y-R2is selected158. The compound or salt of any one of claims 1-157, wherein Y-R2is selected from159. The compound or salt of any one of claims 1, wherein Y is -O- and R2is selected from L-5-membered heteroaryl, wherein L is selected from an optionally substituted C1-C4 alkylene, and wherein the heteroaryl is optionally substituted with one or more R7, wherein each R7is preferably selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl.

160. The compound or salt of any one of claims 159, wherein Y-R2is selected from161. The compound or salt of any one of claims 1 to 158, 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, =0, -CN, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and Ci-e haloalkyl.

162. The compound or salt of claim 159, 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, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, and Ci-e haloalkyl.

163. The compound or salt of any one of claims 1 to 161, wherein R1is an optionally substituted 5- to 12-membered heterocycle.

164. The compound or salt of claim 163, wherein the 5- to 12-membered heterocycle of R1is unsaturated.

165. The compound or salt of claim 163, wherein the 5- to 12-membered heterocycle of R1is saturated.

166. The compound or salt of claim 163, wherein the 5- to 12-membered heterocycle of R1is bridged.

167. The compound or salt of claim 163, wherein the 5- to 12-membered heterocycle of R1is a spiro heterocycle.

168. The compound or salt of claim 163, wherein the 5- to 12-membered heterocycle of R1is non-aromatic.

169. The compound or salt of any one of claims 1 to 168, wherein R1is selected from170. The compound or salt of claim 169, wherein the optional one or more substituents are each independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =0, -CN, C1-6 hydroxyalkyl, and C1-6 haloalkyl.

171. The compound or salt of claim 170, wherein R1is selected fromf which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, =0, -CN, Ci-e hydroxyalkyl, and C 1-6 haloalkyl.

172. The compound or salt of claim 1, wherein R1is selected from173. The compound or salt of any one of claims 1 to 168, wherein R1is selected from 6- to 8-membered heterocycle, which is optionally substituted.

174. The compound or salt of claim 173, 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.

175. The compound or salt of claim 174, wherein R1is selected fromeach of which is optionally substituted.

176. The compound or salt of claim 175, wherein the one or more optional substituents are independently selected from -OH, -CN, oxo, Ci-6 cyanoalkyl.

177. The compound or salt of claims 175 or 176, wherein R1is selected from178. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted 6- to 7-membered heterocycle.

179. The compound or salt of claim 178, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle is optionally substituted.

180. The compound or salt of 179, wherein the 6- to 7-membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom.

181. The compound or salt of any one of claims 178 to 180, wherein R1is selected from an optionally substituted unsaturated 6-membered heterocycle.

182. The compound or salt of any one of claims 178 to 181, wherein R1is selected from an optionally substituted unsaturated 7-membered heterocycle.

183. The compound or salt of any one of claims 178 to 182, wherein R1is selected from, any of which is optionally substituted.

184. The compound or salt of any one of claims 178, wherein R1is selected from, any of which is optionally substituted.

185. The compound or salt of any one of claims 178 to 184, wherein the one or more optional substituents of R1are each independently selected from halogen, -OR20, -N(R20)2, =0, -CN, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C1-6 alkyl, -NHCN, and C2-e alkynyl.

186. The compound or salt of any one of claims 178 to 185, each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

187. The compound or salt of any one of claims 178 to 186, wherein the one or more optional substituents of R1are each independently selected from halogen.

188. The compound or salt of any one of claims 178 to 187, wherein R1is selected189. The compound or salt of any one of claims 178 to 184, wherein R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 haloalkyl, and C1-6 alkyl.

190. The compound or salt of claim 189, wherein R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.

191. The compound or salt of claim 190, wherein R1is selected from, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.

192. The compound or salt of claim 191, wherein R1is selected from193. The compound or salt of claim 184, wherein R1is selected from —J-— , which is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 haloalkyl, and C1-6 alkyl.

194. The compound or salt of claim 193, wherein R1is selected from, which is optionally substituted with one or more substituents independently selected from halogen.

195. The compound or salt of claim 194, wherein R1is selected from196. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted 6- to 7-membered heterocycle.

197. The compound or salt of claim 196, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur.

198. The compound or salt of claim 197, wherein the optionally one or more additional heteroatoms are selected from sulfur.

199. The compound or salt of any one of claims 196 to 198, wherein the 6- to 7- membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms.

200. The compound or salt of any one of claims 196 to 199, wherein the 6- to 7- membered heterocycle is a non-aromatic 6- to 7-membered heterocycle.

201. The compound or salt of any one of claims 196 to 200, wherein the 6- to 7- membered heterocycle of R1is bound to Formula (I) via the only 1 nitrogen atom.

202. The compound or salt of any one of claims 196 to 201, wherein R1is selected from, each of which is optionally substituted.

203. The compound or salt of any one of claims 196 to 202, wherein the one or more optional substituents of R1are each independently selected from halogen, -OH, -CN, Ci-6 cyanoalkyl, -NHCN, Ci-6 alkyl, oxo, and C2-e alkynyl.

204. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted 6- to 10-membered heterocycle.

205. The compound or salt of claim 204, wherein R1is selected from, each of which is optionally substituted.

206. The compound or salt of claim 205, wherein the one or more optional substituents are independently selected from halogen, =0, -OH, -C(O)N(R20)2, C2-6 alkynyl, -NHCN, -CN, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl.

207. The compound or salt of claims 205 or 206, wherein R1is selected from208. The compound or salt of any one of claims 1 to 168, wherein R1is selected from a 7- to 11 -membered spiro heterocycle.

209. The compound or salt of claim 208, wherein R1is selected from a 10-membered spiro heterocycle.

210. The compound or salt of claims 208 or 209, wherein the spiro heterocycle has at least 3 nitrogen atoms.H211. The compound or salt of claim 210, wherein R1is selected from, and, each of which is optionally substituted.H212. The compound or salt of claim 211, wherein R1is selected from, and, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NO2, =0, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, Ci-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-e alkynyl.

213. The compound or salt of claim 212, wherein R1is selected from214. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted unsaturated 9- to 11 -membered heterocycle.

215. The compound or salt of claim 214, wherein R1is selected from an optionally substituted unsaturated 10-membered heterocycle.

216. The compound or salt of claims 214 or 215, wherein, which is optionally substituted.

217. The compound or salt of claim 216, wherein, which is optionally substituted with one or more substituents selected from halogen, -OH, -C(O)N(R20)2, - C(O)NHOR20, -N(R20)2, -C(O)R20, -N02, =0, -CN, Ci-6aminoalkyl, Ci-6alkoxy, Ci-6hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, and C2-e alkynyl.

218. The compound or salt of claim 217, wherein R1is selected fromeach of which is further optionally substituted with one or more substituents selected from halogen, -OH, -N(R20)2, =0, -CN, C i-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, and C2-e alkynyl.

219. The compound or salt of any one of claims 214 to 216, 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(O)NHOR20, -N(R20)2, - C(O)R20, -NO2, =0, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, and C2-e alkynyl.

220. The compound or salt of claims 216 or 219, wherein R1is selected fromsubstituted.

221. The compound or salt of claim 220, wherein R1is selected from222. The compound or salt of claim 216, wherein the one or more optional substituents of R1are independently selected from halogen, -OH, -N(R20)2, =0, -CN, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, -C(O)N(R20)2, Ci-6 alkyl, and C2-6 alkynyl.

223. The compound or salt of claim 222, wherein the one or more optional substituents of R1are independently selected from halogen, and -C(O)N(R20)2.

224. The compound or salt of claim 223, wherein R1is selected from225. The compound or salt of claim 224, wherein226. The compound or salt of claim 224, wherein227. The compound or salt of claim 216, wherein the one or more optional substituents of R1are independently selected from halogen, Ci-6 alkyl, Ci-6 alkyl-N(R20)2, -C(O)NR20OR20, -C(O)N(R20)2, and -C(O)R20.

228. The compound or salt of claims 227, wherein the one or more optional substituents of R1are selected from chlorine,229. The compound or salt of claim 228, wherein R1is selected from230. The compound or salt of any one of claims 214 to 216, wherein the one or more optional substituents of R1are independently selected from halogen, -N(R20)2, -CN, Ci-6 alkyl, Ci-6 cyanoalkyl, Ci-6 alkyl-N(R20)2, Ci-6 alkyl-SCh-Ci-e alkyl, C2-6 alkenyl, - C(O)NR20OR20, -C(O)N(R20)2, -C(O)R20, and 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted independently with one or more R1*, wherein each R1* is independently selected from halogen, -OR20, and C1-6 alkyl.

231. The compound or salt of claims 216 or 230, wherein the one or more optional substituents of R1are selected from chlorine, -NH2, -CN, Ci alkyl, C2 alkenyl,o o o o o233. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted 6- to 11 -membered heterocycle, wherein the 6- to 11 -membered heterocycle has at least one nitrogen atom.

234. The compound or salt of claim 233, wherein the one or more optional substituents of R1is selected from halogen, -OR20, -C(O)N(R20)2, -C(O)R20, -S(O)2R20, =0, -Ci-6alkyl(=NOR20), =NO(R20), -CN, -NHCN, Ci-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1* is independently selected from halogen, and Ci-6 alkyl.

235. The compound or salt of claim 233, wherein R1is selected from238. The compound or salt of any one of claims 1 to 168, wherein R1is selected from hydrogen and optionally substituted 5- to 15-membered heterocycle.

239. The compound or salt of claims 238, wherein R1is selected fromeach of which is optionally substituted.

240. The compound or salt of claim 239, wherein the optional one or more substituents ofR1is selected from -OH, =NO(R20), -NHCN, and Ci-6 alkyl.

241. The compound or salt of any one of claims 238 to 240, wherein R1is selected242. The compound or salt of any one of claims 1 to 168, wherein R1is selected from hydrogen and optionally substituted 7- to 10-membered heterocycle.

243. The compound or salt of claim 242, wherein R1is selected from hydrogenoptionally substituted.

244. The compound or salt of claims 242 or 243, wherein the optional one or more substituents of R1are independently selected from halogen, -NH2, -S(O)2(R20), -C(O)R20, - C(O)N(R20)2, =O,=NO(R20), -CN, -NHCN, C1-6 alkyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R1*; and wherein each R1* is independently selected from halogen, and C1-6 alkyl.

245. The compound or salt of any one of claims 242 to 244, wherein R1is selected246. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted 8- to 10-membered heterocycle.

247. The compound or salt of claim 246, wherein the heterocycle is bicyclic.

248. The compound or salt of claims 246 or 247, wherein the heterocycle has at least one nitrogen atom.

249. The compound or salt of claims 246 or 247, wherein the heterocycle has at least two nitrogen atoms.

250. The compound or salt of any one of claims 246 to 249,each of which is optionally substituted.

251. The compound or salt of any one of claims 246 or 250, wherein the optional one or more substituents of R1are independently selected from halogen,-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is substituted with at least one R1*, wherein the R1* is selected from halogen, and Ci-6 alkyl.

252. The compound or salt of any one of claims 246 or 251, wherein the optional one or more substituents of R1are independently selected from chlorine,254. The compound or salt of any one of claims 1 to 168, wherein R1is an optionally substituted 12- to 15-membered heterocycle.

255. The compound or salt of claim 254, wherein R1is an optionally substituted 12- membered heterocycle.

256. The compound or salt of claim 255, wherein R1is an optionally substituted 13- membered heterocycle.

257. The compound or salt of claim 256, wherein R1is an optionally substituted 14- membered heterocycle.

258. The compound or salt of claim 257, wherein R1is an optionally substituted 15- membered heterocycle.

259. The compound or salt of any one of claims 254 to 258, wherein the heterocycle of R1is tricyclic.

260. The compound or salt of any one of claims 254 to 259, wherein the heterocycle of R1contains a fused heterocycle.

261. The compound or salt of any one of claims 254 to 260, wherein the heterocycle of R1contains a spiro heterocycle.

262. The compound or salt of any one of claims 254 to 261, wherein the heterocycle of R1contains a fused and spiro-heterocycle.

263. The compound or salt of any one of claims 254 to 262, wherein the heterocycle of R1is an unsaturated heterocycle.

264. The compound or salt of any one of claims 254 to 263, wherein the heterocycle of R1is a non-aromatic heterocycle.

265. The compound or salt of any one of claims 254 to 264, wherein the heterocycle of R1has at least one double bond.

266. The compound or salt of any one of claims 254 to 265, wherein the heterocycle of R1has at least two double bonds.

267. The compound or salt of any one of claims 254 to 266, wherein the heterocycle of R1has two double bonds.

268. The compound or salt of any one of claims 254 to 267, wherein R1is selectedsubstituents.

269. The compound or salt of claim 268, 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, =0, -CN, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, and C2-6 alkynyl.

270. The compound or salt of claim 269, wherein the optional one or more substituents are selected from halogen, -OH, Ci-6 alkyl, and -C(O)N(R20)2.

271. The compound or salt of any one of claims 254 to 270, wherein R1is selected272. The compound or salt of any one of claims 1 to 168, 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 Ci-6 alkyl.

273. The compound or salt of claim 272, wherein R1is selected from274. The compound or salt of any one of claims 1 to 168, wherein R1is selected from an optionally substituted bridged 8- to 9-membered heterocycle.

275. The compound or salt of claim 274, wherein the heterocycle of R1is selected fromeach of which is optionally substituted.

276. The compound or salt of claims 274 or 275, wherein the one or more substituents of R1are selected from halogen, Ci-6 alkyl, -N(R20)2, and Ci-6 aminoalkyl.

277. The compound or salt of any one of claims 274 to 276, wherein R1is selected278. The compound or salt of claim 274, wherein R1is selected from an optionally substituted bridged 8-membered heterocycle, wherein the heterocycle contains heteroatoms selected from nitrogen.

279. The compound or salt of claim 278, wherein the one or more substituents of R1are selected from Ci-6 alkyl, -N(R20)2, and Ci-6 aminoalkyl.

280. The compound or salt of claim 279, wherein the heterocycle of R1is selected from each of which is optionally substituted. ound or salt of any one of claims 278 to 280, wherein R1is selected ound or salt of claims 1 to 168, or 281, wherein R1is selected from283. The compound or salt of any one of claims 1 to 163, wherein R1is hydrogen.

284. The compound or salt of any one of claims 1 to 283, wherein n is 0.

285. 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- A):Formula (I- A), or a pharmaceutically acceptable salt thereof wherein:R1is selected from 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -Ci-6alkyl(=NOR20), -C(O)R20, =0, -CN, -NHCN, Ci- 6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Cn 6 alkyl-SO2R20, Ci-6 alkoxyalkyl, Ci-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, - OC(O)R20, -OC(O)N(R20)2, -N02, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6alkyl-N(R20)2, Ci-6aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Cs-Ci2carbocycle;B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15-membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -N02, =0, -N(R21)2, -B(OR21)2, - OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, CI-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-Ci2carbocycle and 5- to 12-membered heterocycle;Y is selected from a bond, and -0-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Ci-Ce haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-C00H, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L-N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCi-Ce alkyl, wherein the heterocycle, the heterocycle portion of-L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, aryl portion of -L-NR23C(O)-aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C 1-6 alkyl -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C 1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, NMO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSChF, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCFh-, - N(R5)2, (C1-C3 alkoxy)Ci-C3alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OCI-C6alkyl, - CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, - CH2OC(O)heterocycle, -OC(O)N(R5)2, -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl), -0C(0)NH(Ci- C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -0C(0)NH(Ci-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, and -CFhheterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(CI-C3 alkyl)(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(0)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=0)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl,C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, Ci-ehydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, Ci-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

286. The compound or salt of claim 285, wherein Formula (I-A) is represented by Formula (I-B),Formula (I-B), or a pharmaceutically acceptable salt thereof wherein:wherein R1is selected fromeach of which is optionally substituted with one or more substituents independently selected from halogen, - S(O)2(R20), -C(O)N(R20)2, -CI-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -OR20, -N(R20)2, -NO2, =0, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C 1-6 haloalkyl, and C1-6 alkyl;Y is -0-;R2is selected from -L-heterocycle, and -L-N(R23)2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R6.B is selected from a 7- to 15-membered heterocycle, wherein the 7- to 15-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, =0, -N(R21)2, -OR21, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, and C2-e alkynyl;R3is selected from hydrogen, halogen, -CN, -N(R20)2, -OR20, -C(O)R20, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; and each R20is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, and oxo.H287. The compound or salt of claims 285 or 286, wherein R1is selected fromoptionally substituted with one or more substituents independently selected from halogen, -S(O)2(R20), -C(O)N(R20)2, -Ci-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*; and each R1* is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl.

288. The compound or salt of any one of claims 285 to 287, wherein Y is -O-.

289. The compound or salt of any one of claims 285 to 288, wherein each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, and C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 4- to 6- membered heterocycle, wherein the C3-C6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen.

290. The compound or salt of any one of claims 285 to 289, wherein each L is selected291. The compound or salt of any one of claims 285 to 290, wherein Y-R2is selectedThe compound or salt of any one of claims 285 to 291, wherein B is selected from an optionally substituted 8- to 10-membered heterocycle.

293. The compound or salt of claim 292, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl.

294. The compound or salt of any one of claims 285 to 293, wherein the heterocycle ofB is selected from295. The compound or salt of any one of claims 285 to 294, whereineach of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl.

297. The compound or salt of any one of claims 285 to 296, wherein R3is -CN.

298. The compound or salt of any one of claims 285 to 297, whereinwhich is optionally substituted with one or more substituents.

299. The compound or salt of any one of claims 285 to 297, wherein300. The compound or salt of any one of claims 285 to 297, wherein301. The compound or salt of any one of claims 285 to 297, wherein302. The compound or salt of any one of claims 285 to 301, wherein the one or more optional substituents of R1are independently selected from halogen, -S(O)2(R20), -C(O)N(R20)2, -Ci-6 alkyl(=NOR20), -C(O)R20=0, and 5- to 9-membered heterocycle, wherein the 5- to - membered heterocycle are each optionally substituted independently with one or more R1*.

303. The compound or salt of any one of claims 285 to 301, wherein the one or more optional substituents of R1are independently selected from halogen, -S(O)2(R20), -C(O)N(R20)2, - Ci-6 alkyl(=NOR20), -C(O)R20, =0, and 5- to 9-membered heterocycle, wherein the 5- to - membered heterocycle are each optionally substituted independently with one or more R1*.

304. The compound or salt of any one of claims 285 to 301, wherein the one or more optional substituents of R1are independently selected from halogen, -C(O)N(R20)2, -Ci-6 alkyl(=NOR20), -C(O)R20, and 5- to 9-membered heterocycle, wherein the 5- to -membered heterocycle are each optionally substituted independently with one or more R1*.

305. The compound or salt of claim 304, wherein each R1* is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl.

306. The compound or salt of any one of claims 285 to 298, whereinwhich is subtituted with at least one substituent.

307. The compound or salt of any one of claims 285 to 298, wherein R1is309. A pharmaceutical composition comprising the compound of any one of claims 1 to 308 and a pharmaceutically acceptable excipient.

310. A method of treating a disease or disorder, using a compound or salt of any one of claims 1 to 308 or a pharmaceutical composition of claim 309.

311. A method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of any one of claims 1 to 308 or a pharmaceutical composition of claim 309.

312. A method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of any one of claims 1 to 308 or a pharmaceutical composition of claim 309.

313. A method of inhibiting KRas G12D and / or other G12 alleles, using a compound or salt of any one of claims 1 to 308 or a pharmaceutical composition of claim 309.

314. A method of inhibiting KRas G12D and / or other alleles, using a compound or salt of any one of claims 1 to 308 or a pharmaceutical composition of claim 309.

315. Use of a compound of any one of claims 1 to 308 thereof in the preparation of a target protein degrading compound by using chemical modification of compound of any one of claims 1-308.

316. A bifunctional compound composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, wherein the target protein-binding moiety is derived from the compound of any of claims 1 to 308.

317. 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, and 111, or a pharmaceutically acceptable salt of anyone thereof.

318. The method of claims 285 or 317, wherein the immunomodulator inhibitor is a PD-1 inhibitor.

319. The method of claim 318, wherein the PD-1 inhibitor is an antibody or antigenbinding fragment.

320. The method of claim 318, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof.

321. The method of claim 318, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.

322. The method of claims 320 or 321, wherein the therapeutically effective amount of nivolumab or biosimilar thereof in the combination is about 240 mg administered every two weeks.

323. The method of claims 320 or 321, wherein the therapeutically effective amount of nivolumab, or biosimilar thereof, in the combination is about 480 mg administered every four weeks.

324. The method of claim 320, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.

325. The method of claim 324, wherein the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 200 mg administered every three weeks.

326. The method of claim 320, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof.

327. The method of claims 285 or 317, wherein the immunomodulator inhibitor is a PD-L1 inhibitor.

328. The method of claim 327, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof.

329. The method of claim 328, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.

330. The method of claims 285 or 317, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor.

331. The method of any one of claims 285 to 330, wherein the immunomodulator inhibitor is administered orally.

332. The method of any one of claims 285 to 331, 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; andAdrenal glands: neuroblastoma.

333. The method of any one of claims 285 to 332, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

334. The method of any one of claims 285 to 332, wherein the cancer is non-small cell lung cancer.

335. The method of any one of claims 285 to 332, wherein the cancer is small cell lung cancer.

336. The method of any one of claims 285 to 332, wherein the cancer is colorectal cancer.

337. The method of any one of claims 285 to 332, wherein the cancer is rectal cancer.

338. The method of any one of claims 285 to 332, wherein the cancer is pancreatic cancer.

339. The method of any one of claims 285 to 332, wherein the cancer is a solid tumor cancer.

340. The method of any one of claims 285 to 339, wherein the cancer is selected from a KRas mutant-associated cancer.

341. The method of any one of claims 285 to 339, wherein the cancer is selected from a KRas wildtype-associated cancer.

342. The method of any one of claims 285 to 341, wherein the cancer is selected from a KRas G12D-associated cancer, a KRas G12V-associated cancer, and a KRas wildtype- associated cancer.

343. The method of any one of claims 285 to 342, wherein the cancer is a KRas G12D- associated cancer.

344. The method of any one of claims 285 to 342, wherein the cancer is a KRas G12V- associated cancer.

345. The method of any one of claims 341 to 344, wherein the KRas wildtype is hyperactivated.

346. The method of any one of claims 285 to 345, wherein the immunomodulator inhibitor synergistically increases the sensitivity of cancer cells to the compound or salt of Formula (I).

347. The method of any one of claims 317 to 346, wherein the compound is selected from compounds 2, 3, 4, 14, 25, and 74, or a pharmaceutical salt thereof.

348. The method of any one of claims 317 to 346, wherein the compound is compound 74, or a pharmaceutical salt thereof.

349. The method of any one of claims 317 to 346, wherein the compound is compound 25, or a pharmaceutical salt thereof.

350. The method of any one of claims 317 to 346, wherein the compound is selected from compound 14, or a pharmaceutical salt thereof.

351. The method of any one of claims 317 to 346, wherein the compound is selected from compound 4, or a pharmaceutical salt thereof.

352. The method of any one of claims 317 to 346, wherein the compound is selected from compound 3, or a pharmaceutical salt thereof.

353. The method of any one of claims 317 to 346, wherein the compound is selected from compound 2, or a pharmaceutical salt thereof.

354. 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.

355. The method of claim 354, wherein the KRas associated cancer is a KRas G12D- associated cancer.

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

357. The method of claim 354, wherein the KRas associated cancer is a KRas wildtype-associated cancer.

358. The method of claim 354, wherein the compound is selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of anyone thereof.

359. The method of any one of claims 317 to 358, wherein the immunomodulator is selected from a checkpoint inhibitor.

360. The method of any one of claims 317 to 358, wherein the immunomodulator is selected from a PD-l / PD-Ll pathway inhibitor.

361. 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, and111, or a pharmaceutically acceptable salt of anyone thereof.

362. 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 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of any one thereof.

363. The method of claim 316, wherein the compound is compound 2.

364. The method of claim 316, wherein the compound is compound 3.

365. The method of claim 316, wherein the compound is compound 4.

366. The method of claim 316, wherein the compound is compound 14.

367. The method of claim 316, wherein the compound is compound 25.

368. The method of claim 316, wherein the compound is compound 74.

369. The method of any one of claims 362 to 368, wherein the immunomodulator inhibitor is a PD-1 inhibitor.

370. The method of claim 369, wherein the PD-1 inhibitor is an antibody or antigenbinding fragment.

371. The method of claim 369, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, and a biosimilar thereof.

372. The method of claim 369, wherein the PD-1 inhibitor is nivolumab or a biosimilar thereof.

373. The method of claim 369, wherein the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.

374. The method of claim 369, wherein the wherein the PD-1 inhibitor is cemiplimab or a biosimilar thereof.

375. The method of any one of claims 362 to 368, wherein the immunomodulator inhibitor is a PD-L1 inhibitor.

376. The method of claim 375, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and a biosimilar thereof.

377. The method of claim 376, wherein the PD-L1 inhibitor is atezolizumab or a biosimilar thereof.

378. The method of any one of claims 362 to 368, wherein the immunomodulator inhibitor is a CTLA-4 inhibitor.

379. The method of any one of claims 361 to 378, wherein the combination exhibits synergy.

380. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an immunomodulator inhibitor and a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein:B is selected from a 7- to 15-membered heterocycle and C7-C15 carbocycle, wherein the 7- to 15- membered heterocycle and C7-C15 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, -C(O)N(R21)2, -C(O)NR21OR21, - N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, -C(0)R21, C(0)0R21, -0C(0)R21, - OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle;R1is selected from hydrogen and 5- to 15-membered heterocycle, wherein the 5- to 15- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, - S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C1-6 alkyl(=NOR20), - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(0)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, -N02, =0, =N(R20), =NO(R20), -CN, -NHCN, Ci-6 alkyl-N(R20)2, Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl-SCLR20, Ci-6 alkoxyalkyl, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3- C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1* is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(0)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, =0, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C3-C12 carbocycle;Y is selected from a bond, -0-, -S-, and -N(R5)-;R2is selected from heterocycle, aryl, Ci-Ce alkyl, -L-heterocycle, -L-N(R23)2, -L-OR23, -L-aryl, - L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R23)2, -L-Ci-Ce haloalkyl, -L- OR23, -L-NR23C(O)-aryl, -L-C00H, -L-NR23S(O)2(R23), -L-S(O)2N(R23)2, -L- N(R23)C(O)(OR23), -L-OC(O)N(R23)2, and -L-C(=O)OCI-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl, the aryl portion of -L- NR23C(O)-aryl, the aryl portion of -L-NR23C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7;R3is selected from hydrogen, halogen, -CN, -NO2, -N(R20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(0)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle; each R4is independently selected from halogen, -NO2, =0, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C 1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, Ci-e hydroxyalkyl, and C1-6 haloalkyl; n is selected from 0, 1, 2, 3, and 4; each R5is independently selected from hydrogen and Ci-Ce alkyl; each R6is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, NMO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSCLF, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Ci-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Ci-C3alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)CI-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl), -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl(Ci-C3alkyl)N(CH3)2, -OC(O)NH(CI-C3alkyl)O(Ci-C3alkyl)phenyl, -OC(O)heterocycle, -O-C1-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and - Cltheterocycle, wherein the phenyl of -NHC(O)phenyl and -0C(0)NH(Ci-C3 alkyl)(Ci-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -C1-C3 alkyl-N(R5)2, -C(O)N(R5)2, and -N(R5)2; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl- N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =0, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-io alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R23is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(CI-6 alkyl)2, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

381. A method of treating a cancer in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-l / PD- L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof; and a compound selected from:pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.

382. A method of treating a subject identified or diagnosed as having a cancer that include (a) detecting resistance of the cancer in the subject to treatment with a PD-1 / PD-L1 inhibitor that was previously administered to the patient; and (b) after (a), administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab,atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof; and aacceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.

383. A method of treating a subject identified or diagnosed as having a cancer and determined to have previously developed resistance to treatment with a KRAS G12D inhibitor that include administering to the subject a therapeutically effective amount of a combination of a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceuticalpharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.

384. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof; and aeutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.

385. A method of treating a subject identified or diagnosed as having a cancer that include (a) detecting resistance of the cancer in the subject to treatment with a PD-1 / PD-L1 inhibitor that was previously administered to the patient; and (b) after (a), administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof, and a compound selected from:one thereof, or a pharmaceutical composition of any one thereof.

386. A method of treating a subject identified or diagnosed as having a cancer and determined to have previously developed resistance to treatment with a KRAS G12D inhibitor that include administering to the subject a therapeutically effective amount of a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical compositionpharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.

387. The method of any one of claims 380 to 386, wherein the compound is pharmaceutically acceptable salt thereof. hod of any one of claims 380 to 387, wherein the compound isharmaceutically acceptable salt thereof.

389. The method of any one of claims 380 to 387, wherein the compound is391. The method of any one of claims 380 to 387, wherein the compound is393. The method of any one of claims 380 to 387, wherein the PD-1 / PD-L1 inhibitor is a PD-1 inhibitor.

394. The method of any one of claims 380 to 387, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, and tislelizumab.

395. The method of any one of claims 380 to 387, wherein the PD-1 inhibitor is nivolumab.

396. The method of any one of claims 380 to 387, wherein the PD-1 inhibitor is pembrolizumab.

397. The method of any one of claims 380 to 387, wherein the wherein the PD-1 inhibitor is cemiplimab.

398. The method of any one of claims 380 to 387, wherein the PD-1 inhibitor is tislelizumab.

399. The method of any one of claims 380 to 387, wherein the PD-1 / PD-L1 inhibitor is a PD-Ll inhibitor.

400. The method of any one of claims 380 to 387, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

401. The method of any one of claims 380 to 387, wherein the PD-L1 inhibitor is atezolizumab.

402. The method of any one of claims 380 to 387, wherein the PD-L1 inhibitor is avelumab.

403. The method of any one of claims 380 to 387, wherein the PD-L1 inhibitor is durvalumab.

404. The method of any one of claims 380 to 387, wherein the PD-1 / PD-L1 inhibitor and the compound, or a pharmaceutically acceptable salt thereof are administered on the same day.

405. The method of any one of claims 380 to 387, wherein the PD-1 / PD-L1 inhibitor and the compound, or a pharmaceutically acceptable salt thereof are administered on different days.

406. The method of any one of claims 380 to 387, wherein the cancer is a KRas G12D- associated cancer.

407. The method of any one of claims 380 to 387, wherein the cancer is a KRas G12V- associated cancer.

408. The method of any one of claims 380 to 407, 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; andAdrenal glands: neuroblastoma.

409. The method of any one of claims 380 to 408, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

410. The method of any one of claims 380 to 408, wherein the cancer is non-small cell lung cancer.

411. The method of any one of claims 380 to 408, wherein the cancer is small cell lung cancer.

412. The method of any one of claims 380 to 408, wherein the cancer is colorectal cancer.

413. The method of any one of claims 380 to 408, wherein the cancer is rectal cancer.

414. The method of any one of claims 380 to 408, wherein the cancer is pancreatic cancer.

415. The method of any one of claims 380 to 408, wherein the cancer is a solid tumor cancer.

416. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and b) a pharmaceutical compositioncomprisingpharmaceutically acceptable salt thereof, for treating a cancer in a subject.

417. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and b) a pharmaceutical composition comprisingpharmaceutically acceptable salt thereof, for treating a cancer in a subject.

418. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and b) a pharmaceutical composition comprisingpharmaceutically acceptable salt thereof, for treating a cancer in a subject.

419. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and b) a pharmaceutical compositioncomprisingpharmaceutically acceptable salt thereof, for treating a cancer in a subject.

420. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and b) a pharmaceutical composition comprisingpharmaceutically acceptable salt thereof, for treating a cancer in a subject.

421. A kit comprising: a) a pharmaceutical composition comprising a PD-1 / PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and b) a pharmaceutical composition comprisingpharmaceutically acceptable salt thereof, for treating a cancer in a subject.

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