Caspase-4 inhibitors and uses thereof

Abstract

The present disclosure relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein Ring A, G1, RC, X, RD1, RD2, and RD3 are as described herein, methods of preparation and intermediates useful in said preparation, methods of treatment and prevention (e.g., of Caspase-4 mediated diseases and disorders), and pharmaceutical compositions comprising same. Compounds of Formula (I), and pharmaceutically acceptable salts thereof, are designed as selective Caspase-4 allosteric inhibitors, sparing Caspase-1, and have also been found to be selective against Caspase-5 and are thus, in embodiments, considered dual Caspase-4 / 5- inhibitors. The present disclosure further relates to the Applicant's discovery of a new and allosteric human Caspase-4 binding pocket, and methods of binding to (and compounds inhibiting the activity of) same, methods of treatment and prevention, and pharmaceutical compositions comprising such compounds.

Description

[0001] CASPASE-4 INHIBITORS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] [1] The present application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application, U.S.S.N. 63 / 691,827, filed September 6, 2024, United States Provisional Patent Application, U.S.S.N. 63 / 768,807, fded March 7, 2025, and United States Provisional Patent Application, U.S.S.N. 63 / 800,835, fded May 6, 2025, the entire contents of each of which are incorporated herein by reference.

[0004] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0005] [2] The contents of the electronic sequence listing (V037570022WO00-SEQ-WLC.xml; Size: 10,435 bytes; and Date of Creation: September 3, 2025) are herein incorporated by reference in their entirety.

[0006] BACKGROUND

[0007] [3] Caspases are a family of dimeric cysteine proteases whose members control the ultimate steps for apoptosis (programmed cell death) and innate inflammation and are thus intrinsically involved both in embryonic development and in dysfunction in various diseases. There are 11 human caspases, and each share a common active site cysteine-histidine dyad, deriving their name, Cysteine ASPartate proteASEs, from their exquisite specificity for cleaving substrate proteins after specific aspartate residues. During apoptosis, the upstream initiators Caspase-8 and -9 activate downstream executioners Caspase-3, -6, and -7 via zymogen maturation. The activated executioner caspases then cleave key proteins and DNA, leading to cell death. The inflammatory Caspase- 1, -4 and -5 play essential roles in the immune response and inflammation. They are typically activated in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which are recognized by specific receptor complexes known as inflammasomes. See, e.g., Ross et al. Annu. Rev. Immunol. (2022) 40: 1-21.

[0008] [4] Human Caspase-4 and -5 and their rodent ortholog Caspase- 11 are part of the non-canonical inflammasome pathway and are activated in response to bacterial infections and some forms of cellular stress. Human Caspase-4 is ubiquitously and constitutively expressed across a wide variety of cell and tissue types such as immune cells and non-hematopoietic cells and is activated in response to the presence of intracellular endotoxins such as LPS (gram negative) and LTA (gram positive), whereas human Caspase-5 expression is induced in response to endotoxin stimulation, with Caspase-4 and -5 induction leading to their respective dimerization and auto-processing. See, e.g., Fu and Wu, Annu. Rev. Immunol. (2023) 41:301-316; Hara etal., Cell (2018) 175: 165 l-1664.e 14; Smith et al., Front.

[0009] Pharmacol. (2022) 13:919567; and Eckhart et al. Biochem. Biophys. Res. Commun. (2006) 348:682-688. Upon activation, Caspase-4 cleaves the pore forming GSDMD protein, which leads to the initiation of “flaming” cell death known as pyroptosis, which in turn causes a release of the pro-inflammatory cytokines IL- 1β and IL- 18 as well as additional chemokines and other inflammatory related proteins, such as high mobility group box 1 protein (HMGB1) and lactate dehydrogenase (LDH). In addition to GSDMD cleavage, Caspase-4 was recently shown to also activate IL- 18 by cleaving pro-IL-18 into its mature form. See, e.g., Devant et al. Nature (2023) 624:451-459; Shi et al. Nature (2023) 624:442-450. Although Caspase-4 is unable to directly cleave IL-1β, its activation can lead to a Caspase-1 dependent increase in IL-1 β processing through cross-talk between the non-canonical and canonical inflammasome pathways. See, e.g., Yang et al., Immunity (2015) 43:923-932. [5] The systemic presence of high levels of endotoxins and pathogens in the blood are the main cause of sepsis, severe sepsis and septic shock. See, e.g., Gabarin et al., J. Innate Immun. (2021) 13:323-332. A rapid drop in blood pressure, decrease in blood brain barrier integrity and multi-organ failures, linked to an increase in vascular permeability, is seen as the main driver of death in sepsis. See, e.g., Gyawali et al., SAGE Open Med. (2019) 7:2050312119835043; Wang et al., Eur. J. Méd. Res. (2023) 28:339. Caspase-11 is the murine functional equivalent of Caspase-4. Endothelial cells specific Caspase- 11 knock-out mice are protected from LPS-induced vascular leakage and septic shock, demonstrating a nexus between vascular leakage through cell death of endothelial cells, septic shock, and Caspase-4. See, e.g., Kajiwara et al., J. Immunol. (2014) 193:335-343; Kayagaki et al., Nature (2011) 479:117–121. Furthermore, Caspase-11 knock-out mice have been shown to be resistant to septic shock-induced death triggered by LPS. See, e.g., Cheng et al., J. Clin. Investig. (2017) 127:4124-4135. Caspase-4 has also been implicated in acute respiratory distress syndrome (ARDS) by promoting inflammation and immunothrombosis. See, e.g., Eltobgy et al. Proc. Natl. Acad. Sci. (2022) 119:e2202012119; Benaoudia et al. EMBO Rep. (2019) 20:e48235. [6] Caspase-4 and -11 activation is also associated with metabolic conditions, such as diabetic nephropathy. Culturing human podocytes (epithelial kidney cells) in the presence of high concentration of glucose has been shown to increase Caspase-4 / 11 expression, increase GSDMD cleavage and increase the secretion of IL-1β in Caspase-4 / 11 knock-down mouse models of diabetic nephropathy. See, e.g., Cheng, et al. Acta Pharmacol. Sin. (2021) 42:954-963. [7] Caspase-4 and -11 activation is also associated with ischemia-reperfusion injury (IRI), which occurs when blood supply returns to tissue after a period of ischemia or lack of oxygen. Caspase-11 expression in murine cardiomyocytes has been shown to be essential for hypoxia / reoxygenation-induced cell pyroptosis and IL-18 production. See, e.g., Shi et al. Circ. Res. (2021) 129:383-396. Furthermore, Caspase-4 expression was shown to be up-regulated in human cardiac microvascular endothelial cells following hypoxia / reoxygenation See, e.g., Sun et al. Cell Commun. Signal. (2021) 19:107. [8] Caspase-4 is also implicated in epithelial tissue damage of inflammatory bowel disease (IBD). For example, local exposure of intestinal epithelial cells to excess endotoxins / OMVs and / or cell invading microbiota promotes chronic production of pro-inflammatory IL-18 as well as a perturbation of the epithelial barrier integrity through pyroptotic cell death, leading to local inflammation and tissue damage, with high levels of Caspase-4 observed. See, e.g., Smith et al., Front. Pharmacol. (2022) 13: 919567. [9] Due to the homologous active site common amongst all 11 human caspases, it has reportedly been difficult to develop selective active site inhibitors. See, e.g., Hardy and Wells, J. Biol. Chem. (2009) 284:26063-26069. Inhibition of caspases with active site inhibitors is challenged by the requirement of high fractional inhibition to attenuate activity in cells. However, this leads to large shifts in enzyme potency to cell potency, resulting in high doses for clinical efficacy. See, e.g., Méthot et al. J. Biol. Chem. (2004) 279:27905-27914. For example, extremely high dosing – up to 1200 mg TID – of the small molecule peptidomimetic VX-765 (later reported to be a Caspase-1 and -4 dual active site inhibitor) was explored in the pursuit of a clinically efficacious dose, and at least one clinical trial was administratively terminated with no reported efficacy. See, e.g., Wannamaker et al., J. Pharmacol. Exp. Ther. (2007) 321: 509-516; French et al. American Epilepsy Society 2013 Annual Meeting, Abstract number 3.31, published December 5, 2013, presented December 7, 2013. Moreover, other known caspase inhibitors, particularly peptide-based caspase inhibitors, suffer from PK / PD issues, resulting in a lack of clinical developability. For example, the peptide Z-YVAD-FMX, a Caspase-4 active site inhibitor, was found to have limited clinical utility due to poor bioavailability and pharmacokinetics. See, e.g., Degterev et al., Oncogene (2003) 22:8543-8567.

[0010] Allosteric Caspase-4 inhibitors (rather than active site inhibitors) may provide a solution to the requirement of high fractional inhibition for active site inhibitors. Furthermore, there is a clear and present need for selective and efficacious small molecule Caspase-4 inhibitors. SUMMARY

[0011] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein Ring A, G1, RC, X, RD1, RD2, and RD3are as described herein. Further provided are methods of preparation and intermediates useful in said preparation, methods of treatment and prevention, and pharmaceutical compositions comprising compounds disclosed herein.

[0012] Further described herein is the Applicant’s discovery of a previously unknown human Caspase-4 allosteric binding pocket, and methods of binding to (and compounds of inhibiting the activity) of same. Further provided are methods of treatment and prevention, and pharmaceutical compositions comprising such compounds.

[0013] Compounds of Formula (I), and pharmaceutically acceptable salts thereof, are designed as selective Caspase-4 allosteric inhibitors, sparing Caspase-1. Exemplary compounds of Formula (I) have also been found to be selective against Caspase-5 and are thus, in some embodiments, considered dual Caspase- 4 / 5-inhibitors. DEFINITIONS

[0014] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0015] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Compounds described herein can additionally encompasses individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0016] Unless otherwise stated, compounds described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms (“isotopically labeled derivative”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C- enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as a therapeutic or prophylactic agent, as analytical tools, or as probes in biological assays. In certain embodiments, the isotopically labeled derivative has 1, 2, 3, 4, 5, 6, 7, or 8 deuterium atoms in place of hydrogen atoms.

[0017] When a range of values is listed, it is intended to encompass each value and sub--range within the range. For example, “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0018] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2- butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents.

[0019] “Haloalkyl” refers to a substituted alkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by one or more halogens, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1-10haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0020] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds) (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.

[0021] “Haloalkenyl” refers to a substituted alkenyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by one or more halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, a haloalkenyl group has 2 to 10 carbon atoms (“C2-10haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 9 carbon atoms (“C2-9haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 8 carbon atoms (“C2-8haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 7 carbon atoms (“C2-7haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 6 carbon atoms (“C2-6haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 5 carbon atoms (“C2-5haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 4 carbon atoms (“C2-4haloalkenyl”). In some embodiments, a haloalkenyl group has 2 to 3 carbon atoms (“C2-3haloalkenyl”). In some embodiments, a haloalkenyl group has 2 carbon atoms (“C2haloalkenyl”).

[0022] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0023] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms (“C3-9carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl rings wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons designate the number of carbons in the polycyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.

[0024] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 9 ring carbon atoms (“C3-9cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0025] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). It is understood that the ring sulfur or ring nitrogen may exist in an oxygenated state, such as an N-oxide (N- O), sulfonyl (S(=O)2), sulfinylimide (S(=O)(=NR) where R may be hydrogen or a non-hydrogen substituent such as alkyl), or sulfinyl (S=O) ring heteroatom. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes (i) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused (e.g., spiro-fused or ring fused) or bridged with one or more carbocyclyl or heterocyclyl rings wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or (ii) polycyclic ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the polycyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.

[0010]

[0026] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0011]

[0027] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5 -membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 7-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, homopiperazinyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, and the like.

[0028] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes polycyclic ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl rings wherein the point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designate the number of carbon atoms in the polycyclic ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.

[0029] “Heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes polycyclic ring systems wherein the heteroaryl ring, as defined above, (i) is fused with one or more carbocyclyl or heterocyclyl rings wherein the point of attachment is on the heteroaryl ring, or (ii) is fused with one or more heteroaryl or aryl rings wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances (i) and (ii), the number of ring members designate the number of ring members in the fused polycyclic ring system.

[0030] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.

[0031] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0032] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I) radicals.

[0033] A “leaving group” is an art–understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501–502). Exemplary leaving groups include, but are not limited to, halogen (e.g., chloro, bromo, iodo) and other leaving groups such as (i) sulfonyl substituted hydroxyl groups (e.g., -O-triflate, -O-tosyl, -O-mesyl, and -O- besyl), and (ii) in context of coupling reaction, such as a Suzuki coupling, a trifluoroborate group.

[0034] “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

[0035] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, haloalkylene is the divalent moiety of haloalkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. One divalent carbon atom provided in an alkylene, haloalkylene, alkenylene, and alkynylene divalent moiety may be replaced with a divalent heteroatom selected from oxygen, nitrogen, or sulfur to provide a heteroalkylene, heterohaloalkylene, heteroalkenylene, and heteroalkynylene divalent moiety, respectively.

[0036] A “bridged” ring system is one that contains at least one ring and a divalent moiety attached thereto, wherein the two ends of the divalent moiety are attached to different ring atoms not vicinal (not next to) each other, thereby forming a second bridging ring.

[0037] A “fused” ring system is one that contains at least one ring and a divalent moiety attached thereto, wherein the two ends of the divalent moiety are attached to different ring atoms which are vicinal (are next to) each other, thereby forming a second fused ring.

[0038] A “spiro-fused” ring system is one that contains at least one ring and a divalent moiety attached thereto, wherein the two ends of the divalent moiety are attached to the same ring atom, thereby forming a second spiro-fused ring.

[0039] “Ortho” to the point of attachment means at the vicinal position, next to the point of attachment.

[0040] “Optionally substituted” refers to a group as described herein (e.g., a “substituted” or “unsubstituted” C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10haloalkenyl, C2-10alkynyl, C3-14carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and / or 5-14 membered heteroaryl) which may be unsubstituted or substituted with at least one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) non-hydrogen substituents. In general, the term “substituted” means that at least one hydrogen present on the group is replaced with a permissible non-hydrogen substituent, e.g., a non-hydrogen substituent which upon substitution results in a stable compound. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. Exemplary substituents include, but are not limited to, C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10haloalkenyl, C2-10alkynyl, C3-14carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 5-14 membered heteroaryl, halo, -CN, -OR’, -SR’, or -N(R’)2, -OR’’, -SR’’, -NHR”, and -N(R”)2, wherein each instance of R’ is independently hydrogen, C1-10alkyl, C1-10haloalkyl, C3-14carbocyclyl, or 3-14 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl; each instance of R’’ is independently C1-10alkyl, C1-10haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-10alkylene or C1-10haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 3-14 membered heterocyclyl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, or heteroaryl is independently substituted with 0 or 1 C1-10alkyl or C1-10haloalkyl, and each instance of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is also independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene- OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene- N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0041] “Salt” refers to any and all salts, including pharmaceutically acceptable salts.

[0042] “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid salts, or salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0043] A “free base” refers to a neutral non-ionized form of a compound which is not a salt or pharmaceutically acceptable salt.

[0044] “Condition,” “disease,” and “disorder” are used interchangeably herein.

[0045] A “patient” or “subject” is used interchangeably herein, and refers to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. In some embodiments, the patient or subject is a human.

[0046] “Administer,” “administering,” or “administration” refer to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0047] “Effective amount” refers to an amount of the compound sufficient to provide a benefit in the treatment or prevention of a disease, disorder or condition in a subject in need thereof. An effective amount can therefore encompass: (i) a “therapeutically effective amount” (useful in the treatment of a disease, disorder, or condition) is an amount that reduces symptoms or causes of the disease, disorder or condition and / or enhances the therapeutic efficacy of another therapeutically active agent in the treatment of the disease, disorder or condition in said subject suffering from said disease, disorder, or condition, and (ii) a “prophylactically effective amount” (useful in the prevention of a disease, disorder, or condition) is an amount that delays or prevents the appearance of at least one symptom of a disease, disorder or condition in a subject that may have or has a predisposition for the disease, disorder or condition but has not yet experienced or displayed symptoms of the disease, disorder or condition, and / or enhances the prophylactic efficacy of another prophylactically active agent in the delay or prevention of the appearance of at least one symptom of a disease, disorder or condition, in said subject. An effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. In some embodiments, an effective amount is an amount sufficient for inhibiting caspase activity in situ (e.g., in a cell relative to a control (e.g., a vehicle)) or in vivo (e.g., in an animal model).

[0048] “Treating” or “treat” or “treatment” describes the therapeutic management and care of a subject for the purpose of combating established symptoms of a disease, condition, or disorder in said subject.

[0049] “Preventing,” “prevent,” or “protecting against” describes the prophylactic management and care of a subject that may have or has a predisposition for the disease, disorder or condition but has not yet experienced or displayed any symptoms of the disease, disorder or condition, for the purpose of preventing the appearance of at least one symptom of the disease, disorder or condition in said subject.

[0050] “Inhibition”, “inhibiting”, “inhibit” and “inhibitor”, and the like, refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological process (e.g., caspase activity) in a cell relative to a control (e.g., a vehicle).

[0051] The phrase “at least one” refers to one instance or more than one instance, e.g., 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0052] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.

[0053] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIGURES 1A-1C: VX-765, a dual Caspase-1 / 4 active site inhibitor, exhibits a substantial (800- fold) shift in potency between results of a Caspase-4 biochemical assay described in the Examples (IC50= 1 nM) and the LPS induced pyroptosis HeLa cellular assay described in the Examples (IC50= 800 nM) (FIG.1A), where a large shift in enzyme potency to cell potency is observed. In contrast, an exemplary Caspase-4 inhibitor of Formula (I), Compound 35, exhibits a minimal (10-fold) shift between the biochemical assay and cellular assay (FIG.1B). Compound 35 also demonstrates significantly improved (130-fold increase in) cellular potency compared to VX-765 (FIG.1C).

[0055] FIGURE 2: Applicants have identified a new and allosteric binding site on human Caspase-4 which is distinct from the catalytic (active) binding site and the proteolytic cysteine 258 residue previously described in Chan et al., Life Sci. Alliance (2023) 9;6(10):e202301908. doi: 10.26508 / lsa.202301908. PMID: 37558421; PMCID: PMC10412805. The allosteric binding pocket is located on the solvent exposed region of the interface between the p10 and the p20 subunits of human Caspase-4 and is defined by three β-strands (residues 228-230, 300-306, and 360-364), an α-helix region (residues -231-238), and a loop region (residues 212-215). FIG.2 depicts the surface representation of human Caspase-4 co- crystal structure (prepared from crystallization with co-former Compound 35, as described in the Examples), showing the location of the newly identified allosteric binding site (light grey) compared to the location of the previously identified catalytic (active) binding site (black).

[0056] FIGURES 3A-3C: Preparation of a co-crystal of the human Caspase-4 and Compound 35 (FIG. 3A) is described in the Examples. FIG. 3B is a 3D schematic representation of that crystal structure, showing the compound bound within the allosteric binding pocket, and depicting an important H-bond donor and acceptor interaction between the oxygen atom of the cyclic lactam C=O group of Compound 35 and an NH moiety of Arg364. Other core and right-hand side interactions include an H-bond interaction between the nitrogen atom of the ortho -CN Ring A substituent of Compound 35 and an NH moiety of Asp232, an H-bond interaction between the nitrogen atom of the ortho -CN Ring A substituent of Compound 35 and Leu230, and a CH-pi interaction between aromatic Ring A of Compound 35 and Glu214. Left-hand side interactions include an H-bond interaction between the NH2Ring E substituent of Compound 35 and Ser306, and an H-bond interaction between Ring E and Thr361. FIG.3C provides the corresponding 2D schematic representation.

[0057] FIGURES 4A-4C: Preparation of a co-crystal of human Caspase-4 and Compound 55-NH2(FIG. 4A) is described in the Examples. FIG. 4B is a 3D schematic representation of that crystal structure, showing the compound bound within the allosteric binding pocket, and depicting an important H-bond donor and acceptor interaction between the oxygen atom of the cyclic lactam C=O group of Compound 55-NH2and an NH moiety of Arg364. Other core and right-hand side interactions include an H-bond interaction between the C=O group of the cyclic lactone of Compound 55-NH2and an NH moiety of Asp232, an H-bond interaction between the C=O group of the cyclic lactone of Compound 55-NH2and Leu230, and a CH-pi interaction between aromatic Ring A of Compound 55-NH2and Glu214. Left-hand side interactions include an H-bond interaction between the NH2Ring E substituent of Compound 55- NH2and Ser306, and an H-bond interaction between Ring E and Thr361. FIG.4C provides the corresponding 2D schematic representation. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS (i) Compounds

[0058] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein: Ring A is an optionally substituted 6-membered aryl or optionally substituted 6-membered heteroaryl, and wherein the aryl or heteroaryl is monocyclic or further comprises fused thereto an optionally substituted 5-6 membered heterocyclyl; G1is CH, CF, or N; RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo; X is O, S, or NH; RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E: , wherein: Ring E is a C3-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3; each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3), -C(=O)N(RE3)2, -S(=O)RE3or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; y is 0, 1, 2, or 3; RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo; and RD3is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo.

[0059] In some embodiments: Ring A is an optionally substituted 6-membered aryl or optionally substituted 6-membered heteroaryl, and wherein the aryl or heteroaryl is monocyclic or further comprises fused thereto an optionally substituted 5-6 membered heterocyclyl; G1is CH, CF, or N; RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo; X is O, S, or NH; RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E: , wherein: Ring E is a C4-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3; each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3), -C(=O)N(RE3)2, -S(=O)RE3or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; y is 0, 1, 2, or 3; RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo; and RD3is hydrogen or halo.

[0060] In some embodiments, wherein Ring A is an optionally substituted monocyclic 6-membered aryl or optionally substituted monocyclic 6-membered heteroaryl, the compound of Formula (I) is of Formula (II): or a pharmaceutically acceptable salt thereof, wherein G2, G3, G4, and RA5are as defined herein.

[0061] In some embodiments, wherein Ring A is aryl or heteroaryl and further comprises fused thereto a substituted 5-6 membered heterocyclyl, the compound of Formula (I) is of Formula (III): or a pharmaceutically acceptable salt thereof, wherein x, G2, G3, G7, and RA6are as defined herein.

[0062] Additional embodiments are further described below and herein. Ring A

[0063] As generally described herein, Ring A is an optionally substituted 6-membered aryl or optionally substituted 6-membered heteroaryl, and wherein the aryl or heteroaryl is monocyclic or further comprises fused thereto an optionally substituted 5-6 membered heterocyclyl.

[0064] In some embodiments, Ring A is independently substituted with at least one or more (e.g., 1, 2, 3, 4, 5, 6, or 7) of the following groups: -CN; and / or halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl; wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene- NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene- OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0065] In some embodiments, Ring A is an optionally substituted monocyclic 6-membered aryl or monocyclic 6-membered heteroaryl. In some embodiments, Ring A is a monocyclic 6-membered aryl or monocyclic 6-membered heteroaryl substituted with at least one -CN group. In some embodiments, Ring A is a monocyclic 6-membered aryl or monocyclic 6-membered heteroaryl substituted with at least one - CN group ortho to the point of attachment to Ring B.

[0066] In some embodiments, Ring A is a monocyclic 6-membered aryl, wherein Ring A is substituted with at least one -CN group ortho to the point of attachment to Ring B.

[0067] In some embodiments, Ring A is a monocyclic 6-membered heteroaryl, wherein Ring A is substituted with at least one -CN group ortho to the point of attachment to Ring B. In some embodiments, Ring A is a monocyclic 6-membered heteroaryl containing 1 or 2 ring N atoms, wherein Ring A is substituted with at least one -CN group ortho to the point of attachment to Ring B. In some embodiments, Ring A is a monocyclic 6-membered heteroaryl containing 1 ring N atom, wherein Ring A is substituted with at least one -CN group ortho to the point of attachment to Ring B. In some embodiments, Ring A is a monocyclic 6-membered heteroaryl containing 2 ring N atoms, wherein Ring A is substituted with at least one -CN group ortho to the point of attachment to Ring B.

[0068] In any of the above described embodiments, wherein Ring A is monocyclic and comprises at least one -CN group, Ring A may be further unsubstituted or substituted with one or more of the following groups: halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3 haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl; wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene- NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene- OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0069] In other embodiments, Ring A is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl, wherein the aryl or heteroaryl further comprises fused thereto an optionally substituted 5-6 membered heterocyclyl.

[0070] In some embodiments, Ring A is an optionally substituted 6-membered aryl or optionally substituted 6-membered heteroaryl, wherein the aryl or heteroaryl further comprises fused thereto an optionally substituted 5-6 membered lactone ring.

[0071] In some embodiments, Ring A is an optionally substituted 6-membered aryl, wherein the aryl further comprises fused thereto an optionally substituted 5-6 membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered aryl, wherein the aryl further comprises fused thereto an optionally substituted 5-membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered aryl, wherein the aryl further comprises fused thereto an optionally substituted a 6-membered lactone ring.

[0072] In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl, wherein the heteroaryl further comprises fused thereto an optionally substituted 5-6 membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl, wherein the heteroaryl further comprises fused thereto an optionally substituted 5-membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl, wherein the heteroaryl further comprises fused thereto an optionally substituted 6-membered lactone ring.

[0073] In some embodiments, Ring A is a an optionally substituted 6-membered heteroaryl containing 1 or 2 ring N atoms, wherein the heteroaryl further comprises fused thereto an optionally substituted 5-6 membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl containing 1 or 2 ring N atoms, wherein the heteroaryl further comprises fused thereto an optionally substituted 5-membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl containing 1 or 2 ring N atoms, wherein the heteroaryl further comprises fused thereto an optionally substituted 6-membered lactone ring.

[0074] In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl containing 1 ring N atom, wherein the heteroaryl further comprises fused thereto an optionally substituted 5-6 membered lactone ring. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl containing 1 ring N atom, wherein the heteroaryl further comprises fused thereto an optionally substituted 5-membered lactone ring. In some embodiments, Ring A is an optionally substituted 6- membered heteroaryl containing 1 ring N atom, wherein the heteroaryl further comprises fused thereto an optionally substituted 6-membered lactone ring.

[0075] In some embodiments, Ring A is a 6-membered heteroaryl containing 2 ring N atoms, wherein the heteroaryl further comprises fused thereto a 5-6 membered lactone ring. In some embodiments, Ring A is a 6-membered heteroaryl containing 2 ring N atoms, wherein the heteroaryl further comprises fused thereto a 5-membered lactone ring. In some embodiments, Ring A is a 6-membered heteroaryl containing 2 ring N atoms, wherein the heteroaryl further comprises fused thereto a 6-membered lactone ring.

[0076] In some embodiments, the *-C(=O)-O- moiety of the fused 5- to 6-membered lactone ring is ortho to the point of attachment of Ring A to Ring B, wherein the asterix (*) signifies the point of attachment of the carbon atom directly attached to Ring A. In some embodiments, the lactone ring is a 5-membered lactone ring comprising one internal carbon-carbon double bond (as a result of ring fusion to the optionally substituted 6-membered aryl or the optionally substituted 6-membered heteroaryl ring). In some embodiments, the lactone ring is a 6-membered lactone ring comprising one internal carbon-carbon double bond (as a result of ring fusion to the optionally substituted 6-membered aryl or the optionally substituted 6-membered heteroaryl ring).

[0077] In any of the above-described embodiments, wherein Ring A is a 6-membered aryl or 6-membered heteroaryl comprising fused thereto a 5-6 membered heterocyclyl ring, Ring A may be unsubstituted or substituted with one or more of the following groups: halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl; wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene- NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene- OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl; and / or C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5- membered heteroaryl, or two non-hydrogen groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0078] In some embodiments, Ring A is a group of formula: wherein: G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; G7is CRA7or N; provided no more than two of G2, G3, and G4or no more than two of G2, G3, and G7are N; each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5- membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each of RA5and RA7is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3 alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups; wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and x is 1 or 2.

[0079] In some embodiments, Ring A is a group of formula (a-1):

[0080] In some embodiments, the group of formula (a-1) is of formula:

[0012]

[0081] In some embodiments, the group of formula (a-1) is of formula (a-la). In some embodiments, the group of formula (a-1) is of formula (a-lb). In some embodiments, the group of formula (a-1) is of formula (a-lc). In some embodiments, the group of formula (a-1) is of formula (a-ld). In some embodiments, the group of formula (a-1) is of formula (a-le). In some embodiments, the group of formula (a-1) is of formula (a-lf). In some embodiments, the group of formula (a-1) is of formula (a-lg). In some embodiments, the group of formula (a-1) is of formula (a-lh). In some embodiments, the group of formula (a-1) is of formula (a-li). In some embodiments, the group of formula (a-1) is of formula (a- Ij). In some embodiments, the group of formula (a-1) is of formula (a-lk). In some embodiments, the group of formula (a-1) is of formula (a-11). In some embodiments, the group of formula (a-1) is of formula (a-lm). In some embodiments, the group of formula (a-1) is of formula (a-ln). In some embodiments, the group of formula (a-1) is of formula (a-lo). In some embodiments, the group of formula (a-1) is of formula (a-lp).

[0013]

[0082] In some embodiments, Ring A is a group of formula (a-2):

[0083] In some embodiments, the group of formula (a-2) is of formula.

[0014]

[0084] In some embodiments, the group of formula (a-2) is of formula (a-2a). In some embodiments, the group of formula (a-2) is of formula (a-2b). In some embodiments, the group of formula (a-2) is of formula (a-2c). In some embodiments, the group of formula (a-2) is of formula (a-2d). In some embodiments, the group of formula (a-2) is of formula (a-2e). In some embodiments, the group of formula (a-2) is of formula (a-2f). In some embodiments, the group of formula (a-2) is of formula (a-2g). In some embodiments, the group of formula (a-2) is of formula (a-2h). In some embodiments, the group of formula (a-2) is of formula (a-2i). In some embodiments, the group of formula (a-2) is of formula (a- 2j). In some embodiments, the group of formula (a-2) is of formula (a-2k). In some embodiments, the group of formula (a-2) is of formula (a-2l). In some embodiments, the group of formula (a-2) is of formula (a-2m). In some embodiments, the group of formula (a-2) is of formula (a-2n). In some embodiments, the group of formula (a-2) is of formula (a-2o). In some embodiments, the group of formula (a-2) is of formula (a-2p). In some embodiments, the group of formula (a-2) is of formula (a- 2q). In some embodiments, the group of formula (a-2) is of formula (a-2r). In some embodiments, the group of formula (a-2) is of formula (a-2s). In some embodiments, the group of formula (a-2) is of formula (a-2t). In some embodiments, the group of formula (a-2) is of formula (a-2u). In some embodiments, the group of formula (a-2) is of formula (a-2v). In some embodiments, the group of formula (a-2) is of formula (a-2w). In some embodiments, the group of formula (a-2) is of formula (a- 2x).

[0085] In some embodiments, the group of formula (a-2) is of formula:

[0015]

[0086] In some embodiments, the group of formula (a-2) is of formula (a-2aa). In some embodiments, the group of formula (a-2) is of formula (a-2bb). In some embodiments, the group of formula (a-2) is of formula (a-2cc). In some embodiments, the group of formula (a-2) is of formula (a-2dd). In some embodiments, the group of formula (a-2) is of formula (a-2ee). In some embodiments, the group of formula (a-2) is of formula (a-2ff). In some embodiments, the group of formula (a-2) is of formula (a- 2gg). In some embodiments, the group of formula (a-2) is of formula (a-2hh). In some embodiments, the group of formula (a-2) is of formula (a-2ii).

[0016]

[0087] In some embodiments, the group of formula (a-2) is of formula:

[0088] As generally described herein, G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; and G7is CRA7or N; provided no more than two of G2, G3, and G4or no more than two of G2, G3, and G7are N.

[0089] In some embodiments, G2is CRA2. In some embodiments, G2is N.

[0090] In some embodiments, G3is CRA3. In some embodiments, G3is N.

[0091] In some embodiments, G4is CRA4. In some embodiments, G4is N.

[0092] In some embodiments, G7is CRA7. In some embodiments, G7is N.

[0093] In some embodiments, G2is CRA2and G3is CRA3. In some embodiments, G2is CRA2and G3is N. In some embodiments, G2is N and G3is CRA3. In some embodiments, G2is N and G3is N.

[0094] In some embodiments, G2is CRA2and G4is CRA4. In some embodiments, G2is CRA2and G4is N. In some embodiments, G2is N and G4is CRA4. In some embodiments, G2is N and G4is N.

[0095] In some embodiments, G2is CRA2and G7is CRA7. In some embodiments, G2is CRA2and G7is N. In some embodiments, G2is N and G7is CRA7. In some embodiments, G2is N and G7is N.

[0096] In some embodiments, G3is CRA3and G4is CRA4. In some embodiments, G3is CRA3and G4is N. In some embodiments, G3is N and G4is CRA4. In some embodiments, G3is N and G4is N.

[0097] In some embodiments, G3is CRA3and G7is CRA7. In some embodiments, G3is CRA3and G7is N. In some embodiments, G3is N and G7is CRA7. In some embodiments, G3is N and G7is N.

[0098] In some embodiments, G2is CRA2, G3is CRA3, and G4is CRA4.

[0099] In some embodiments, G2is CRA2, G3is CRA3, and G4is N.

[0100] In some embodiments, G2is CRA2, G3is N, and G4is CRA4.

[0101] In some embodiments, G2is CRA2, G3is N, and G4is N.

[0102] In some embodiments, G2is N, G3is CRA3, and G4is CRA4.

[0103] In some embodiments, G2is N, G3is CRA3, and G4is N.

[0104] In some embodiments, G2is N, G3is N, and G4is CRA4.

[0105] In some embodiments, G2is CRA2, G3is CRA3, and G7is CRA7.

[0106] In some embodiments, G2is CRA2, G3is CRA3, and G7is N.

[0107] In some embodiments, G2is CRA2, G3is N, and G7is CRA7.

[0108] In some embodiments, G2is CRA2, G3is N, and G7is N.

[0109] In some embodiments, G2is N, G3is CRA3, and G7is CRA7.

[0110] In some embodiments, G2is N, G3is CRA3, and G7is N.

[0111] In some embodiments, G2is N, G3is N, and G7is CRA7.

[0112] As generally described herein, each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0113] In some embodiments, RA2is hydrogen.

[0114] In some embodiments, RA2is halo. In some embodiments, RA2is -F, -Cl, or -Br.

[0115] In some embodiments, RA2is C1-3alkyl. In some embodiments, RA2is -CH3.

[0116] In some embodiments, RA2is C1-3haloalkyl.

[0117] In some embodiments, RA2is C3-8carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0118] In some embodiments, RA2is 4-8 membered heterocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0119] In some embodiments, RA2is -CN.

[0120] In some embodiments, RA2is -OR’. In some embodiments, RA2is -OCH3.

[0121] In some embodiments, RA2is -SR’.

[0122] In some embodiments, RA2is -N(R’)2. In some embodiments, RA2is -N(CH3)2,

[0123] In some embodiments, RA2is hydrogen, -F, -Cl, -Br, -CH3, -CN, -OCH3, -N(CH3)2,

[0124] In some embodiments, RA2is hydrogen, -F, -Cl, -CH3, -OCH3, or -N(CH3)2. In some embodiments, RA2is hydrogen, -F, -Cl, or -CH3.

[0125] In some embodiments, RA2is hydrogen, -F, -Cl, -Br, -CH3, -CN, -OCH3, In some embodiments, RA2is hydrogen or -F.

[0126] In some embodiments, RA3is hydrogen.

[0127] In some embodiments, RA3is halo. In some embodiments, RA3is -F, -Cl, or -Br.

[0128] In some embodiments, RA3is C1-3alkyl. In some embodiments, RA3is -CH3.

[0129] In some embodiments, RA3is C1-3haloalkyl.

[0130] In some embodiments, RA3is C3-8carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0131] In some embodiments, RA3is 4-8 membered heterocyclyl substituted with 0 or 1 C1-3alkyl or C1-3 haloalkyl.

[0132] In some embodiments, RA3is -CN.

[0133] In some embodiments, RA3is -OR’. In some embodiments, RA3is -OCH3.

[0134] In some embodiments, RA3is -SR’.

[0135] In some embodiments, RA3is -N(R’)2. In some embodiments, RA3is -N(CH3)2,

[0136] In some embodiments, RA3is hydrogen, -F, -Cl, -Br, -CH3, -CN, -OCH3, -N(CH3)2,

[0137] In some embodiments, RA3is hydrogen, -F, -Cl, -CH3, -OCH3, or -N(CH3)2. In some embodiments, RA3is hydrogen, -CH3, -OCH3, or -N(CH3)2.

[0138] In some embodiments, RA3is hydrogen, -F, -Cl, -Br, -CH3, -CN, -OCH3, In some embodiments, RA3is hydrogen, -Cl, -Br, -CH3, -CN, -OCH3,

[0139] In some embodiments, RA4is hydrogen.

[0140] In some embodiments, RA4is halo. In some embodiments, RA4is -F, -Cl, or -Br.

[0141] In some embodiments, RA4is C1-3alkyl. In some embodiments, RA4is -CH3.

[0142] In some embodiments, RA4is C1-3haloalkyl.

[0143] In some embodiments, RA4is C3-8carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0144] In some embodiments, RA4is 4-8 membered heterocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0145] In some embodiments, RA4is -CN.

[0146] In some embodiments, RA4is -OR’. In some embodiments, RA4is -OH. In some embodiments, RA4is -OCH3.

[0147] In some embodiments, RA4is -SR’.

[0148] In some embodiments, RA4is -N(R’)2. In some embodiments, RA4is -N(CH3)2,

[0149] In some embodiments, RA4is hydrogen, -F, -Cl, -Br, -CH3, -CN, -OCH3, -N(CH3)2,

[0150] In some embodiments, RA4is hydrogen, -F, -Cl, -CH3, -OH, -OCH3, or -N(CH3)2. In some embodiments, RA4is hydrogen, -F, -Cl, or -CH3.

[0151] In some embodiments, RA4is hydrogen, -F, -Cl, -Br, -CH3, -CN, -OH, -OCH3, In some embodiments, RA4is hydrogen, -Cl, -CH3, -OH, -OCH3,

[0152] In some embodiments, each of RA2, RA3, and RA4is independently hydrogen, -F, -Cl, -Br, -CH3, -CN, -OCH3, -N(CH3)2,

[0153] In some embodiments, each of RA2, RA3, and RA4is independently hydrogen, -F, -Cl, -CH3, -OCH3, or -N(CH3)2.

[0154] In some embodiments, each of RA2, RA3, and RA4is independently hydrogen, -F, -Cl, -Br, -CH3, -CN, -OH, -OCH3,

[0155] As generally described herein, each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0156] In some embodiments, at least one instance of R’ is hydrogen.

[0157] In some embodiments, at least one instance of R’ is C1-3alkyl. In some embodiments, at least one instance of R’ is -CH3.

[0158] In some embodiments, at least one instance of R’ is C1-3haloalkyl.

[0159] In some embodiments, at least one instance of R’ is C3-8carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0160] In some embodiments, at least one instance of R’ is 4-8 membered heterocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0161] In some embodiments, two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein the heterocyclyl or heteroaryl is substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, two R’ groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl or 5-membered heteroaryl; wherein the heterocyclyl or heteroaryl is substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0162] In some embodiments, two R’ groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 C1-3alkyl or C1-3haloalkyl. In some embodiments, two R’ groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, two R’ groups together with the nitrogen to which they are attached form

[0163] In some embodiments, two R’ groups together with the nitrogen to which they are attached form a 5-membered heteroaryl substituted with 0 C1-3alkyl or C1-3haloalkyl. In some embodiments, two R’ groups together with the nitrogen to which they are attached form a 5-membered heteroaryl substituted with 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, two R’ groups together with the nitrogen to which they are attached form

[0164] As generally described herein, each of RA5and RA7is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene- NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene- OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0165] In some embodiments, RA5is hydrogen. In some embodiments, RA7is hydrogen.

[0166] In some embodiments, RA5or RA7is independently halo. In some embodiments, RA5or RA7is independently -F or -Cl. In some embodiments, RA5is -F or -Cl. In some embodiments, RA7is -F or -Cl.

[0167] In some embodiments, RA5or RA7is independently C1-3alkyl. In some embodiments, RA5or RA7is independently -CH3. In some embodiments, RA7is -CH3.

[0168] In some embodiments, RA5or RA7is independently C1-3haloalkyl.

[0169] In some embodiments, RA5or RA7is independently -OR’’. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl, 4-10 membered heterocyclyl, or -CH2-(4-10 membered heterocyclyl), wherein the alkyl or heterocyclyl is substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl, 4-10 membered heterocyclyl, or -CH2-(4-10 membered heterocyclyl), wherein the alkyl or heterocyclyl is substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl, 4-6 membered heterocyclyl, or -CH2-(4-6 membered heterocyclyl), wherein the alkyl or heterocyclyl is substituted with 0 or 1 R* groups.

[0170] In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl, 4-6 membered heterocyclyl, or -CH2-(4-6 membered heterocyclyl), wherein the alkyl or heterocyclyl is substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl, 4- 6 membered heterocyclyl, or -CH2-(4-6 membered heterocyclyl), wherein the alkyl or heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl, 4-6 membered heterocyclyl, or -CH2-(4-6 membered heterocyclyl), wherein the alkyl or heterocyclyl is substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0171] In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is C1-3alkyl substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0172] In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is 4-6 membered heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is 4-6 membered heterocyclyl substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0173] In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is -CH2-(4-6 membered heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is -CH2-(4-6 membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -OR’’, wherein R’’ is -CH2-(4-6 membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0174] In some embodiments, RA5or RA7is independently -OH, In some embodiments, RA5is In some embodiments, RA7is -OH or

[0175] In some embodiments, RA5or RA7is independently -OH,

[0176] In some embodiments, RA5or RA7is independently -SR’’.

[0177] In some embodiments, RA5or RA7is independently -NHR”. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-10carbocyclyl or 4-10 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-10carbocyclyl or 4-10 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-6carbocyclyl or 6-8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0 or 1 R* groups.

[0178] In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-6carbocyclyl or 6-8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -NH2, -NHR**, -N(R**)2, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-6carbocyclyl or 6-8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -NH2, -NHR**, -N(R**)2, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0179] In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-6carbocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -NH2, -NHR**, -N(R**)2, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-6carbocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is C3-6carbocyclyl substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -NH2, -NHR**, -N(R**)2, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0180] In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is 6-8 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl, C1-3haloalkyl, -NH2, -NHR**, -N(R**)2, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is 6-8 membered heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -NHR”, wherein R’’ is 6-8 membered heterocyclyl substituted with 1 R* group selected from C1-3alkyl, C1-3haloalkyl, -NH2, -NHR**, -N(R**)2, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, and -(C=O)OR**.

[0181] In some embodiments, RA5or RA7is independently

[0182] In some embodiments, RA5or RA7is independently

[0183] In some embodiments, RA5or RA7is independently -N(R”)2. In some embodiments, RA5or RA7is independently -N(R”)2, wherein each instance of R’’ is independently C1-3alkyl or -L2-(4-10 membered heterocyclyl), or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl, wherein each instance of alkyl and heterocyclyl is independently substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein each instance of R’’ is independently C1-3alkyl or -L2-(4-10 membered heterocyclyl), or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl, wherein each instance of alkyl and heterocyclyl is independently substituted with 0 or 1 R* groups.

[0184] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is C1-3alkyl substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is C1-3alkyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is C1-3alkyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently -N(CH3)(R”).

[0185] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -L2-(4-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-10 membered heterocyclyl substituted with 0 or 1 R* groups.

[0186] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 1 R* group.

[0187] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 0 or 1 R* groups selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 1 R* group selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl.

[0188] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 0 or 1 R* groups selected from halo, C1-3alkyl, -OR**, -(C=O)OR**, and -C1-3alkylene-C3-4carbocyclyl. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 4-6 membered monocyclic heterocyclyl substituted with 1 R* group selected from halo, C1-3alkyl, -OR**, -(C=O)OR**, and -C1-3alkylene-C3-4carbocyclyl.

[0189] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 1 R* group.

[0190] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 0 or 1 R* groups selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4 carbocyclyl, and -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 1 R* group selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl.

[0191] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -(C=O)OR**. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered bridged heterocyclyl substituted with 1 R* group selected from C1-3alkyl and -(C=O)OR**.

[0192] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 1 R* group.

[0193] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 0 or 1 R* groups selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 1 R* group selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl.

[0194] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 0 or 1 C1-3alkyl groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is 6-10 membered spirocyclic heterocyclyl substituted with 1 C1-3alkyl group.

[0195] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 1 R* group.

[0196] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 R* groups selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 1 R* group selected from halo, C1-3alkyl, C1-3haloalkyl, -OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, and -C3-4carbocyclyl.

[0197] In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 0 or 1 -OR**. In some embodiments, RA5or RA7is independently -N(R”)2, wherein at least one instance of R’’ is -(C1-3alkylene)-(4-6 membered monocyclic heterocyclyl), wherein the heterocyclyl is substituted with 1 -OR**.

[0198] In some embodiments, RA5or RA7is independently

[0199] In some embodiments, RA5or RA7is independently .

[0200] In some embodiments, RA5or RA7is independently -N(R”)2, wherein two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently -N(R”)2, wherein two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 2 R* groups. In some embodiments, RA5or RA7is independently -N(R”)2, wherein two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 3 R* groups.

[0201] In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 0 or 1 R* groups. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 2 R* groups. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 3 R* groups.

[0202] In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 0 or 1 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently C3-4carbocyclyl substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0203] In some embodiments, RA5or RA7is independently C3carbocyclyl substituted with 0 or 1 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently C3carbocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently C3carbocyclyl substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0204] In some embodiments, RA5or RA7is independently . In some embodiments, RA5is .

[0205] In some embodiments, RA5or RA7is independently 4-10 membered heterocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently 4-10 membered heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 4-10 membered heterocyclyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently 4-10 membered heterocyclyl substituted with 2 R* groups. In some embodiments, RA5or RA7is independently 4-10 membered heterocyclyl substituted with 3 R* groups.

[0206] In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0207] In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -OR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -OR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 4-6 membered monocyclic heterocyclyl substituted with 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -OR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0208] In some embodiments, RA5or RA7is independently 7-membered monocyclic heterocyclyl substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -OR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is a homopiperazinyl group substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -OR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0209] In some embodiments, RA5or RA7is independently In some embodiments, RA5is In some embodiments, RA7is

[0210] In some embodiments, RA5or RA7is independently , ,

[0211] In some embodiments, RA5or RA7is independently 6-10 membered bicyclic heterocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bicyclic heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bicyclic heterocyclyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered bicyclic heterocyclyl substituted with 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bicyclic heterocyclyl substituted with 3 R* groups.

[0212] In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups.

[0213] In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 2 ring N atoms, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 2 ring N atoms, wherein the heterocyclyl is substituted with 0 R* groups.

[0214] In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered fused heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0215] In some embodiments, RA5or RA7is independently In some embodiments, RA5is .

[0216] In some embodiments, RA5or RA7is independently In some embodiments, RA5is

[0217] In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl substituted with 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl substituted with 3 R* groups.

[0218] In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups.

[0219] In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 2 R* groups.

[0220] In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0221] In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, C1-3alkyl, C1-3haloalkyl, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group, wherein R* is =O, C1-3alkyl, C1-3haloalkyl, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered bridged heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups, wherein each instance of R* is independently =O, C1-3alkyl, C1-3haloalkyl, or -C3-4carbocyclyl.

[0222] In some embodiments, RA5or RA7is independently

[0223] In some embodiments, RA5or RA7is independently

[0224] In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl substituted with 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl substituted with 3 R* groups.

[0225] In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups.

[0226] In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 1 R* group. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 2 ring N atoms, or 1 ring O atom and 1 ring N atom, wherein the heterocyclyl is substituted with 2 R* groups.

[0227] In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group, wherein R* is =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene- OR**, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, or -C3-4carbocyclyl.

[0228] In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently C1-3alkyl, C1-3haloalkyl, -C1-3alkylene- OR**, -C1-3haloalkylene-OR**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, RA5or RA7is independently 6-10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 1 R* group, wherein R* is C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -(C=O)OR**, - C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 6- 10 membered spirocyclic heterocyclyl containing 1 or 2 ring heteroatoms selected from O and N, wherein the heterocyclyl is substituted with 2 R* groups, wherein each instance of R* is independently C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl.

[0229] In some embodiments, RA5or RA7is independently

[0230] In some embodiments, RA5or RA7is independently 5-membered heteroaryl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, RA5or RA7is independently 5-membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene- OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene- N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl. In some embodiments, RA5or RA7is independently 5-membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 0 R* groups.

[0231] In some embodiments, RA5or RA7is independently 5-membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 0, 1, or 2 R* groups, wherein each instance of R* is independently halo, C1-3alkyl, or C1-3haloalkyl. In some embodiments, RA5or RA7is independently 5- membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 1 R* group, wherein the R* group is halo, C1-3alkyl, or C1-3haloalkyl. In some embodiments, RA5or RA7is independently 5-membered heteroaryl containing 1, 2, or 3 ring N atoms, wherein the heteroaryl is substituted with 2 R* groups, wherein each instance of R* is independently halo, C1-3alkyl, or C1-3haloalkyl.

[0232] In some embodiments, RA5or RA7is independently .

[0233] In some embodiments, RA5or RA7is: -F, -Cl,

[0017]

[0234] In some embodiments, RA5or RA7is of formula: -F, -Cl, ,

[0018]

[0235] In some embodiments, RA5is: In some embodiments, RA5is:

[0236] In some embodiments, RA7is hydrogen, -OH, -OCH3, -CH3, -Cl, In some embodiments, RA7is -OCH3,

[0237] As generally described herein, each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl, wherein each instance of alkyl, haloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups.

[0238] In some embodiments, at least one instance of R’’ is C1-3alkyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, at least one instance of R’’ is C1-3alkyl substituted with 0 R* groups. In some embodiments, at least one instance of R’’ is C1-3alkyl substituted with 1 R* group. In some embodiments, at least one instance of R’’ is C1-3alkyl substituted with 2 R* groups. In some embodiments, at least one instance of R’’ is C1-3alkyl substituted with 3 R* groups.

[0239] In some embodiments, at least one instance of R’’ is C1-3haloalkyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, at least one instance of R’’ is C1-3haloalkyl substituted with 0 R* groups. In some embodiments, at least one instance of R’’ is C1-3haloalkyl substituted with 1 R* group. In some embodiments, at least one instance of R’’ is C1-3haloalkyl substituted with 2 R* groups. In some embodiments, at least one instance of R’’ is C1-3haloalkyl substituted with 3 R* groups.

[0240] In some embodiments, at least one instance of R’’ is -L2-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 R* groups. In some embodiments, at least one instance of R’’ is -L2-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 0 R* groups. In some embodiments, at least one instance of R’’ is -L2-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 1 R* group. In some embodiments, at least one instance of R’’ is -L2-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 2 R* groups. In some embodiments, at least one instance of R’’ is -L2-C3-10carbocyclyl, wherein the carbocyclyl is substituted with 3 R* groups.

[0241] In some embodiments, at least one instance of R’’ is -L2-(4-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 0, 1, 2, or 3 R* groups. In some embodiments, at least one instance of R’’ is -L2-(4-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 0 R* groups. In some embodiments, at least one instance of R’’ is -L2-(4-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 1 R* group. In some embodiments, at least one instance of R’’ is -L2-(4- 10 membered heterocyclyl), wherein the heterocyclyl is substituted with 2 R* groups. In some embodiments, at least one instance of R’’ is -L2-(4-10 membered heterocyclyl), wherein the heterocyclyl is substituted with 3 R* groups.

[0242] In some embodiments, at least one instance of R’’ is -L2-(6-membered aryl), wherein the aryl is substituted with 0, 1, 2, or 3 R* groups. In some embodiments, at least one instance of R’’ is -L2-(6- membered aryl), wherein the aryl is substituted with 0 R* groups. In some embodiments, at least one instance of R’’ is -L2-(6-membered aryl), wherein the aryl is substituted with 1 R* group. In some embodiments, at least one instance of R’’ is -L2-(6-membered aryl), wherein the aryl is substituted with 2 R* groups. In some embodiments, at least one instance of R’’ is -L2-(6-membered aryl), wherein the aryl is substituted with 3 R* groups.

[0243] In some embodiments, at least one instance of R’’ is -L2-(5-membered heteroaryl), wherein the heteroaryl is substituted with 0, 1, 2, or 3 R* groups. In some embodiments, at least one instance of R’’ is -L2-(5-membered heteroaryl), wherein the heteroaryl is substituted with 0 R* groups. In some embodiments, at least one instance of R’’ is -L2-(5-membered heteroaryl), wherein the heteroaryl is substituted with 1 R* group. In some embodiments, at least one instance of R’’ is -L2-(5-membered heteroaryl), wherein the heteroaryl is substituted with 2 R* groups. In some embodiments, at least one instance of R’’ is -L2-(5-membered heteroaryl), wherein the heteroaryl is substituted with 3 R* groups.

[0244] In some embodiments, two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 0, 1, 2, or 3 R* groups. In some embodiments, two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 0 R* groups. In some embodiments, two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 1 R* group. In some embodiments, two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 2 R* groups. In some embodiments, two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl substituted with 3 R* groups.

[0245] As generally described herein, L2is absent, C1-3alkylene or C1-3haloalkylene, wherein each instance of alkylene or haloalkylene is independently substituted with 0, 1, 2, or 3 R* groups.

[0246] In some embodiments, L2is absent.

[0247] In some embodiments, L2is C1-3alkylene substituted with 0, 1, 2, or 3 R* groups. In some embodiments, L2is C1-3alkylene substituted with 0 R* groups. In some embodiments, L2is C1-3alkylene substituted with 1 R* group. In some embodiments, L2is C1-3alkylene substituted with 2 R* groups. In some embodiments, L2is C1-3alkylene substituted with 3 R* groups.

[0248] In some embodiments, L2is C1-3haloalkylene substituted with 0, 1, 2, or 3 R* groups. In some embodiments, L2is C1-3haloalkylene substituted with 0 R* groups. In some embodiments, L2is C1-3haloalkylene substituted with 1 R* group. In some embodiments, L2is C1-3haloalkylene substituted with 2 R* groups. In some embodiments, L2is C1-3haloalkylene substituted with 3 R* groups.

[0249] As generally described herein, each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3 haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits.

[0250] In some embodiments, each instance of R* is independently halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl.

[0251] In some embodiments, at least one instance of R* is =O.

[0252] In some embodiments, at least one instance of R* is =NH.

[0253] In some embodiments, at least one instance of R* is =NR**. In some embodiments, at least one instance of R* is =NCH3.

[0254] In some embodiments, at least one instance of R* is halo. In some embodiments, at least one instance of R* is -F or -Cl.

[0255] In some embodiments, at least one instance of R* is C1-3alkyl. In some embodiments, at least one instance of R* is -CH3or -CH2CH3.

[0256] In some embodiments, at least one instance of R* is C1-3haloalkyl.

[0257] In some embodiments, at least one instance of R* is -C1-3alkylene-OR**. In some embodiments, at least one instance of R* is -CH2CH2OCH3.

[0258] In some embodiments, at least one instance of R* is -C1-3haloalkylene-OR**.

[0259] In some embodiments, at least one instance of R* is -C1-3alkylene-NHR**.

[0260] In some embodiments, at least one instance of R* is -C1-3haloalkylene-NHR**.

[0261] In some embodiments, at least one instance of R* is -C1-3alkylene-N(R**)2.

[0262] In some embodiments, at least one instance of R* is -C1-3haloalkylene-N(R**)2.

[0263] In some embodiments, at least one instance of R* is -OR**. In some embodiments, at least one instance of R* is -OCH3.

[0264] In some embodiments, at least one instance of R* is -NH2.

[0265] In some embodiments, at least one instance of R* is -NHR**.

[0266] In some embodiments, at least one instance of R* is -N(R**)2. In some embodiments, at least one instance of R* is -N(CH3)2.

[0267] In some embodiments, at least one instance of R* is -NH(C=O)R**. In some embodiments, at least one instance of R* is -NH(C=O)CH3.

[0268] In some embodiments, at least one instance of R* is -N(R**)(C=O)R**. In some embodiments, at least one instance of R* is -N(CH3)(C=O)CH3.

[0269] In some embodiments, at least one instance of R* is -NH(C=O)OR**. In some embodiments, at least one instance of R* is -NH(C=O)OC(CH3)3.

[0270] In some embodiments, at least one instance of R* is -N(R**)(C=O)OR**.

[0271] In some embodiments, at least one instance of R* is -(C=O)NHR**.

[0272] In some embodiments, at least one instance of R* is -(C=O)N(R**)2. In some embodiments, at least one instance of R* is -(C=O)N(CH3)2or

[0273] In some embodiments, at least one instance of R* is -(C=O)R**. In some embodiments, at least one instance of R* is -(C=O)CH3, -(C=O)CH2CH3, or -(C=O)CH(CH3)OCH3.

[0274] In some embodiments, at least one instance of R* is -(C=O)OR**. In some embodiments, at least one instance of R* is -(C=O)OC(CH3)3.

[0275] In some embodiments, at least one instance of R* is -C1-3alkylene-C3-4carbocyclyl. In some embodiments, at least one instance of R* is

[0276] In some embodiments, at least one instance of R* is C3-4carbocyclyl. In some embodiments, at least one instance of R* is cyclopropyl.

[0277] As generally described herein, each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0278] In some embodiments, at least one instance of R** is C1-6alkyl. In some embodiments, at least one instance of R** is C1-4alkyl. In some embodiments, at least one instance of R** is -CH3, -CH2CH3, or -C(CH3)3.

[0279] In some embodiments, at least one instance of R** is C1-6haloalkyl. In some embodiments, at least one instance of R** is C1-3haloalkyl.

[0280] In some embodiments, at least one instance of R** is -C1-3alkylene-OR#. In some embodiments, at least one instance of R** is -CH(CH3)OCH3.

[0281] In some embodiments, at least one instance of R** is -C1-3haloalkylene-OR#.

[0282] In some embodiments, two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl. In some embodiments, two R** groups together with the nitrogen to which they are attached form

[0283] As generally described herein, each instance of R#is independently C1-3alkyl or C1-3haloalkyl.

[0284] In some embodiments, at least one instance of R#is C1-3alkyl. In some embodiments, at least one instance of R#is -CH3.

[0285] In some embodiments, at least one instance of R#is C1-3haloalkyl.

[0286] As generally described herein, each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0287] In some embodiments, at least one instance of RA6is hydrogen.

[0288] In some embodiments, two instances of RA6are hydrogen.

[0289] In some embodiments, at least one instance of RA6is C1-3alkyl substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2. In some embodiments, at least one instance of RA6is C1-3alkyl substituted with 0 -CN, -OR’’’, -SR’’’, or -N(R’’’)2. In some embodiments, at least one instance of RA6is -CH3.

[0290] In some embodiments, two instances of RA6are -CH3.

[0291] In some embodiments, one instance of RA6is hydrogen, and one instance of RA6is -CH3.

[0292] In some embodiments, at least one instance of RA6is C1-3alkyl substituted with 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2. In some embodiments, at least one instance of RA6is C1-3alkyl substituted with 1 -OR’’’ or -N(R’’’)2. In some embodiments, at least one instance of RA6is -CH2OCH3or -CH2N(CH3)2.

[0293] In some embodiments, one instance of RA6is hydrogen, and one instance of RA6is -CH2OCH3or -CH2N(CH3)2.

[0294] In some embodiments, at least one instance of RA6is C1-3haloalkyl substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2. In some embodiments, at least one instance of RA6is C1-3haloalkyl substituted with 0 -CN, -OR’’’, -SR’’’, or -N(R’’’)2. In some embodiments, at least one instance of RA6is C1-3haloalkyl substituted with 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2.

[0295] In some embodiments, at least one instance of RA6is C3-4carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is C3-4carbocyclyl substituted with 0 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is C3-4carbocyclyl substituted with 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is cyclopropyl.

[0296] In some embodiments, one instance of RA6is hydrogen, and one instance of RA6is cyclopropyl.

[0297] In some embodiments, at least one instance of RA6is 4-5 membered heterocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 4-5 membered heterocyclyl substituted with 0 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 4-5 membered heterocyclyl substituted with 1 C1-3alkyl or C1-3haloalkyl.

[0298] In some embodiments, at least one instance of RA6is 6-membered aryl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 6-membered aryl substituted with 0 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 6-membered aryl substituted with 1 C1-3alkyl or C1-3haloalkyl.

[0299] In some embodiments, at least one instance of RA6is 5-membered heteroaryl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 5-membered heteroaryl substituted with 0 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 5- membered heteroaryl substituted with 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is 5-membered heteroaryl containing 1 or 2 ring N atoms, wherein the heteroaryl is substituted with 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, at least one instance of RA6is . In some embodiments, one instance of RA6is hydrogen, and one instance of RA6is .

[0300] In some embodiments, two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, two RA6groups attached to the same carbon atom are joined to form a C3carbocyclyl substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl. In some embodiments, two RA6groups attached to the same carbon atom are joined to form a C3carbocyclyl. In some embodiments, two RA6groups attached to the same carbon atom are joined to form cyclopropyl.

[0301] In some embodiments, at least one instance of RA6is hydrogen, -CH3, -CH2OCH3, -CH2N(CH3)2, cyclopropyl, or or two RA6groups attached to the same carbon atom are joined to form cyclopropyl. In some embodiments, one instance of RA6is hydrogen, and one instance of RA6is hydrogen, -CH3, -CH2OCH3, -CH2N(CH3)2, cyclopropyl, or or two RA6groups attached to the same carbon atom are joined to form cyclopropyl.

[0302] As generally described herein, each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl.

[0303] In some embodiments, at least one instance of R’’’ is hydrogen.

[0304] In some embodiments, at least one instance of R’’’ is C1-3alkyl. In some embodiments, at least one instance of R’’’ is -CH3.

[0305] In some embodiments, at least one instance of R’’’ is C1-3haloalkyl.

[0306] In some embodiments, two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl.

[0307] As generally described herein, x is 1 or 2.

[0308] In some embodiments, x is 1. In some embodiments, x is 2. G1and RC

[0309] As generally described herein, G1is CH, CF, or N.

[0310] In some embodiments, G1is CH.

[0311] In some embodiments, G1is CF.

[0312] In some embodiments, G1is N.

[0313] As generally described herein, RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo.

[0314] In some embodiments, RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkenyl, or -C1alkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo. In some embodiments, RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkenyl, or -C1alkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0 halo.

[0315] In some embodiments, RCis C2-5alkyl or C2-5haloalkyl.

[0316] In some embodiments, RCis C2-5alkyl. In some embodiments, RCis C2-4alkyl. In some embodiments, RCis C2-3alkyl.

[0317] In some embodiments, RCis linear C2-5alkyl. In some embodiments, RCis linear C2-4alkyl. In some embodiments, RCis linear C2-3alkyl.

[0318] In some embodiments, RCis selected from the group consisting of: , , C In some embodiments, R is

[0319] In some embodiments, RCis C2-5haloalkyl. In some embodiments, RCis C2-4haloalkyl. In some embodiments, RCis C2-3haloalkyl.

[0320] In some embodiments, RCis C2-5alkenyl or C2-5haloalkenyl.

[0321] In some embodiments, RCis C2-5alkenyl. In some embodiments, RCis C3-5alkenyl. In some embodiments, RCis C3-4alkenyl.

[0322] In some embodiments, RCis linear C2-5alkenyl. In some embodiments, RCis linear C3-5alkenyl. In some embodiments, RCis linear C3-4alkenyl.

[0323] In some embodiments, RCis selected from the group consisting of: , , and .

[0324] In some embodiments, RCis C2-5haloalkenyl. In some embodiments, RCis C3-5haloalkenyl. In some embodiments, RCis C3-4haloalkenyl.

[0325] In some embodiments, RCis C2-5fluoroalkenyl. In some embodiments, RCis C3-5fluoroalkenyl. In some embodiments, RCis C3-4fluoroalkenyl.

[0326] In some embodiments, RCis

[0327] In some embodiments, RCis -C1alkylene-C3carbocyclyl or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo.

[0328] In some embodiments, RCis -C1alkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo. In some embodiments, RCis -C1alkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 halo. In some embodiments, RCis -C1alkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0 halo.

[0329] In some embodiments, RCis

[0330] In some embodiments, RCis -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo. In some embodiments, RCis -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 halo. In some embodiments, RCis -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0 halo.

[0331] In some embodiments, RCis selected from the group consisting of: , ,

[0332] In some embodiments, G1is N; and RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkenyl, or -C1alkylene- C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo. In some embodiments, G1is N; and RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkenyl, or -C1alkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0 halo.

[0333] In some embodiments, G1is N; and RCis selected from the group consisting of: , In some embodiments, G1is N; and RCis X and RD1

[0334] As generally described herein, X is O, S, or NH.

[0335] In some embodiments, X is O.

[0336] In some embodiments, X is S.

[0337] In some embodiments, X is NH.

[0338] As generally described herein, RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E: , wherein: Ring E is a C3-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3; each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3) -C(=O)N(RE3)2, -S(=O)RE3or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; and y is 0, 1, 2, or 3.

[0339] In some embodiments, RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 RD1Agroups. In some embodiments, RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 1 RD1Agroup.

[0340] In some embodiments, RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with -ORD1Bor -CN. In some embodiments, RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with -OCH3or -CN.

[0341] In some embodiments, RD1is C1-3alkyl or C1-3haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-3alkyl or C1-3haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 RD1Agroups. In some embodiments, RD1is C1-3alkyl or C1-3haloalkyl, wherein the alkyl or haloalkyl is substituted with 1 RD1Agroup.

[0342] In some embodiments, RD1is C1-3alkyl or C1-3haloalkyl, wherein the alkyl or haloalkyl is substituted with -ORD1Bor -CN. In some embodiments, RD1is C1-3alkyl or C1-3haloalkyl, wherein the alkyl or haloalkyl is substituted with -OCH3or -CN.

[0343] In some embodiments, RD1is C1-6alkyl substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-6alkyl substituted with 0 RD1Agroups. In some embodiments, RD1is C1-6alkyl substituted with 1 RD1Agroup.

[0344] In some embodiments, RD1is C1-6alkyl substituted with -ORD1Bor -CN. In some embodiments, RD1is C1-6alkyl substituted with -OCH3or -CN.

[0345] In some embodiments, RD1is C1-3alkyl substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-3alkyl substituted with 0 RD1Agroups. In some embodiments, RD1is C1-3alkyl substituted with 1 RD1Agroup.

[0346] In some embodiments, RD1is -CH3or -CH2CH3.

[0347] In some embodiments, RD1is C1-3alkyl substituted with -ORD1Bor -CN. In some embodiments, RD1is C1-3alkyl substituted with -OCH3or -CN.

[0348] In some embodiments, RD1is -CH2CH2OCH3or -CH2CN.

[0349] In some embodiments, RD1is C1-6haloalkyl substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-6haloalkyl substituted with 0 RD1Agroups. In some embodiments, RD1is C1-6haloalkyl substituted with 1 RD1Agroup.

[0350] In some embodiments, RD1is C1-3haloalkyl substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-3haloalkyl substituted with 0 RD1Agroups. In some embodiments, RD1is C1-3haloalkyl substituted with 1 RD1Agroup.

[0351] In some embodiments, RD1is C1-3fluoroalkyl substituted with 0 or 1 RD1Agroups. In some embodiments, RD1is C1-3fluoroalkyl substituted with 0 RD1Agroups. In some embodiments, RD1is C1-3fluoroalkyl substituted with 1 RD1Agroup. In some embodiments, RD1is -CH2CHF2.

[0352] In some embodiments, RD1is -CH3, -CH2CH3, -CH2CHF2, -CH2CH2OCH3, or -CH2CN.

[0353] In some embodiments, RD1Ais -OH.

[0354] In some embodiments, RD1Ais -ORD1B. In some embodiments, RD1Ais -OCH3.

[0355] In some embodiments, RD1Ais -NH2.

[0356] In some embodiments, RD1Ais -NH(RD1B).

[0357] In some embodiments, RD1Ais -N(RD1B)2.

[0358] In some embodiments, RD1Ais -SH.

[0359] In some embodiments, RD1Ais -SRD1B.

[0360] In some embodiments, RD1Ais -CN.

[0361] In some embodiments, RD1Ais -C(=O)RD1B.

[0362] In some embodiments, RD1Ais -C(=O)ORD1B.

[0363] In some embodiments, RD1Ais -C(=O)NH(RD1B).

[0364] In some embodiments, RD1Ais -C(=O)N(RD1B)2.

[0365] In some embodiments, RD1Ais -S(=O)RD1B.

[0366] In some embodiments, RD1Ais -S(=O)2RD1B.

[0367] In some embodiments, RD1Ais -ORD1Bor -CN.

[0368] In some embodiments, at least one instance of RD1Bis C1-3alkyl. In some embodiments, at least one instance of RD1Bis -CH3.

[0369] In some embodiments, at least one instance of RD1Bis C1-3haloalkyl.

[0370] In some embodiments, RD1is Ring E of formula , wherein Ring E is a C3-8carbocyclyl or a 4-8 membered heterocyclyl. In some embodiments, RD1is Ring E of formula , wherein Ring E is a C4-8carbocyclyl or a 4-8 membered heterocyclyl. In some embodiments, RD1is Ring E of formula , wherein Ring E is a C3-8carbocyclyl. In some embodiments, RD1is Ring E of formula wherein Ring E is a 4-8 membered heterocyclyl.

[0371] In some embodiments, Ring E is a C3-8carbocyclyl. In some embodiments, Ring E is a C4-8carbocyclyl. In some embodiments, Ring E is a C4-6carbocyclyl. In some embodiments, Ring E is a C4-5carbocyclyl. In some embodiments, Ring E is a C4carbocyclyl. In some embodiments, Ring E is a C5carbocyclyl.

[0372] In some embodiments, Ring E is a 4-8 membered heterocyclyl. In some embodiments, Ring E is a 4-5 membered heterocyclyl.

[0373] In some embodiments, Ring E is a 4-8 membered monocyclic heterocyclyl. In some embodiments, Ring E is a 4-5 membered monocyclic heterocyclyl.

[0374] In some embodiments, Ring E is a 4-8 membered heterocyclyl containing 1 ring heteroatom selected from O and N. In some embodiments, Ring E is a 4-5 membered heterocyclyl containing 1 ring heteroatom selected from O and N. In some embodiments, Ring E is a 4-5 membered heterocyclyl containing 1 ring O atom. In some embodiments, Ring E is a 4-5 membered heterocyclyl containing 1 ring N atom.

[0375] In some embodiments, Ring E is a 4-8 membered monocyclic heterocyclyl containing 1 ring heteroatom selected from O and N. In some embodiments, Ring E is a 4-5 membered monocyclic heterocyclyl containing 1 ring heteroatom selected from O and N. In some embodiments, Ring E is a 4-5 membered monocyclic heterocyclyl containing 1 ring O atom. In some embodiments, Ring E is a 4-5 membered monocyclic heterocyclyl containing 1 ring N atom.

[0376] In some embodiments, Ring E is a 6-8 membered heterocyclyl. In some embodiments, Ring E is a 6-8 membered spirocyclic heterocyclyl. In some embodiments, Ring E is a 6-8 membered spirocyclic heterocyclyl containing 1 ring N atom. In some embodiments, Ring E is a 6-8 membered spirocyclic heterocyclyl containing 1 ring O atom. In some embodiments, Ring E is a 6-8 membered bridged heterocyclyl. In some embodiments, Ring E is a 6-8 membered bridged heterocyclyl containing 1 ring O atom.

[0377] In some embodiments, RD1is Ring E selected from the group consisting of: wherein y is 0, 1, 2 or 3, as valency permits.

[0378] It is understood that when polycyclic ring systems are contemplated for Ring E, as depicted above for various spiro-fused or bridged ring systems, that any of the rings so depicted may be substituted with RE. The hovering group REover one ring is depicted for simplicity and is not limiting.

[0379] In some embodiments, RD1is Ring E of formula (E-1). In some embodiments, RD1is Ring E of formula (E-2). In some embodiments, RD1is Ring E of formula (E-3). In some embodiments, RD1is Ring E of formula (E-4). In some embodiments, RD1is Ring E of formula (E-5). In some embodiments, RD1is Ring E of formula (E-6). In some embodiments, RD1is Ring E of formula (E-7). In some embodiments, RD1is Ring E of formula (E-8). In some embodiments, RD1is Ring E of formula (E-9). In some embodiments, RD1is Ring E of formula (E-10). In some embodiments, RD1is Ring E of formula (E-11). In some embodiments, RD1is Ring E of formula (E-12). In some embodiments, RD1is Ring E of formula (E-13).

[0380] In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2), (E-3), (E- 4), (E-5), (E-6), (E-8), (E-10), (E-12), and (E-13), wherein y is 0. In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2), (E-3), (E-4), (E-5), (E-6), (E-7), (E-8), (E-9), (E-10), (E-11), (E-12), and (E-13), wherein y is 1. In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2), (E-3), (E-4), (E-5), (E-6), (E-7), (E-8), (E-9), (E-10), (E-11), (E-12), and (E- 13), wherein y is 2. In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E- 2), (E-3), (E-4), (E-5), (E-6), (E-7), (E-8), (E-9), (E-10), (E-11), (E-12), and (E-13), wherein y is 3.

[0381] In some embodiments, RD1is Ring E selected from the group consisting of:

[0019] wherein y is 0, 1, 2 or 3, as valency permits.

[0382] In some embodiments, RD1is Ring E of formula (E-2a). In some embodiments, RD1is Ring E of formula (E-2b). In some embodiments, RD1is Ring E of formula (E-3a). In some embodiments, RD1is Ring E of formula (E-3b). In some embodiments, RD1is Ring E of formula (E-8a). In some embodiments, RD1is Ring E of formula (E-8b). In some embodiments, RD1is Ring E of formula (E-9a). In some embodiments, RD1is Ring E of formula (E-9b). In some embodiments, RD1is Ring E of formula (E-10a). In some embodiments, RD1is Ring E of formula (E-10b). In some embodiments, RD1is Ring E of formula (E-11a). In some embodiments, RD1is Ring E of formula (E-11b). In some embodiments, RD1is Ring E of formula (E-12a). In some embodiments, RD1is Ring E of formula (E-12b). In some embodiments, RD1is Ring E of formula (E-13a). In some embodiments, RD1is Ring E of formula (E- 13b). In some embodiments, RD1is Ring E of formula (E-13c). In some embodiments, RD1is Ring E of formula (E-13d).

[0383] In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2a), (E-2b), (E-3a), (E-3b), (E-4), (E-5), (E-6), (E-8a), (E-8b), (E-10a), (E-10b), (E-12a), (E-12b), (E-13a), (E- 13b), (E-13c), and (E-13d), wherein y is 0. In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2a), (E-2b), (E-3a), (E-3b), (E-4), (E-5), (E-6), (E-7), (E-8a), (E-8b), (E-9a), (E-9b), (E-10a), (E-10b), (E-11a), (E-11b), (E-12a), (E-12b), (E-13a), (E-13b), (E-13c), and (E-13d), wherein y is 1. In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2a), (E-2b), (E-3a), (E-3b), (E-4), (E-5), (E-6), (E-7), (E-8a), (E-8b), (E-9a), (E-9b), (E-10a), (E-10b), (E- 11a), (E-11b), (E-12a), (E-12b), (E-13a), (E-13b), (E-13c), and (E-13d), wherein y is 2. In some embodiments, RD1is Ring E selected from the group consisting of (E-1), (E-2a), (E-2b), (E-3a), (E-3b), (E-4), (E-5), (E-6), (E-7), (E-8a), (E-8b), (E-9a), (E-9b), (E-10a), (E-10b), (E-11a), (E-11b), (E-12a), (E-12b), (E-13a), (E-13b), (E-13c), and (E-13d), wherein y is 3.

[0384] In some embodiments, RD1is Ring E of formula:

[0385] In some embodiments, RD1is Ring E of formula (E-2c). In some embodiments, RD1is Ring E of formula (E-2d). In some embodiments, RD1is Ring E of formula (E-2e). In some embodiments, RD1is Ring E of formula (E-2f). In some embodiments, RD1is Ring E of formula (E-2g). In some embodiments, RD1is Ring E of formula (E-2h). In some embodiments, RD1is Ring E of formula (E-2i).

[0386] In some embodiments, RD1is Ring E of formula:

[0387] In some embodiments, RD1is Ring E of formula (E-2j). In some embodiments, RD1is Ring E of formula (E-2k). In some embodiments, RD1is Ring E of formula (E-2l). In some embodiments, RD1is Ring E of formula (E-2m). In some embodiments, RD1is Ring E of formula (E-2n). In some embodiments, RD1is Ring E of formula (E-2o). In some embodiments, RD1is Ring E of formula (E-2p). In some embodiments, RD1is Ring E of formula (E-2q). In some embodiments, RD1is Ring E of formula (E-2r). In some embodiments, RD1is Ring E of formula (E-2s). In some embodiments, RD1is Ring E of formula (E-2t). In some embodiments, RD1is Ring E of formula (E-2u). In some embodiments, RD1is Ring E of formula (E-2v). In some embodiments, RD1is Ring E of formula (E-2w). In some embodiments, RD1is Ring E of formula (E-2x). In some embodiments, RD1is Ring E of formula (E-2y). In some embodiments, RD1is Ring E of formula (E-2z). In some embodiments, RD1is Ring E of formula (E-2aa). In some embodiments, RD1is Ring E of formula (E-2ab). In some embodiments, RD1is Ring E of formula (E-2ac).

[0388] In some embodiments, RD1is Ring E of formula (E-4) or (E-5).

[0389] In some embodiments, RD1is Ring E of formula:

[0390] In some embodiments, RD1is Ring E of formula:

[0391] In some embodiments, RD1is Ring E of formula (E-4a) or (E-4b). In some embodiments, RD1is Ring E of formula (E-4a). In some embodiments, RD1is Ring E of formula (E-4b). In some embodiments, RD1is Ring E of formula (E-4c), (E-4d), or (E-4e). In some embodiments, RD1is Ring E of formula (E-4c). In some embodiments, RD1is Ring E of formula (E-4d). In some embodiments, RD1is Ring E of formula (E-4e). In some embodiments, RD1is Ring E of formula (E-4f) or (E-4g). In some embodiments, RD1is Ring E of formula (E-4f). In some embodiments, RD1is Ring E of formula (E-4g).

[0392] In some embodiments, RD1is Ring E of formula: wherein RE* is a group RE, and RE** is the same or a different group RE. In some embodiments, RE* is a group RE, and RE** is a different group RE.

[0393] In some embodiments, RD1is Ring E of formula:

[0394] In some embodiments, RD1is Ring E of formula (E-4h). In some embodiments, RD1is Ring E of formula (E-4i). In some embodiments, RD1is Ring E of formula (E-4j). In some embodiments, RD1is Ring E of formula (E-4k). In some embodiments, RD1is Ring E of formula (E-4l). In some embodiments, RD1is Ring E of formula (E-4m). In some embodiments, RD1is Ring E of formula (E-4n). In some embodiments, RD1is Ring E of formula (E-4o). In some embodiments, RD1is Ring E of formula (E-4p). In some embodiments, RD1is Ring E of formula (E-4q). In some embodiments, RD1is Ring E of formula (E-4r). In some embodiments, RD1is Ring E of formula (E-4s). In some embodiments, RD1is Ring E of formula (E-4t). In some embodiments, RD1is Ring E of formula (E-4u). In some embodiments, RD1is Ring E of formula (E-4v). In some embodiments, RD1is Ring E of formula (E-4w).

[0395] In some embodiments, RD1is Ring E of formula:

[0396] In some embodiments, RD1is Ring E of formula:

[0397] In some embodiments, RD1is Ring E of formula:

[0398] In some embodiments, RD1is Ring E of formula:

[0399] In some embodiments, RD1is Ring E of formula:

[0020]

[0400] In some embodiments, RD1is Ring E of formula:

[0021]

[0401] In some embodiments, Ring D of formula: is a group of formula:

[0402] In some embodiments, Ring D is a group of formula (D-1). In some embodiments, Ring D is a group of formula (D-2). In some embodiments, Ring D is a group of formula (D-3). In some embodiments, Ring D is a group of formula (D-4). In some embodiments, Ring D is a group of formula (D-5). In some embodiments, Ring D is a group of formula (D-6). In some embodiments, Ring D is a group of formula (D-7). In some embodiments, Ring D is a group of formula (D-8).

[0403] In some embodiments, Ring D is a group of formula: wherein y is 0, 1, 2 or 3.

[0404] In some embodiments, Ring D is a group of formula (D-1a). In some embodiments, Ring D is a group of formula (D-2a). In some embodiments, Ring D is a group of formula (D-3a). In some embodiments, Ring D is a group of formula (D-4a). In some embodiments, Ring D is a group of formula (D-5a). In some embodiments, Ring D is a group of formula (D-6a). In some embodiments, Ring D is a group of formula (D-7a). In some embodiments, Ring D is a group of formula (D-8a).

[0405] In some embodiments, Ring D is a group of formula (D-1a), (D-2a), (D-3a), (D-4a), (D-5a), (D- 6a), (D-7a), or (D-8a), wherein y is 0. In some embodiments, Ring D is a group of formula (D-1a), (D- 2a), (D-3a), (D-4a), (D-5a), (D-6a), (D-7a), or (D-8a), wherein y is 1. In some embodiments, Ring D is a group of formula (D-1a), (D-2a), (D-3a), (D-4a), (D-5a), (D-6a), (D-7a), or (D-8a), wherein y is 2. In some embodiments, Ring D is a group of formula (D-1a), (D-2a), (D-3a), (D-4a), (D-5a), (D-6a), (D- 7a), or (D-8a), wherein y is 3.

[0406] In some embodiments, Ring D is a group of formula: wherein y is 0, 1, 2 or 3.

[0407] In some embodiments, Ring D is a group of formula (D-1b). In some embodiments, Ring D is a group of formula (D-2b). In some embodiments, Ring D is a group of formula (D-3b). In some embodiments, Ring D is a group of formula (D-4b). In some embodiments, Ring D is a group of formula (D-5b). In some embodiments, Ring D is a group of formula (D-6b). In some embodiments, Ring D is a group of formula (D-7b). In some embodiments, Ring D is a group of formula (D-8b).

[0408] In some embodiments, Ring D is a group of formula (D-1b), (D-2b), (D-3b), (D-4b), (D-5b), (D- 6b), (D-7b), or (D-8b), wherein y is 0. In some embodiments, Ring D is a group of formula (D-1b), (D- 2b), (D-3b), (D-4b), (D-5b), (D-6b), (D-7b), or (D-8b), wherein y is 1. In some embodiments, Ring D is a group of formula (D-1b), (D-2b), (D-3b), (D-4b), (D-5b), (D-6b), (D-7b), or (D-8b), wherein y is 2. In some embodiments, Ring D is a group of formula (D-1b), (D-2b), (D-3b), (D-4b), (D-5b), (D-6b), (D- 7b), or (D-8b), wherein y is 3.

[0409] As generally described herein, each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2;

[0410] In some embodiments, at least one instance of REis halo. In some embodiments, at least one instance of REis -F.

[0411] In some embodiments, at least one instance of REis C1-6alkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of REis C1-6alkyl substituted with 0 RE2. In some embodiments, at least one instance of REis C1-3alkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of REis C1-3alkyl substituted with 0 RE2. In some embodiments, at least one instance of REis - CH3.

[0412] In some embodiments, at least one instance of REis C1-6haloalkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of REis C1-6haloalkyl substituted with 0 RE2. In some embodiments, at least one instance of REis C1-3haloalkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of REis C1-3haloalkyl substituted with 0 RE2.

[0413] In some embodiments, at least one instance of REis C3-4carbocyclyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of REis C3-4carbocyclyl substituted with 0 RE2. In some embodiments, at least one instance of REis

[0414] In some embodiments, at least one instance of REis 4 membered heterocyclyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of REis 4 membered heterocyclyl substituted with 0 RE2. In some embodiments, at least one instance of REis

[0415] In some embodiments, at least one instance of REis -OH.

[0416] In some embodiments, at least one instance of REis -ORE1. In some embodiments, at least one instance of REis -OCH3.

[0417] In some embodiments, at least one instance of REis -NH2.

[0418] In some embodiments, at least one instance of REis -NH(RE1). In some embodiments, at least one instance of REis

[0419] In some embodiments, at least one instance of REis -N(RE1)2. In some embodiments, at least one instance of REis -N(CH3)2.

[0420] In some embodiments, at least one instance of REis -SH.

[0421] In some embodiments, at least one instance of REis -SRE1.

[0422] In some embodiments, at least one instance of REis -CN.

[0423] In some embodiments, at least one instance of REis -NHC(=O)RE1. In some embodiments, at least one instance of REis

[0424] In some embodiments, at least one instance of REis -NHC(=O)ORE1. In some embodiments, at least one instance of REis

[0425] In some embodiments, at least one instance of REis -N(RE1)C(=O)ORE1. In some embodiments, at least one instance of REis

[0426] In some embodiments, at least one instance of REis -NHC(=O)NH(RE1).

[0427] In some embodiments, at least one instance of REis -NHC(=O)N(RE1)2.

[0428] In some embodiments, at least one instance of REis -N(RE1)C(=O)NH(RE1).

[0429] In some embodiments, at least one instance of REis -N(RE1)C(=O)N(RE1)2.

[0430] In some embodiments, at least one instance of REis -OC(=O)RE1.

[0431] In some embodiments, at least one instance of REis -OC(=O)ORE1.

[0432] In some embodiments, at least one instance of REis -OC(=O)NH(RE1).

[0433] In some embodiments, at least one instance of REis -OC(=O)N(RE1)2.

[0434] In some embodiments, at least one instance of REis -C(=O)RE1.

[0435] In some embodiments, at least one instance of REis -C(=O)ORE1. In some embodiments, at least one instance of REis

[0436] In some embodiments, at least one instance of REis -C(=O)NH(RE1). In some embodiments, at least one instance of REis

[0437] In some embodiments, at least one instance of REis -C(=O)N(RE1)2.

[0438] In some embodiments, at least one instance of REis -S(=O)RE1.

[0439] In some embodiments, at least one instance of REis -S(=O)2RE1.

[0440] In some embodiments, two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl substituted with 0, 1, or 2 RE2.

[0441] As generally described herein, each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3.

[0442] In some embodiments, at least one instance of RE1is C1-6alkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of RE1is C1-6alkyl substituted with 0 RE2. In some embodiments, at least one instance of RE1is C1-6alkyl substituted with 1 RE2. In some embodiments, at least one instance of RE1is C1-6alkyl substituted with 2 RE2.

[0443] In some embodiments, at least one instance of RE1is C1-3alkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of RE1is C1-3alkyl substituted with 0 RE2. In some embodiments, at least one instance of RE1is C1-3alkyl substituted with 1 RE2. In some embodiments, at least one instance of RE1is C1-3alkyl substituted with 2 RE2. In some embodiments, at least one instance of RE1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH(CH3)2, or -CH2C(CH3)3. In some embodiments, at least one instance of RE1is -CH2CH2OCH3, -CH2CH2S(=O)2CH3, or -CH2CH(OH)CH3.

[0444] In some embodiments, at least one instance of RE1is C1-6haloalkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of RE1is C1-6haloalkyl substituted with 0 RE2. In some embodiments, at least one instance of RE1is C1-6haloalkyl substituted with 1 RE2. In some embodiments, at least one instance of RE1is C1-6haloalkyl substituted with 2 RE2.

[0445] In some embodiments, at least one instance of RE1is C1-3haloalkyl substituted with 0, 1, or 2 RE2. In some embodiments, at least one instance of RE1is C1-3haloalkyl substituted with 0 RE2. In some embodiments, at least one instance of RE1is C1-3haloalkyl substituted with 1 RE2. In some embodiments, at least one instance of RE1is C1-3haloalkyl substituted with 2 RE2. In some embodiments, at least one instance of RE1is -CH2CHF2or -CH2CH2CHF2.

[0446] In some embodiments, at least one instance of RE1is -L1-C3-5carbocyclyl substituted with 0, 1, or 2 RE2and further substituted with 0, 1, or 2 RE3. In some embodiments, at least one instance of RE1is -L1- C3-5carbocyclyl substituted with 0 RE2and substituted with 0, 1, or 2 RE3. In some embodiments, at least one instance of RE1is -L1-C3-5carbocyclyl substituted with 0, 1, or 2 RE2and substituted with 0 RE3. In some embodiments, at least one instance of RE1is -L1-C3-5carbocyclyl substituted with 0 RE2and 0 RE3. In some embodiments, at least one instance of RE1is -L1-C3-5carbocyclyl substituted with 0 RE2and substituted with 1 RE3. In some embodiments, at least one instance of RE1is -L1-C3-5carbocyclyl substituted with 1 RE2and substituted with 0 RE3. In some embodiments, at least one instance of RE1is - L1-C3-5carbocyclyl substituted with 1 RE2and further substituted with 1 RE3.

[0447] In some embodiments, at least one instance of RE1is -CH2-C3-5carbocyclyl substituted with 0 RE2and 0 RE3. In some embodiments, at least one instance of RE1is -CH2-C3-5carbocyclyl substituted with 0 RE2and substituted with 1 RE3. In some embodiments, at least one instance of RE1is -CH2-C3-5carbocyclyl substituted with 1 RE2and substituted with 0 RE3. In some embodiments, at least one instance of RE1is -CH2-C3-5carbocyclyl substituted with 1 RE2and further substituted with 1 RE3. In some embodiments, at least one instance of RE1is

[0448] In some embodiments, at least one instance of RE1is C3-5carbocyclyl substituted with 0 RE2and 0 RE3. In some embodiments, at least one instance of RE1is C3-5carbocyclyl substituted with 0 RE2and substituted with 1 RE3. In some embodiments, at least one instance of RE1is C3-5carbocyclyl substituted with 1 RE2and substituted with 0 RE3. In some embodiments, at least one instance of RE1is C3-5carbocyclyl substituted with 1 RE2and further substituted with 1 RE3. In some embodiments, at least one instance of RE1is

[0449] In some embodiments, at least one instance of RE1is -L1-(4-5 membered heterocyclyl); wherein the heterocyclyl is substituted with 0, 1, or 2 RE2and further substituted with 0, 1, or 2 RE3. In some embodiments, at least one instance of RE1is -L1-(4-5 membered heterocyclyl); wherein the heterocyclyl is substituted with 0 RE2and substituted with 0, 1, or 2 RE3. In some embodiments, at least one instance of RE1is -L1-(4-5 membered heterocyclyl); wherein the heterocyclyl is substituted with 0, 1, or 2 RE2and substituted with 0 RE3. In some embodiments, at least one instance of RE1is -L1-(4-5 membered heterocyclyl); wherein the heterocyclyl is substituted with 0 RE2and 0 RE3.

[0450] In some embodiments, at least one instance of RE1is 4-5 membered heterocyclyl; wherein the heterocyclyl is substituted with 0, 1, or 2 RE2and further substituted with 0, 1, or 2 RE3. In some embodiments, at least one instance of RE1is 4-5 membered heterocyclyl; wherein the heterocyclyl is substituted with 0 RE2and 0 RE3. In some embodiments, at least one instance of RE1is

[0451] In some embodiments, two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl substituted with 0, 1, or 2 RE2and further substituted with 0, 1, or 2 RE3.

[0452] In some embodiments, at least one instance of RE1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH2CH2OCH3, -CH2CH2S(=O)2CH3, -CH2CH(OH)CH3, -CH2CHF2, -CH2CH2CHF2,

[0453] As generally described herein, L1is absent, C1-3alkylene or C1-3haloalkylene.

[0454] In some embodiments, L1is absent.

[0455] In some embodiments, L1is C1-3alkylene. In some embodiments, L1is -CH2-.

[0456] In some embodiments, L1is C1-3haloalkylene.

[0457] As generally described herein, each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3) -C(=O)N(RE3)2, -S(=O)RE3or -S(=O)2RE3.

[0458] In some embodiments, at least one instance of RE2is halo. In some embodiments, at least one instance of RE2is -F.

[0459] In some embodiments, at least one instance of RE2is -OH.

[0460] In some embodiments, at least one instance of RE2is -ORE3. In some embodiments, at least one instance of RE2is -OCH3.

[0461] In some embodiments, at least one instance of RE2is -NH2.

[0462] In some embodiments, at least one instance of RE2is -NH(RE3).

[0463] In some embodiments, at least one instance of RE2is -N(RE3)2.

[0464] In some embodiments, at least one instance of RE2is -SH.

[0465] In some embodiments, at least one instance of RE2is -SRE3.

[0466] In some embodiments, at least one instance of RE2is -CN.

[0467] In some embodiments, at least one instance of RE2is -C(=O)RE3.

[0468] In some embodiments, at least one instance of RE2is -C(=O)ORE3.

[0469] In some embodiments, at least one instance of RE2is -C(=O)NH(RE3).

[0470] In some embodiments, at least one instance of RE2is -C(=O)N(RE3)2.

[0471] In some embodiments, at least one instance of RE2is -S(=O)RE3.

[0472] In some embodiments, at least one instance of RE2is -S(=O)2RE3. In some embodiments, at least one instance of RE2is -S(=O)2CH3,

[0473] As generally described herein, each instance of RE3is independently C1-3alkyl or C1-3haloalkyl.

[0474] In some embodiments, at least one instance of RE3is C1-3alkyl. In some embodiments, at least one instance of RE3is -CH3.

[0475] In some embodiments, at least one instance of RE3is C1-3haloalkyl. In some embodiments, at least one instance of RE3is C1haloalkyl. In some embodiments, at least one instance of RE3is C1fluoroalkyl. In some embodiments, at least one instance of RE3is -CHF2.

[0476] As generally described herein, y is 0, 1, 2, or 3.

[0477] In some embodiments, y is 0, 1, or 2. In some embodiments, y is 0 or 1. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. RD2and RD3

[0478] As generally described herein, RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo.

[0479] In some embodiments, RD2is halo, C1alkyl, C1haloalkyl, or C3carbocyclyl. In some embodiments, RD2is bromo, chloro, -CH3, -CHF2, or cyclopropyl. In some embodiments, RD2is chloro or -CH3.

[0480] In some embodiments, RD2is halo. In some embodiments, RD2is fluoro, chloro, or bromo. In some embodiments, RD2is chloro or bromo. In some embodiments, RD2is chloro.

[0481] In some embodiments, RD2is C1-3alkyl. In some embodiments, RD2is C1-2alkyl. In some embodiments, RD2is C1alkyl. In some embodiments, RD2is -CH3.

[0482] In some embodiments, RD2is C1-3haloalkyl. In some embodiments, RD2is C1-2haloalkyl. In some embodiments, RD2is C1haloalkyl.

[0483] In some embodiments, RD2is C1-3fluoroalkyl. In some embodiments, RD2is C1-2fluoroalkyl. In some embodiments, RD2is C1fluoroalkyl. In some embodiments, RD2is -CH2F, -CHF2, or -CF3. In some embodiments, RD2is -CHF2.

[0484] In some embodiments, RD2is C3carbocyclyl substituted with 0, 1, 2, or 3 halo. In some embodiments, RD2is C3carbocyclyl substituted with 0, 1, or 2 halo. In some embodiments, RD2is C3carbocyclyl substituted with 0 or 1 halo. In some embodiments, RD2is C3carbocyclyl. In some embodiments, RD2is cyclopropyl.

[0485] As generally described herein, RD3is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo.

[0486] In some embodiments, RD3is hydrogen or halo.

[0487] In some embodiments, RD3is hydrogen or fluoro.

[0488] In some embodiments, RD3is hydrogen.

[0489] In some embodiments, RD3is fluoro, chloro, or bromo. In some embodiments, RD3is fluoro or chloro. In some embodiments, RD3is fluoro.

[0490] In some embodiments, RD3is C1-3alkyl. In some embodiments, RD3is C1-2alkyl. In some embodiments, RD3is C1alkyl.

[0491] In some embodiments, RD3is C1-3haloalkyl. In some embodiments, RD3is C1-2haloalkyl. In some embodiments, RD3is C1haloalkyl.

[0492] In some embodiments, RD3is C3carbocyclyl substituted with 0, 1, 2, or 3 halo. In some embodiments, RD3is C3carbocyclyl substituted with 0, 1, or 2 halo. In some embodiments, RD3is C3carbocyclyl substituted with 0 or 1 halo. In some embodiments, RD3is C3carbocyclyl.

[0493] In some embodiments, RD2is halo, C1alkyl, C1haloalkyl, or C3carbocyclyl; and RD3is hydrogen or fluoro. In some embodiments, RD2is bromo, chloro, -CH3, -CHF2, or cyclopropyl; and RD3is hydrogen or fluoro. In some embodiments, RD2is chloro or -CH3; and RD3is hydrogen or fluoro.

[0494] In some embodiments, RD2is halo, C1alkyl, C1haloalkyl, or C3carbocyclyl; and RD3is fluoro. In some embodiments, RD2is bromo, chloro, -CH3, -CHF2, or cyclopropyl; and RD3is fluoro. In some embodiments, RD2is chloro or -CH3; and RD3is fluoro.

[0495] In some embodiments, RD2is halo, C1alkyl, C1haloalkyl, or C3carbocyclyl; and RD3is hydrogen. In some embodiments, RD2is bromo, chloro, -CH3, -CHF2, or cyclopropyl; and RD3is hydrogen. In some embodiments, RD2is chloro or -CH3; and RD3is hydrogen. Subgenera

[0496] It is understood that, for a compound of the present disclosure, variables Ring A, Ring E, G1, G2, G3, G4, G7, RA2, RA3, RA4, RA5, RA6, RA7, RC, RD1, RD1A, RD1B, RD2, RD3, RE, RE1, RE2, RE3, R’, R’’, R*, R**, R#, R’’’, L1, L2, X, x, and y can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables Ring A, Ring E, G1, G2, G3, G4, G7, RA2, RA3, RA4, RA5, RA6, RA7, RC, RD1, RD1A, RD1B, RD2, RD3, RE, RE1, RE2, RE3, R’, R’’, R*, R**, R#, R’’’, L1, L2, X, x, and y can be combined, where applicable, with any group described herein for one or more of the remainder of variables Ring A, Ring E, G1, G2, G3, G4, G7, RA2, RA3, RA4, RA5, RA6, RA7, RC, RD1, RD1A, RD1B, RD2, RD3, RE, RE1, RE2, RE3, R’, R’’, R*, R**, R#, R’’’, L1, L2, X, x, and y. Additional exemplary combinations of the above described embodiments are further contemplated herein.

[0497] For example, in some embodiments of Formula (I), wherein X is O, G1is N, and RD1is Ring E, provided is a compound of Formula (I-A): or a pharmaceutically acceptable salt thereof. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e), or (E-4p). In some embodiments, RD3is F. In some embodiments, RD3is hydrogen. In some embodiments, RD2is Cl. In some embodiments, RD3is F and RD2is Cl. In some embodiments, RCis - CH2CH3. In some embodiments, Ring A is a group of formula (a-1). In some embodiments, the group of formula (a-1) is (a-1f), (a-1g), or (a-1n). In some embodiments, Ring A is a group of formula (a-2). In some embodiments, the group of formula (a-2) is (a-2a), (a-2i), (a-2k), (a-2l), (a-2m), (a-2o), (a-2p), (a- 2r), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2k), (a-2m), (a-2o), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2aa) or (a-2bb).

[0498] In some embodiments of Formula (I-A), wherein RD3is F and RD2is Cl, provided is a compound of Formula (I-B): or a pharmaceutically acceptable salt thereof. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is(E-4d), (E-4e), or (E-4p). In some embodiments, Ring A is a group of formula (a-1). In some embodiments, the group of formula (a-1) is (a-1f), (a-1g), or (a-1n). In some embodiments, Ring A is a group of formula (a-2). In some embodiments, the group of formula (a-2) is (a-2a), (a-2i), (a-2k), (a-2l), (a-2m), (a-2o), (a-2p), (a- 2r), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2k), (a-2m), (a-2o), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2aa) or (a-2bb).

[0499] In some embodiments of Formula (I-B), wherein RCis -CH2CH3, provided is a compound of Formula (I-C): or a pharmaceutically acceptable salt thereof. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p). In some embodiments, Ring A is a group of formula (a-1). In some embodiments, the group of formula (a-1) is (a-1f), (a-1g), or (a-1n). In some embodiments, Ring A is a group of formula (a-2). In some embodiments, the group of formula (a-2) is (a-2a), (a-2i), (a-2k), (a-2l), (a-2m), (a-2o), (a-2p), (a- 2r), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2k), (a-2m), (a-2o), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2aa) or (a-2bb).

[0500] In some embodiments of Formula (I-C), wherein Ring E is a group of formula (E-2), provided is a compound of Formula (I-D): or a pharmaceutically acceptable salt thereof. In some embodiments, y is 0 (and REis absent). In some embodiments, Ring A is a group of formula (a-1). In some embodiments, the group of formula (a-1) is (a-1f), (a-1g), or (a-1n). In some embodiments, Ring A is a group of formula (a-2). In some embodiments, the group of formula (a-2) is (a-2a), (a-2i), (a-2k), (a-2l), (a-2m), (a-2o), (a-2p), (a-2r), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2k), (a-2m), (a-2o), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2aa) or (a-2bb).

[0501] In some embodiments of Formula (I-C), wherein Ring E is a group of formula (E-4), provided is a compound of Formula (I-E): or a pharmaceutically acceptable salt thereof. In some embodiments, y is 1. In some embodiments, at least one REis -NH(RE1). In some embodiments, y is 1 and REis -NH(RE1). In some embodiments, Ring A is a group of formula (a-1). In some embodiments, the group of formula (a-1) is (a-1f), (a-1g), or (a- 1n). In some embodiments, Ring A is a group of formula (a-2). In some embodiments, the group of formula (a-2) is (a-2a), (a-2i), (a-2k), (a-2l), (a-2m), (a-2o), (a-2p), (a-2r), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2k), (a-2m), (a-2o), or (a-2v). In some embodiments, the group of formula (a-2) is (a-2aa) or (a-2bb).

[0502] In some embodiments of Formula (I), wherein Ring A is a group of formula (a-1), provided is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: G1is CH, CF, or N; RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo; X is O, S, or NH; RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E: , wherein: Ring E is a C4-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3; each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3), -C(=O)N(RE3)2, -S(=O)RE3or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; y is 0, 1, 2, or 3; RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo; RD3is hydrogen or halo; G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; provided no more than two of G2, G3, and G4are N; each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5- membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and RA5is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0503] In some embodiments of Formula (II), wherein X is O and RA5is -N(R”)2, provided is a compound of Formula (II’): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis -CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, G2is N, G3is CRA3, G4is N, wherein RA3is hydrogen. In some embodiments, G2is CRA2, G3is CRA3, G4is N, wherein RA2is hydrogen or fluoro, and RA3is hydrogen. In some embodiments, at least one instance of R’’ is C1-3alkyl, 4-6 membered monocyclic heterocyclyl, or 6-10 membered bridged heterocyclyl, or two R’’ groups together with the nitrogen to which they are attached form 4-6 membered monocyclic heterocyclyl, a 6-10 membered spirocyclic heterocyclyl, or a 5-membered heteroaryl, wherein each instance of alkyl, heterocyclyl, and heteroaryl is independently substituted with 0 or 1 R* groups. In some embodiments, at least one instance of R’’ is C1-3alkyl, or two R’’ groups together with the nitrogen to which they are attached form 4-6 membered monocyclic heterocyclyl, wherein each instance of alkyl and heterocyclyl is independently substituted with 0 or 1 R* groups. In some embodiments, each instance of R’’ is C1-3alkyl. In some embodiments, RD1is Ring E.

[0504] In some embodiments of Formula (II’), wherein RD1is Ring E, provided is a compound of Formula (II-A): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, G2is N, G3is CRA3, G4is N, wherein RA3is hydrogen. In some embodiments, G2is CRA2, G3is CRA3, G4is N, wherein RA2is hydrogen or fluoro, and RA3is hydrogen. In some embodiments, at least one instance of R’’ is C1-3alkyl, 4-6 membered monocyclic heterocyclyl, or 6-10 membered bridged heterocyclyl, or two R’’ groups together with the nitrogen to which they are attached form 4-6 membered monocyclic heterocyclyl, a 6-10 membered spirocyclic heterocyclyl, or a 5-membered heteroaryl, wherein each instance of alkyl, heterocyclyl, and heteroaryl is independently substituted with 0 or 1 R* groups. In some embodiments, at least one instance of R’’ is C1-3alkyl, or two R’’ groups together with the nitrogen to which they are attached form 4-6 membered monocyclic heterocyclyl, wherein each instance of alkyl and heterocyclyl is independently substituted with 0 or 1 R* groups. In some embodiments, each instance of R’’ is C1-3alkyl. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0505] In some embodiments, the compound of Formula (II-A) is of Formula (II-A1) or (II-A2): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, RA2is hydrogen or fluoro. In some embodiments, RA2is hydrogen. In some embodiments, at least one instance of R’’ is C1-3alkyl, 4-6 membered monocyclic heterocyclyl, or 6-10 membered bridged heterocyclyl, or two R’’ groups together with the nitrogen to which they are attached form 4-6 membered monocyclic heterocyclyl, a 6-10 membered spirocyclic heterocyclyl, or a 5-membered heteroaryl, wherein each instance of alkyl, heterocyclyl, and heteroaryl is independently substituted with 0 or 1 R* groups. In some embodiments, at least one instance of R’’ is C1-3alkyl, or two R’’ groups together with the nitrogen to which they are attached form 4-6 membered monocyclic heterocyclyl, wherein each instance of alkyl and heterocyclyl is independently substituted with 0 or 1 R* groups. In some embodiments, each instance of R’’ is C1-3alkyl. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0506] In some embodiments of Formula (II) and subgenera as described above, and pharmaceutically acceptable salts thereof, RA5is -N(R”)2. In some embodiments of Formula (II) and subgenera as described above, and pharmaceutically acceptable salts thereof, RA5is: In some embodiments of Formula (II) and subgenera as described above, and pharmaceutically acceptable salts thereof, RA5is:

[0507] In some embodiments of Formula (I), wherein Ring A is a group of formula (a-2), provided is a compound of Formula (III): or a pharmaceutically acceptable salt thereof; wherein: G1is CH, CF, or N; RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo; X is O, S, or NH; RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E: , wherein: Ring E is a C4-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3; each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3), -C(=O)N(RE3)2, -S(=O)RE3or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; y is 0, 1, 2, or 3; RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo; RD3is hydrogen or halo; G2is CRA2or N; G3is CRA3or N; G7is CRA7or N; provided no more than two of G2, G3, and G7are N; each of RA2and RA3is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; RA7is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl; and x is 1 or 2.

[0508] In some embodiments of Formula (III), wherein X is O and x is 1, provided is a compound of Formula (III’): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, each instance of RA6is C1-3alkyl. In some embodiments, each instance of RA6is methyl. In some embodiments, G2is CRA2, G3is CRA3, and G7is CRA7, wherein each of RA2, RA3, and RA7is hydrogen. In some embodiments, G2is CRA2, G3is CRA3, G7is N, and RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3or -OCH3. In some embodiments, G2is N, G3is CRA3, and G7is CRA7, wherein each of RA3and RA7is hydrogen. In some embodiments, G2is CRA2, G3is N, and G7is CRA7, wherein RA7is -OR’’, and wherein R’’ is C1-3alkyl; or wherein RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, In some embodiments, G2is CRA2, G3is CRA3, and G7is N, wherein each of RA2and RA3is hydrogen. In some embodiments, RD1is Ring E.

[0509] In some embodiments of Formula (III’), wherein RD1is Ring E, provided is a compound of Formula (III-A): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, each instance of RA6is C1-3alkyl. In some embodiments, each instance of RA6is methyl. In some embodiments, G2is CRA2, G3is CRA3, and G7is CRA7, wherein each of RA2, RA3, and RA7is hydrogen. In some embodiments, G2is CRA2, G3is CRA3, G7is N, and RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3or -OCH3. In some embodiments, G2is N, G3is CRA3, and G7is CRA7, wherein each of RA3and RA7is hydrogen. In some embodiments, G2is CRA2, G3is N, and G7is CRA7, wherein RA7is -OR’’, and wherein R’’ is C1-3alkyl; or wherein RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, In some embodiments, G2is CRA2, G3is CRA3, and G7is N, wherein each of RA2and RA3is hydrogen. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E- 2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0510] In some embodiments, the compound of Formula (III-A) is of Formula (III-A1), (III-A2), (III- A3), (III-A4), or (III-A5): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, each instance of RA6is C1-3alkyl. In some embodiments, each instance of RA6is methyl. In some embodiments, RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3 or -OCH3. In some embodiments, RA7is -OR’’, wherein R’’ is C1-3alkyl; or RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0511] In some embodiments of Formula (III’), wherein RD1is Ring E and both instances of RA6are hydrogen, provided is a compound of Formula (III-B): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, G2is CRA2, G3is CRA3, and G7is CRA7, wherein each of RA2, RA3, and RA7is hydrogen. In some embodiments, G2is CRA2, G3is CRA3, G7is N, and RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3or -OCH3. In some embodiments, G2is N, G3is CRA3, and G7is CRA7, wherein each of RA3and RA7is hydrogen. In some embodiments, G2is CRA2, G3is N, and G7is CRA7, wherein RA7is -OR’’, and wherein R’’ is C1-3alkyl; or wherein RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, In some embodiments, G2is CRA2, G3is CRA3, and G7is N, wherein each of RA2and RA3is hydrogen. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0512] In some embodiments, the compound of Formula (III-B) is of Formula (III-B1), (III-B2), (III- B3), (III-B4), or (III-B5): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3or - OCH3. In some embodiments, RA7is -OR’’, wherein R’’ is C1-3alkyl; or RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0513] In some embodiments of Formula (III’), wherein RA7is -N(R”)2, provided is a compound of Formula (III-C): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, each instance of RA6is C1-3alkyl. In some embodiments, each instance of RA6is methyl. In some embodiments, G2is CRA2, G3is N, and two R” groups in the group -N(R”)2together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, wherein R** is C1-3alkyl. In some embodiments, G2is CRA2, G3is N, and two R” groups in the group -N(R”)2together with the nitrogen to which they are attached form In some embodiments, RD1is Ring E. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E- 2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0514] In some embodiments of Formula (III’), wherein RA7is -OR”, provided is a compound of Formula (III-D): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, each instance of RA6is C1-3alkyl. In some embodiments, each instance of RA6is methyl. In some embodiments, G2is CRA2, G3is N, and R” is C1-3alkyl. In some embodiments, G2is CRA2, G3is N, and the group -OR” is -OCH3. In some embodiments, RD1is Ring E. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0515] In some embodiments of Formula (III’), wherein G7is N, provided is a compound of Formula (III- E): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, each instance of RA6is C1-3alkyl. In some embodiments, each instance of RA6is methyl. In some embodiments, G2is CRA2and G3is CRA3. In some embodiments, G2is CRA2and G3is CRA3, wherein each of RA2and RA3is hydrogen, or RA2is hydrogen and RA3is C1-3alkyl. In some embodiments, RD1is Ring E. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0516] In some embodiments of Formula (III’), wherein RD1is Ring E and both instances of RA6are methyl, provided is a compound of Formula (III-F): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, G2is CRA2, G3is CRA3, and G7is CRA7, wherein each of RA2, RA3, and RA7is hydrogen. In some embodiments, G2is CRA2, G3is CRA3, G7is N, and RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3or -OCH3. In some embodiments, G2is N, G3is CRA3, and G7is CRA7, wherein each of RA3and RA7is hydrogen. In some embodiments, G2is CRA2, G3is N, and G7is CRA7, wherein RA7is -OR’’, and wherein R’’ is C1-3alkyl; or wherein RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, , or In some embodiments, G2is CRA2, G3is CRA3, and G7is N, wherein each of RA2and RA3is hydrogen. In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0517] In some embodiments, the compound of Formula (III-F) is of Formula (III-F1), (III-F2), (III-F3), (III-F4), or (III-F5): or a pharmaceutically acceptable salt thereof. In some embodiments, G1is N. In some embodiments, RCis -CH2CH3. In some embodiments, RD2is -Cl. In some embodiments, RD3is -F. In some embodiments, RD3is hydrogen. In some embodiments, RD3is F and RD2is Cl. In some embodiments, G1is N; RCis - CH2CH3; RD2is -Cl; and RD3is -F. In some embodiments, each instance of RA6is hydrogen. In some embodiments, RA3is C1-3alkyl or -OR’, wherein R’ is C1-3alkyl. In some embodiments, RA3is -CH3or - OCH3. In some embodiments, G2is CRA2, G3is N, and G7is CRA7, wherein RA7is -OR’’, and wherein R’’ is C1-3alkyl; or wherein RA7is -N(R”)2, wherein two R” groups together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl substituted with 0 or 1 R* groups selected from C1-3alkyl and -OR**, and wherein R** is C1-3alkyl. In some embodiments, RA7is -OCH3, In some embodiments, Ring E is a group of formula (E-2). In some embodiments, the group of formula (E-2) is (E-2a), (E-2c), or (E-2j). In some embodiments, Ring E is a group of formula (E-4). In some embodiments, the group of formula (E-4) is (E-4d), (E-4e) or (E-4p).

[0518] In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Tables 1A, 1B, 2A, 2B, and 2C, or a pharmaceutically acceptable salt thereof.

[0519] In some embodiments, the compound of Formula (I) is selected from a pharmaceutically acceptable salt of any one of the compounds of Tables 1A, 1B, 2A, 2B, and 2C. In some embodiments, the compound of Formula (I) is a free base selected from any one of the compounds of Tables 1A, 1B, 2A, 2B, and 2C.

[0520] The below Tables 1A, 1B, 2A, 2B, and 2C also provide the location of the Compound (Comp’d #) in the Examples by Example Number (Ex #) or Table C (TA). The Asterix (*) next to the Compound Number signifies that arbitrary stereochemistry has been assigned. “Rac” indicates a mixture of two or more stereoisomers in equal or unequal proportions.

[0022]

[0521] In some embodiments, the compound of Table 1A is selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 11, Compound 17, Compound 26, Compound 27A, Compound 49, Compound 81, Compound 151, Compound 159A*, Compound 159B*, and pharmaceutically acceptable salts of any one of the foregoing.

[0023]

[0522] In some embodiments, the compound of Table 1A is selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 11, Compound 27A, Compound 159A*, Compound 159B*, and pharmaceutically acceptable salts of any one of the foregoing.

[0024]

[0523] In some embodiments, the compound of Table 1A is selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 11, Compound 17, Compound 26, Compound 49, Compound 81, Compound 151, and pharmaceutically acceptable salts of any one of the foregoing.

[0025]

[0524] In some embodiments, the compound of Tables 2A-2C is selected from the group consisting of Compound 54, Compound 55, Compound 60, Compound 62, Compound 65, Compound 66, Compound 82, Compound 163, Compound 169, Compound 180, Compound 184, and pharmaceutically acceptable salts of any one of the foregoing.

[0026]

[0525] In some embodiments, the compound of Table 2A is selected from the group consisting of Compound 55, Compound 60, and pharmaceutically acceptable salts of any one of the foregoing.

[0027]

[0526] In some embodiments, the compound of Tables 2A-2C is selected from the group consisting of Compound 54, Compound 62, Compound 65, Compound 66, Compound 82, Compound 163, Compound 169, Compound 180, Compound 184, and pharmaceutically acceptable salts of any one of the foregoing.

[0028] (ii) Pharmaceutical Compositions

[0029]

[0527] The present disclosure provides pharmaceutical compositions comprising compounds described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0528] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound of Formula (I), or a pharmaceutically acceptable salt thereof, into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0030]

[0529] Relative amounts of the compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable carrier(s), and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0031]

[0530] Pharmaceutically acceptable carriers used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0032]

[0531] The compounds and compositions described herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the compound (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).

[0033]

[0532] Although the descriptions of pharmaceutical compositions described herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0034]

[0533] Compounds described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0035]

[0534] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0036]

[0535] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents, for example, to improve the compound or composition activity (e.g., potency and / or efficacy) in treating a disease, disorder, or condition in a subject in need thereof, in preventing a disease, disorder, or condition in a subject in need thereof (e.g., in reducing the risk of developing a disease, disorder, or condition in a subject with such a predisposition), and / or to improve bioavailability and / or safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the treatment employed may achieve a desired effect for the same disease, disorder, or condition, and / or it may achieve different effects.

[0037] (iii) Methods of Treatment and Prevention

[0038]

[0536] Compounds of Formula (I), and pharmaceutically acceptable salts thereof, have been found to bind to Caspase-4, and thus may be useful as inhibitors of Caspase-4 activity and useful in the treatment and prevention of Caspase-4 mediated diseases and disorders. Exemplary compounds of Formula (I), and pharmaceutically acceptable salts thereof, have also been found to bind to Caspase-5, acting as dual Caspase-4 / 5 inhibitors.

[0039]

[0537] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, a compound described herein is provided in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0040]

[0538] In some aspects, the present disclosure provides a compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating or preventing a disease or disorder.

[0539] In some aspects, the present disclosure provides use of a compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a disease or disorder.

[0041]

[0540] In some aspects, the present disclosure provides use of a compound described herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating or preventing a disease or disorder.

[0042]

[0541] In some embodiments, the disease or disorder is a Caspase-4 mediated disorder, i.e., a disease or disorder where there is an improvement to symptoms of the disease or disorder in the subject, or a biological response signifying an improvement in a subject or cell, upon treatment with a Caspase-4 inhibitor to the subject, or upon contact of a Caspase-4 inhibitor to the subject or cell.

[0043]

[0542] In some embodiments, the disease or disorder is treated or prevented by inhibiting Caspase-4 activity in the subject. For example, in some aspects, the present disclosure provides a method of inhibiting Caspase-4 activity in a subject in need thereof, the method comprising administering to the subject a compound described herein, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further and optionally comprises inhibiting Caspase-5 activity in a subject.

[0044]

[0543] In some aspects, the present disclosure provides a method of inhibiting Caspase-4 activity in a cell (e.g., in vitro or in vivo) comprising contacting the cell with a compound described herein, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further and optionally comprises inhibiting Caspase-5 activity in a cell.

[0045]

[0544] In some embodiments, the Caspase-4 mediated disorder is associated with the release of endotoxins. In some embodiments, such diseases and disorders include, but are not limited to, sepsis (including severe sepsis and septic shock), acute respiratory distress syndrome (ARDS), inflammatory bowel disease (IBD), and hidradenitis suppurativa (HS).

[0046]

[0545] In some embodiments, the disease or disorder is sepsis, severe sepsis and septic shock. In some embodiments, the sepsis is septic arthritis.

[0047]

[0546] In some embodiments, the disease or disorder is acute respiratory distress syndrome (ARDS). In some embodiments, the ARDS is caused by a coronavirus infection. In some embodiments, the ARDS is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0048]

[0547] In some embodiments, the disease or disorder is inflammatory bowel disease (IBD).

[0049]

[0548] In some embodiments, the disease or disorder is hidradenitis suppurativa (HS).

[0050]

[0549] In some embodiments, the Caspase-4 mediated disorder is a metabolic condition associated with the release of endotoxins and / or stress. In some embodiments, such diseases and disorders include, but are not limited to, diabetic nephropathy and diabetic retinopathy.

[0051]

[0550] In some embodiments, the disease or disorder is diabetic nephropathy.

[0052]

[0551] In some embodiments, the disease or disorder is diabetic retinopathy.

[0053]

[0552] In some embodiments, the Caspase-4 mediated disorder is associated with ischemia-reperfusion injury (IRI) to tissue, e.g., to cardiac and / or kidney tissue. In some embodiments, such diseases and disorders include, but are not limited to, myocardial infarction, stroke, and acute kidney injury.

[0553] In some embodiments, the disease or disorder is myocardial infarction.

[0554] In some embodiments, the disease or disorder is stroke.

[0555] In some embodiments, the disease or disorder is acute kidney injury.

[0556] In some embodiments, the disease or disorder is pulmonary arterial hypertension (PAH), capillary leak syndrome, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or Still’s disease.

[0557] In some embodiments, the disease or disorder is pulmonary arterial hypertension (PAH).

[0558] In some embodiments, the disease or disorder is capillary leak syndrome.

[0559] In some embodiments, the disease or disorder is multiple sclerosis (MS).

[0560] In some embodiments, the disease or disorder is amyotrophic lateral sclerosis (ALS).

[0561] In some embodiments, the disease or disorder is Still’s disease. (iv) Methods of Preparation

[0562] Compounds of Formula (I), and salts thereof, may be synthesized following General Schemes A-F as provided below. The Examples further describe these and other non-limiting methods of preparation.

[0563] For example, as depicted in Step 1 of General Scheme A, coupling a compound of Formula (A1), or salt thereof, wherein W is XRD1, or a compound of Formula (A2), or salt thereof, wherein W is Hal2, with a compound of Formula (B1), or salt thereof, provides a compound of Formula (C1), or salt thereof, wherein W is XRD1, or a compound of Formula (C2), or salt thereof, wherein W is Hal2, wherein Hal1is halogen (preferably bromo or chloro) or other leaving group, Hal2is halogen (preferably fluoro), and ROis halogen or -ORDwherein RDis hydrogen or C1-4alkyl. Step 2 involves treating a compound of Formula (C1) or (C2), or salt thereof, with an amine of formula RC-NH2, or salt thereof, to provide a compound of Formula (D1), or salt thereof, wherein W is XRD1, or a compound of Formula (D2), or salt thereof, wherein W is Hal2. Step 3 involves cyclizing the compound of Formula (D1) or (D2), or salt thereof, to provide a compound of Formula (E1), or salt thereof, wherein W is XRD1, or a compound of Formula (E2), or salt thereof, wherein W is Hal2. Step 4 involves first converting the compound of Formula (E2), or salt thereof, to (E1), or salt thereof (see General Schemes D and E), and then (i) borylating the compound of Formula (E1), or salt thereof, with a diboron compound of formula (B(ORB)2)2, or salt thereof, wherein each RBis independently C1-4alkyl or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl, to provide a boronic ester of Formula (F1) or salt thereof (wherein each RBis independently C1-4alkyl or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl), optionally followed by hydrolysis of the boronic ester to a boronic acid of Formula (F1) or salt thereof (wherein each RBis independently hydrogen), or (ii) borylating the compound of Formula (E1), or salt thereof, with a diboronic acid of formula (B(OH)2)2, or salt thereof, to provide a boronic acid of Formula (F1), or salt thereof, wherein each RBis independently hydrogen. Hydrolysis of the boronic ester of (F1) (wherein each RBis independently non-hydrogen) to the boronic acid (wherein each RBis independently hydrogen) may occur in situ or upon workup (e.g., acidic workup), or may be a separate step conducted after the isolation of the boronic ester of Formula (F1). General Scheme A

[0564] Alternatively, as depicted in General Scheme B, the compound of Formula (D1) or (D2), or salt thereof, may be prepared as follows. In Step 5: coupling of a compound of Formula (B1), or salt thereof, with an amine of formula RC-NH2, or salt thereof, to provide a compound of Formula (B2), or salt thereof; and in Step 6: coupling a compound of Formula (A1) or (A2), or salt thereof, with a compound of Formula (B2), or salt thereof, to provide a compound of Formula (D1) or (D2), or salt thereof. General Scheme B

[0565] Alternatively, as depicted in General Scheme C, the compound of Formula (E1) or (E2), or salt thereof, wherein G1is CH or CF, may be prepared as follows. In Step 7: cyclizing a compound of Formula (D1) or (D2), or salt thereof, wherein G1is CH or CF, to provide a compound of Formula (G1), or salt thereof, wherein W is XRD1, or a compound of Formula (G2), or salt thereof, wherein W is Hal2; and in Step 8: treating the compound of Formula (G1) or (G2), or salt thereof, with an amine of formula RC-NH2, or salt thereof, to provide a compound of Formula (E1) or (E2), or salt thereof. General Scheme C

[0566] Step 4 of General Scheme A, depicting the preparation of a compound of Formula (F1), or salt thereof, from a compound of Formula (E1) or (E2), or salt thereof, may require additional modification steps depending upon the nature of the group W, as provided in General Schemes D and E. For example, as shown in Step 9 of General Scheme D, coupling the compound of Formula (E2), or salt thereof, wherein W is Hal2, with a compound of formula H-X-RD1, or salt thereof, provides a compound of Formula (E1), or salt thereof. Step 10 then involves (i) borylating the compound of Formula (E1), or salt thereof, with a diboron compound of formula (B(ORB)2)2, or salt thereof, wherein each instance of RBis independently C1-4alkyl or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl, to provide a boronic ester of Formula (F1) or salt thereof (wherein each RBis independently C1-4alkyl or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl), optionally followed by hydrolysis of the boronic ester to a boronic acid of Formula (F1) or salt thereof (wherein each RBis independently hydrogen), or (ii) borylating the compound of Formula (E1), or salt thereof, with a diboronic acid of formula (B(OH)2)2, or salt thereof, to provide a boronic acid of Formula (F1), or salt thereof, wherein each RBis independently hydrogen. In some embodiments, provided is a compound of Formula (E2), or a salt thereof, wherein G1, RD2, RD3, and RCare as defined herein, and Hal1is halogen or other leaving group and Hal2is halogen. In some embodiments, Hal1is bromo. In some embodiments, Hal2is fluoro. In some embodiments, Hal1is bromo and Hal2is fluoro.

[0567] General Scheme E describes a similar sequence of preparatory steps as General Scheme D, but requires the Hal1to be bromo and Hal2to be fluoro, to provide a compound of Formula (F1), or salt thereof. The fluoro / bromo intermediate, a compound of Formula (E2-a), is a key stable intermediate in the synthesis of compounds of Formula (I), as large amounts may be prepared and stored over time. In some embodiments, the key intermediate is Intermediate 2, or salt thereof, as described in the Examples. General Scheme D General Scheme E

[0568] General Schemes D and E show one example of the conversion of Hal2of group W to -XRDby coupling said compound comprising a Hal2group with a compound of formula H-X-RD1, or salt thereof. A similar conversion may be implemented in any one of the early preparation steps, e.g., prior to Step 3. For example, a compound of Formula (A2), (C2), or (D2), or salt thereof, wherein W is Hal2, may be coupled with a compound of formula H-X-RD1, or salt thereof, to respectively provide a compound of Formula (A1), (C1), or (D1), or salt thereof, and those coupled products may be carried forward in the synthesis as set forth in General Scheme A.

[0569] With compounds of Formulae (F1) and (E1), and salts thereof, in hand, compounds of Formula (I), or salts thereof, with Ring A installed, may be prepared in one coupling step, as provided in General Scheme F. For example, as shown in Step 11a of General Scheme F, the compound of Formula (F1), or salt thereof, may be coupled (e.g., by Suzuki coupling) with a compound of Formula (H1), or salt thereof, to provide a compound of Formula (I), or salt thereof, wherein Hal3is halogen (preferably chloro, bromo, or iodo) or other leaving group. Alternatively, as shown in Step 11b of General Scheme F, the compound of Formula (E1), or salt thereof, may be coupled with a compound of formula (H2), or salt thereof, wherein each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl, to provide a compound of Formula (I), or salt thereof. General Scheme F (v) Allosteric Inhibitors of Human Caspase-4

[0563] Applicants have identified a new and allosteric binding site on Caspase-4 which is distinct from the catalytic (active) binding site and the proteolytic cysteine 258 residue previously described in Chan et al., Life Sci. Alliance (2023) 9;6(10):e202301908. doi: 10.26508 / lsa.202301908. PMID: 37558421; PMCID: PMC10412805. The allosteric binding pocket is located on the solvent exposed region of the interface between the p10 and the p20 subunits of human Caspase-4 and is defined by three β-strands (residues 228-230, 300-306, and 360-364), an α-helix region (residues 231-238), and a loop region (residues 212-215).

[0564] Thus, in one aspect, provided is a method of inhibiting Caspase-4 comprising contacting a compound, or a pharmaceutically acceptable salt thereof, with human Caspase-4, wherein the compound, or a pharmaceutically acceptable salt thereof, binds to amino acid residue Arg364 of the allosteric binding pocket of human Caspase-4, and wherein the compound has a human Caspase-4 inhibitory activity of less than 100 nM, a human Caspase-5 inhibitory activity of less than 100 nM, and a human Caspase-1 inhibitory activity of greater than 10,000 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0565] In another aspect, provided is a compound, or a pharmaceutically acceptable salt thereof, which binds to amino acid residue Arg364 of the allosteric binding pocket of human Caspase-4, and has a human Caspase-4 inhibitory activity of less than 100 nM, a human Caspase-5 inhibitory activity of less than 100 nM, and a human Caspase-1 inhibitory activity of greater than 10,000 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0566] As noted above, the allosteric binding pocket is defined by residues 228-230, 300-306, 360-364, 231-238, and 212-215 of human Caspase-4. “Binding to” and “interacts with” are used interchangeably herein to refer to one or more non-covalent interactions between the compound and an amino acid residue within the allosteric binding pocket.

[0570] In some embodiments, the binding to amino acid residue Arg364 comprises at least one hydrogen bond (H-bond) donor and acceptor interaction between the compound, or a pharmaceutically acceptable salt thereof, and Arg364. In some embodiments, provided is an H-bond interaction between an oxygen atom of the compound and an NH moiety of Arg364. In some embodiments, the oxygen atom of the compound is an oxygen atom of a C=O group.

[0571] In some embodiments, the compound further binds to Asp232 of the allosteric binding pocket of human Caspase-4. In some embodiments, the binding to Asp232 comprises at least one H-bond donor and acceptor interaction between the compound, or a pharmaceutically acceptable salt thereof, and Asp232. In some embodiments, provided is an H-bond interaction between a nitrogen or oxygen atom of the compound and an NH moiety of Asp232. In some embodiments, the nitrogen atom of the compound is the nitrogen atom of a CN group. In some embodiments, the oxygen atom of the compound is an oxygen atom of a C=O group.

[0572] In some embodiments, the compound further binds to Leu230 of the allosteric binding pocket of human Caspase-4.

[0573] In some embodiments, the compound further binds to Glu214 of the allosteric binding pocket of human Caspase-4. In some embodiments, provided is a CH-pi interaction between the compound, or a pharmaceutically acceptable salt thereof, and Glu214.

[0574] In some embodiments, the compound further binds to Ser206 and / or Thr361 of the allosteric binding pocket of human Caspase-4.

[0575] In some embodiments, the compound has a human Caspase-4 inhibitory activity of less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, between 5 nM and 10 nM (inclusive), between 10 nM and 20 nM (inclusive), or between 20 nM and 50 nM (inclusive), as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0576] In some embodiments, the compound has a human Caspase-5 inhibitory activity of less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, between 5 nM and 10 nM (inclusive), between 10 nM and 20 nM (inclusive), or between 20 nM and 50 nM (inclusive), as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0577] In some embodiments, the compound has a human Caspase-4 inhibitory activity of less than 20 nM, and a human Caspase-5 inhibitory activity of less than 50 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0578] In some embodiments, the compound has a human Caspase-1 inhibitory activity of greater than 10,000 nM, greater than 20,000 nM, greater than 30,000 nM, greater than 40,000 nM, or greater than 50,000 nM.

[0579] In some embodiments, the compound exhibits a less than 100-fold IC50shift, less than 50-fold IC50shift, less than 40-fold IC50shift, less than 30-fold IC50shift, or less than 20-fold IC50shift, between a human Caspase-4 biochemical assay and an LPS induced pyroptosis HeLa cellular assay.

[0580] In some embodiments, the compound has a molecular weight of less than 800 g / mol, less than 750 g / mol, less than 700 g / mol, less than 650 g / mol, less than 600 g / mol, less than 550 g / mol, or less than 500 g / mol.

[0581] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. (vi) Additional Embodiments

[0582] Embodiments of the present disclosure further include:

[0583] Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted 6-membered aryl or optionally substituted 6-membered heteroaryl, and wherein the aryl or heteroaryl is monocyclic or further comprises fused thereto an optionally substituted 5-6 membered heterocyclyl; G1is CH, CF, or N; RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo; X is O, S, or NH; RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E: wherein: Ring E is a C3-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3; each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3), -C(=O)N(RE3)2, -S(=O)RE3, or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; y is 0, 1, 2, or 3; RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo; and RD3is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo.

[0584] Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein X is O.

[0585] Embodiment 3. The compound of any one of embodiments 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G1is N.

[0586] Embodiment 4. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein RCis C2-5alkyl or C2-5haloalkyl.

[0587] Embodiment 5. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein RCis C2-5alkenyl or C2-5haloalkenyl.

[0588] Embodiment 6. The compound of any one of embodiments 4 or 5, or a pharmaceutically acceptable salt thereof, wherein RCis selected from the group consisting of:

[0589] Embodiment 7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein RCis

[0590] Embodiment 8. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein RD2is halo, C1alkyl, C1haloalkyl, or C3carbocyclyl.

[0591] Embodiment 9. The compound of embodiment 8, or a pharmaceutically acceptable salt thereof, wherein RD2is bromo, chloro, -CH3, -CHF2, or cyclopropyl.

[0592] Embodiment 10. The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein RD2is chloro.

[0593] Embodiment 11. The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein RD2is -CH3.

[0594] Embodiment 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein RD3is hydrogen.

[0595] Embodiment 13. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein RD3is fluoro.

[0596] Embodiment 14. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula .

[0597] Embodiment 15. The compound of embodiment 1, wherein the compound is of Formula (I-C): or a pharmaceutically acceptable salt thereof.

[0598] Embodiment 16. The compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E selected from the group consisting of: wherein y is 0, 1, 2 or 3, as valency permits.

[0599] Embodiment 17. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0600] Embodiment 18. The compound of embodiment 16 or embodiment 17, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0601] Embodiment 19. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0602] Embodiment 20. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0603] Embodiment 21. The compound of embodiment 16 or embodiment 20, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0604] Embodiment 22. The compound of any one of embodiments 16, 20, and 21, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0605] Embodiment 23. The compound of any one of embodiments 16, 20, and 21, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0606] Embodiment 24. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0607] Embodiment 25. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0608] Embodiment 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula: , , , , , , ,

[0054]

[0609] Embodiment 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:

[0610] Embodiment 28. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein RD1is C1-3alkyl or C1-3haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups.

[0611] Embodiment 29. The compound of embodiment 28, or a pharmaceutically acceptable salt thereof, wherein RD1is -CH3, -CH2CH3, -CH2CHF2, -CH2CH2OCH3, or -CH2CN.

[0612] Embodiment 30. The compound of any one of embodiments 1-14 and 16-29, or a pharmaceutically acceptable salt thereof, wherein Ring D of formula: is a group of formula:

[0613] Embodiment 31. The compound of embodiment 30, or a pharmaceutically acceptable salt thereof, wherein Ring D is a group of formula:

[0055] wherein y is 0, 1, 2 or 3.

[0614] Embodiment 32. The compound of embodiment 30, or a pharmaceutically acceptable salt thereof, wherein Ring D is a group of formula: wherein y is 0, 1, 2 or 3.

[0615] Embodiment 33. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein Ring A is a monocyclic 6-membered aryl or monocyclic 6-membered heteroaryl, and wherein Ring A is substituted with one or more of the following groups: -CN; and / or halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3 haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5- membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0616] Embodiment 34. The compound of embodiment 33, or a pharmaceutically acceptable salt thereof, wherein Ring A is substituted with at least one -CN group ortho to the point of attachment to Ring B.

[0617] Embodiment 35. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered aryl or 6-membered heteroaryl, and wherein the aryl or heteroaryl further comprises fused thereto a 5-6 membered heterocyclyl ring, and further wherein Ring A is unsubstituted or substituted with one or more of the following groups: halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5- membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3 alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl; and / or C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5- membered heteroaryl, or two non-hydrogen groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 - CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

[0618] Embodiment 36. The compound of embodiment 35, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered aryl or 6-membered heteroaryl, wherein the aryl or heteroaryl further comprises fused thereto a 5-6 membered lactone ring.

[0619] Embodiment 37. The compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, wherein Ring A is a group of formula: G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; G7is CRA7or N; provided no more than two of G2, G3, and G4or no more than two of G2, G3, and G7are N; each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5- membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each of RA5and RA7is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and x is 1 or 2.

[0620] Embodiment 38. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is N, G3is CRA3, and G4is CRA4or G7is CRA7.

[0621] Embodiment 39. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is N, G3is CRA3, and G4or G7is N.

[0622] Embodiment 40. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is CRA2, G3is CRA3, and G4or G7is N.

[0623] Embodiment 41. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is CRA2, G3is N, and G4is CRA4or G7is CRA7.

[0624] Embodiment 42. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is CRA2, G3is N, and G4or G7is N.

[0625] Embodiment 43. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is N, G3is N, and G4is CRA4or G7is CRA7.

[0626] Embodiment 44. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof, wherein G2is CRA2, G3is CRA3, and G4is CRA4or G7is CRA7.

[0627] Embodiment 45. The compound of any one of embodiments 37-44, or a pharmaceutically acceptable salt thereof, wherein Ring A is a group of formula (a-1): to provide a compound of Formula (II): or a pharmaceutically acceptable salt thereof.

[0628] Embodiment 46. The compound of embodiment 45, or a pharmaceutically acceptable salt thereof, wherein the group of formula (a-1) is:

[0629] Embodiment 47. The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein RA5or RA7is of formula: -F, -Cl,

[0630] Embodiment 48. The compound of any one of embodiments 37-44 and 47, or a pharmaceutically acceptable salt thereof, wherein Ring A is a group of formula (a-2): to provide a compound of Formula (III): or a pharmaceutically acceptable salt thereof.

[0631] Embodiment 49. The compound of embodiment 48, or a pharmaceutically acceptable salt thereof, wherein the group of formula (a-2) is:

[0632] Embodiment 50. The compound of any one of embodiments 48 or 49, or a pharmaceutically acceptable salt thereof, wherein at least one instance of RA6is hydrogen, -CH3, -CH2OCH3, - CH2N(CH3)2, cyclopropyl, or or two RA6groups attached to the same carbon atom are joined to form cyclopropyl.

[0633] Embodiment 51. The compound of any one of embodiments 48-50, or a pharmaceutically acceptable salt thereof, wherein two instances of RA6are hydrogen.

[0634] Embodiment 52. The compound of any one of embodiments 48-51, or a pharmaceutically acceptable salt thereof, wherein two instances of RA6are -CH3.

[0635] Embodiment 53. The compound of any one of embodiments 48-52, or a pharmaceutically acceptable salt thereof, wherein x is 1.

[0636] Embodiment 54. The compound of any one of embodiments 48-52, or a pharmaceutically acceptable salt thereof, wherein x is 2.

[0637] Embodiment 55. The compound of any one of embodiments 48-49, or a pharmaceutically acceptable salt thereof, wherein the group of formula (a-2) is of formula:

[0638] Embodiment 56. The compound of any one of embodiments 1-32, 35-44, and 48-55, wherein the compound is of Formula (III’): or a pharmaceutically acceptable salt thereof, wherein: G2is CRA2or N; G3is CRA3or N; G7is CRA7or N; provided no more than two of G2, G3, and G7are N; each of RA2and RA3is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and RA7is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0639] Embodiment 57. The compound of any one of embodiments 1-32, 35-44, and 48-56, wherein the compound is of Formula (III-C), (III-D), or (III-E): or a pharmaceutically acceptable salt thereof, wherein: G2is CRA2or N; G3is CRA3or N; each of RA2and RA3is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NHR**, -NH2, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0640] Embodiment 58. The compound of any one of embodiments 1-34 and 37-47, wherein the compound is of Formula (II’): or a pharmaceutically acceptable salt thereof, wherein: G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; provided no more than two of G2, G3, and G4are N; each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5- membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NHR**, -NH2, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

[0641] Embodiment 59. The compound of any one of the preceding embodiments, wherein Ring E is a C4-8carbocyclyl or a 4-8 membered heterocyclyl, and RD3is hydrogen or halo;

[0642] Embodiment 60. The compound of any one of the preceding embodiments, wherein the compound is selected from the compounds described in Tables 1A, 1B, 2A, 2B, and 2C, or a pharmaceutically acceptable salt of any of the foregoing.

[0643] Embodiment 61. A pharmaceutical composition comprising the compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0644] Embodiment 62. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of any one of embodiments 1- 60, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 61.

[0645] Embodiment 63. The compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 61, for use in treating or preventing a disease or disorder.

[0646] Embodiment 64. Use of the compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 61, in the manufacture of a medicament, for the treatment or prevention of a disease or disorder.

[0647] Embodiment 65. Use of the compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 61, for the treatment or prevention of a disease or disorder.

[0648] Embodiment 66. A method of inhibiting Caspase-4 activity in a subject in need thereof, the method comprising administering to the subject a compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 61.

[0649] Embodiment 67. A method of inhibiting Caspase-4 activity in a cell, the method comprising contacting the cell with a compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof.

[0650] Embodiment 68. The method, use, or compound of any one of embodiments 62-65, wherein the disease or disorder is sepsis, severe sepsis and septic shock, acute respiratory distress syndrome (ARDS), inflammatory bowel disease (IBD), hidradenitis suppurativa (HS), diabetic nephropathy, diabetic retinopathy, ischemia-reperfusion injury (IRI), myocardial infarction, stroke, or acute kidney injury.

[0651] Embodiment 69. A method for preparing a compound of Formula (I) of any one of embodiments 1-60, or a salt thereof, wherein X, RD1, RD2, RD3, RC, G1, and Ring A are as defined in any one of embodiments 1-60, the method comprising: (i) treating a compound of Formula (F1), or salt thereof, with a compound of Formula (H1), or salt thereof, wherein Hal3is halogen or other leaving group, and each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl: to provide the compound of Formula (I), or salt thereof; or (ii) treating a compound of Formula (E1), or salt thereof, with a compound of Formula (H2), or salt thereof, wherein Hal1is halogen or other leaving group, and each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl: to provide the compound of Formula (I), or salt thereof.

[0652] Embodiment 70. The method of embodiment 69, further comprising coupling a compound of Formula (E2), or salt thereof, with a compound of formula H-X-RD1, or salt thereof: to provide the compound of Formula (E1), or salt thereof.

[0653] Embodiment 71. The method of embodiment 70, further comprising: (i) borylating the compound of Formula (E1), or salt thereof, with a diboron compound of formula (B(ORB)2)2, or salt thereof, wherein each instance of RBis independently C1-4alkyl or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl, to provide a boronic ester of Formula (F1) or salt thereof (wherein each RBis independently C1-4alkyl or each - ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl), optionally followed by hydrolysis of the boronic ester to a boronic acid of Formula (F1) or salt thereof (wherein each RBis independently hydrogen); or (ii) borylating the compound of Formula (E1), or salt thereof, with a diboronic acid of formula (B(OH)2)2, or salt thereof, to provide a boronic acid of Formula (F1), or salt thereof, wherein each RBis independently hydrogen.

[0654] Embodiment 72. The method of embodiment 70 or 71, further comprising cyclizing a compound of Formula (D2), or salt thereof: to provide the compound of Formula (E2), or salt thereof.

[0655] Embodiment 73. The method of embodiment 72, further comprising treating a compound of Formula (C2), or salt thereof, with an amine of formula RC-NH2, or salt thereof: to provide the compound of Formula (D2), or salt thereof.

[0656] Embodiment 74. The method of embodiment 73, further comprising coupling a compound of Formula (A2), or salt thereof, wherein ROis halogen or -ORD, wherein RDis hydrogen or C1-4alkyl, with a compound of Formula (B1), or salt thereof: to provide the compound of Formula (C2), or salt thereof.

[0657] Embodiment 75. A compound of Formula (E2): or salt thereof, wherein G1, RD2, RD3, and RCare as defined in any one of embodiments 1-60, and Hal1is halogen or other leaving group and Hal2is halogen.

[0658] Embodiment 76. The compound of embodiment 75, wherein Hal1is bromo.

[0659] Embodiment 77. The compound of embodiment 75 or 76, wherein Hal2is fluoro.

[0660] Embodiment 78. The compound of embodiment 75, wherein the compound is: or salt thereof.

[0661] Embodiment 79. A compound of Formula (E1): or salt thereof, wherein G1, X, RD1, RD2, RD3, and RCare as defined in any one of embodiments 1-60, and Hal1is halogen or other leaving group.

[0662] Embodiment 80. The compound of embodiment 79, wherein Hal1is bromo.

[0663] Embodiment 81. A compound of Formula (F1): or salt thereof, wherein G1, X, RD1, RD2, RD3, and RCare as defined in any one of embodiments 1-60, and each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl.

[0664] Embodiment 82. A method of inhibiting Caspase-4 comprising contacting a compound, or a pharmaceutically acceptable salt thereof, with human Caspase-4, wherein the compound, or a pharmaceutically acceptable salt thereof, binds to amino acid residue Arg364 of the allosteric binding pocket of human Caspase-4, and wherein the compound has a human Caspase-4 inhibitory activity of less than 100 nM, a human Caspase-5 inhibitory activity of less than 100 nM, and a human Caspase-1 inhibitory activity of greater than 10,000 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0665] Embodiment 83. A compound, or a pharmaceutically acceptable salt thereof, which binds to amino acid residue Arg364 of the allosteric binding pocket of human Caspase-4, and has a human Caspase-4 inhibitory activity of less than 100 nM, a human Caspase-5 inhibitory activity of less than 100 nM, and a human Caspase-1 inhibitory activity of greater than 10,000 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0666] Embodiment 84. The method or compound of embodiment 82 or 83, wherein the compound comprises at least one H-bond donor and acceptor interaction between the compound, or a pharmaceutically acceptable salt thereof, and Arg364.

[0667] Embodiment 85. The method or compound of embodiment 84, wherein the compound further binds to Asp232.

[0668] Embodiment 86. The method or compound of any one of embodiments 82-85, wherein the compound further binds to Leu230.

[0669] Embodiment 87. The method or compound of any one of embodiments 82-86, wherein the compound further binds to Glu214.

[0670] Embodiment 88. The method or compound of any one of embodiments 82-87, wherein the compound further binds to Ser206 and / or Thr361.

[0671] Embodiment 89. The method or compound of any one of embodiments 82-88, wherein the compound has a human Caspase-4 inhibitory activity of less than 20 nM as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0672] Embodiment 90. The method or compound of any one of embodiments 82-89, wherein the compound has a human Caspase-5 inhibitory activity of less than 50 nM as determined by Homogeneous Time Resolved Fluorescence (HTRF).

[0673] Embodiment 91. The method or compound of any one of embodiments 82-90, wherein the compound exhibits a less than 100-fold IC50shift between a human Caspase-4 biochemical assay and an LPS induced pyroptosis HeLa cellular assay.

[0674] Embodiment 92. The method or compound of any one of embodiments 82-91, wherein the compound is of any one of embodiments 1-60, or a pharmaceutically acceptable salt thereof.

[0675] Embodiment 93. A pharmaceutical composition comprising the compound of any one of embodiments 82-92, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0676] Embodiment 94. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of any one of embodiments 82- 92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 93.

[0677] Embodiment 95. The method of embodiment 82, comprising inhibiting Caspase-4 activity in a subject in need thereof, the method comprising administering to the subject a compound of any one of embodiments 82-92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 93.

[0678] Embodiment 96. The method of embodiment 82, comprising inhibiting Caspase-4 activity in a cell, the method comprising contacting the cell with a compound of any one of embodiments 83-92, or a pharmaceutically acceptable salt thereof. EXEMPLIFICATION

[0679] In order that this disclosure may be more fully understood, the following Examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner. Analytical Methods

[0680] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16 or 32 scans. Typical NMR solvents include deuterated dimethylsulfoxide (DMSO-d6) and deuterated methanol (CD3OD).

[0681] Liquid Chromatography - Mass Spectrometry (LCMS) chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7 – 8.0 µl and the flow rates were typically 0.8 or 1.2 mL / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da. Mobile phases of water and / or acetonitrile (MeCN) may contain a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate. ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes).

[0682] Purification / Separation Methods. The synthetic methods describe purification and / or separation chromatographic methods which have been employed in the purification and / or isolation of the exemplified compounds. Rf = retention factor; RT = retention time (minutes); Prep-HPLC = Preparative High-performance liquid chromatography. SFC = supercritical fluid chromatography.

[0683] Additional abbreviations used herein are provided in the below Table A.

[0056] Synthetic Methods

[0057]

[0684] The Asterix (*) next to the Compound Number (#) signifies that arbitrary stereochemistry has been assigned. “Rac” indicates a mixture of two or more stereoisomers in equal or unequal proportions. Future tense language (“may be” prepared) indicates experiments not yet conducted. (i) Building blocks Building block Example 1: Synthesis of 4-chloro-6-(4-ethylpiperazin-1-yl)pyrimidine-5- carbonitrile (BB1)

[0563] Step 1: To a solution of 4,6-dichloropyrimidine-5-carbonitrile (3.00 g, 17.2 mmol) in acetonitrile (30 mL) was added K2CO3(4.77 g, 34.5 mmol) and 1-ethylpiperazine (1.77 g, 15.5 mmol). The reaction was stirred at room temperature for 4 hours, poured into water and extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with 0% to 10% methanol in dichloromethane to afford 4-chloro-6-(4-ethylpiperazin-1-yl)pyrimidine-5-carbonitrile (Building Block 1) (2.40 g, 55% yield). LCMS: m / z [M+H]+= 252.2. Building Block Example 2: Synthesis of 3-bromo-5-(4-ethylpiperazin-1-yl)isonicotinonitrile (BB2)

[0564] Step 1: To a mixture of 3-bromo-5-fluoroisonicotinonitrile (500 mg, 2.49 mmol), 1-ethylpiperazine (348 μL, 2.74 mmol) in acetonitrile (8 mL) was added K2CO3(688 mg, 4.98 mmol). The reaction was stirred at room temperature for 2 hours, diluted with water and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- bromo-5-(4-ethylpiperazin-1-yl)isonicotinonitrile (Building Block 2) (600 mg, 82% crude yield). LCMS: m / z [M+H]+= 295.1. Building Block Example 3: Synthesis of tert-butyl (S)-3-((6-chloro-5-cyanopyrimidin-4- yl)(methyl)amino)piperidine-1-carboxylate (BB3)

[0565] Step 1: To a solution of 4,6-dichloropyrimidine-5-carbonitrile (400 mg, 2.30 mmol) in THF (10 mL) was added DIPEA (481 μL, 2.76 mmol) and tert-butyl (S)-3-(methylamino)piperidine-1-carboxylate (246 mg, 1.15 mmol). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was poured into water. The aqueous phase was extracted with EtOAc, dried over anhydrous Na2SO4, filtered and filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography eluting with 0 to 100% EtOAc in petroleum ether to afford tert-butyl (S)-3-((6- chloro-5-cyanopyrimidin-4-yl)(methyl)amino)piperidine-1-carboxylate (Building Block 3) (200 mg, 24% yield). LCMS: m / z [M+H]+= 352.2. Building Block Example 4: Synthesis of tert-butyl (R)-3-((6-chloro-5-cyanopyrimidin-4- yl)(methyl)amino)piperidine-1-carboxylate (BB4)

[0566] Step 1: To a solution of 4,6-dichloropyrimidine-5-carbonitrile (200 mg, 1.15 mmol) in THF (5.0 mL) was added tert-butyl (R)-3-(methylamino)piperidine-1-carboxylate (246 mg, 1.15 mmol) and diisopropylethylamine (149 mg, 1.15 mmol). The reaction was stirred at room temperature for 2 hours under N2, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 5% to 35% EtOAc in petroleum ether to afford tert-butyl (R)-3-((6-chloro-5-cyanopyrimidin-4-yl)(methyl)amino)piperidine-1- carboxylate (Building Block 4) (110 mg, 26% yield). LCMS: m / z [M+H]+= 352.2. Building Block Example 5: Synthesis of 1-cyclopropylpiperazin-2-one (BB5)

[0567] Step 1: To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (500 mg, 2.50 mmol) in toluene (5.0 mL) was added copper(II) acetate (125 mg, 624 μmol), DMAP (915 mg, 7.49 mmol), NaHMDS (458 mg, 2.50 mmol) and cyclopropylboronic acid (429 mg, 4.99 mmol). The reaction was stirred at 95°C for 16 hours under oxygen, cooled down to room temperature and concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with 0% to 10% methanol in dichloromethane to afford tert-butyl 4- cyclopropyl-3-oxopiperazine-1-carboxylate (460 mg, 77% yield). LCMS: m / z [M-tert-butyl+H]+= 185.2.

[0568] Step 2: To a solution of tert-butyl 4-cyclopropyl-3-oxopiperazine-1-carboxylate (230 mg, 957 μmol) in dichloromethane (5.0 mL) was added TFA (1.0 mL). The reaction was stirred at room temperature for 2 hours, and then the mixture was concentrated under vacuum to afford 1- cyclopropylpiperazin-2-one (Building Block 5) as the TFA salt (120 mg, crude). LCMS: m / z [M+H]+= 141.0. Building Block Example 6: Synthesis of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-3-one (BB6)

[0569] Step 1: To a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-3-one (200 mg, 1.78 mmol) in THF (5 mL) was added Et3N (361 mg, 3.57 mmol) and Boc2O (389 mg, 1.78 mmol) at 0 °C. The reaction was stirred at room temperature for 16 hours, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl (1S,4S)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (350 mg, 75% yield). LCMS: m / z [M+H]+= 213.2.

[0570] Step 2: To a solution of tert-butyl (1S,4S)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 1.41 mmol) in THF (10 mL) under N2was added NaH (68.0 mg, 2.83 mmol, 60% in mineral oil) and iodomethane (201 mg, 1.41 mmol). The reaction was stirred at room temperature for 1 hour, quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-methyl-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, crude). To the crude product (300 mg, 1.33 mmol) in dichloromethane (5.0 mL) was added HCl (3.0 mL, 12 mmol, 4.0 M in 1,4-dioxane). The reaction was stirred at room temperature for 2 hours, and then was concentrated under vacuum to afford (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-3-one (hydrochloride salt) (Building Block 6) (290 mg, crude). LCMS: m / z [M+H]+= 127.0. Building Block Example 7: Synthesis of (1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptane (BB7)

[0571] Step 1: To a solution of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (600 mg, 3.03 mmol) in chlorobenzene (2.0 mL) was added cyclopropylboronic acid (390 mg, 4.54 mmol), 2-(2- pyridyl)pyridine (473 mg, 3.03 mmol), copper(II) acetate monohydrate (604 mg, 3.03 mmol) and Na2CO3(642 mg, 6.05 mmol). The reaction was stirred at 80°C for 3 hours under O2, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography eluting with 0% to 60% EtOAc in petroleum ether to give tert-butyl (1S,4S)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (372 mg, 52% yield). LCMS: m / z [M+H]+= 239.2.

[0572] Step 2: To a solution of tert-butyl (1S,4S)-5-cyclopropyl-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (372 mg, 1.56 mmol) in dichloromethane (2.0 mL) was added HCl (2.0 mL, 8.00 mmol, 4.0 M in EtOAc). The reaction was stirred at room temperature for 1 hour, and then was concentrated under vacuum to afford (1S,4S)-2-cyclopropyl-2,5-diazabicyclo[2.2.1]heptane (hydrochloride salt) (Building Block 7) (301 mg, crude). LCMS: m / z [M+H]+= 139.2. Building Block Example 8: Synthesis of tert-butyl (1S,4S)-5-(6-chloro-5-cyanopyrimidin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (BB8)

[0573] Step 1: To a solution of 4,6-dichloropyrimidine-5-carbonitrile (600 mg, 3.45 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (615 mg, 3.10 mmol) in acetonitrile (10 mL) was added K2CO3(953 mg, 6.90 mmol). The reaction was stirred at room temperature for 4 hours, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 10% methanol in dichloromethane to afford tert-butyl (1S,4S)-5-(6-chloro-5- cyanopyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Building Block 8) (800 mg, 69% yield). LCMS: m / z [M-tert-butyl+H]+= 280.2. Building Block Example 9: Synthesis of tert-butyl (S)-3-((6-chloro-5-cyanopyrimidin-4- yl)(methyl)amino)piperidine-1-carboxylate (BB9)

[0058]

[0574] Step 1: To a solution of 4,6-dichloropyrimidine-5-carbonitrile (500 mg, 2.87 mmol) in THF (10 mL) was added diisopropylethylamine (445 mg, 3.45 mmol) and tert-butyl (3S)-3- (methylamino)piperidine-1-carboxylate (307 mg, 1.44 mmol). The reaction was stirred at room temperature for 3 hours, diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0% to 20% EtOAc in petroleum ether to afford tert-butyl (S)-3-((6-chloro-5-cyanopyrimidin-4-yl)(methyl)amino)piperidine-1-carboxylate (Building Block 9) (370 mg, 73% yield). LCMS: m / z [M+H]+= 352.3. Building Block Example 10: Synthesis of tert-butyl (R)-3-((6-chloro-5-cyanopyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate (BB10)

[0575] Step 1: To a solution of 4,6-dichloropyrimidine-5-carbonitrile (1.00 g, 5.75 mmol) and tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (1.04 g, 5.17 mmol) in acetonitrile (10 mL) was added K2CO3(1.59 g, 11.5 mmol). The reaction was stirred at room temperature for 2 hours, diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% to 30% EtOAc in petroleum ether to afford tert-butyl (R)-3-((6-chloro-5- cyanopyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (Building Block 10) (708 mg, 41% yield). LCMS: m / z [M-tert-butyl+H]+= 282.2. Building Block Example 11: Synthesis of tert-butyl (S)-3-((6-chloro-5-cyanopyrimidin-4- yl)(methyl)amino)pyrrolidine-1-carboxylate (BB11)

[0576] Step 1: tert-Butyl (S)-3-((6-chloro-5-cyanopyrimidin-4-yl)(methyl)amino)pyrrolidine-1- carboxylate (Building Block 11) was prepared following Building Block 10, Step 1, but using tert- butyl (S)-3-(methylamino)pyrrolidine-1-carboxylate in Step 1 instead of tert-butyl (R)-3- (methylamino)pyrrolidine-1-carboxylate. Building Block Example 12: Synthesis of 2-(3-methoxyazetidin-1-yl)-N-methylethan-1-amine (BB12)

[0577] Step 1: To a solution of 2-(3-methoxyazetidin-1-yl)ethan-1-amine (200 mg, 1.54 mmol) in dichloromethane (3.0 mL) was added formaldehyde (52.0 mg, 1.54 mmol) and NaBH(OAc)3(326 mg, 1.54 mmol). The reaction was stirred at room temperature for 3 hours, diluted with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0% to 10% methanol in dichloromethane to afford 2-(3-methoxyazetidin-1-yl)-N- methylethan-1-amine (Building Block 12) (104 mg, 47% yield). LCMS: m / z [M+H]+= 145.2. Building Block Example 13: Synthesis of azetidin-1-yl(piperidin-4-yl)methanone (BB13)

[0578] Step 1: To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1.31 mmol), azetidine (112 mg, 1.96 mmol) and HATU (597 mg, 1.57 mmol) in DMF (8 mL) was added Et3N (397 mg, 3.93 mmol). The reaction was stirred at room temperature for 2 hours, quenched with water and extracted with EtOAc. The combine organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford tert-butyl 4-(azetidine-1-carbonyl)piperidine- 1-carboxylate (300 mg, 85% yield). LCMS: m / z [M-tert-butyl+H]+= 213.2.

[0579] Step 2: A solution of tert-butyl 4-(azetidine-1-carbonyl)piperidine-1-carboxylate (300 mg, 1.12 mmol) in HCl (5.0 mL, 20 mmol, 4.0 M in EtOAc) was stirred at room temperature for 30 minutes. The mixture was then concentrated under vacuum to afford azetidin-1-yl(piperidin-4-yl)methanone (hydrochloride salt) (Building Block 13) (210 mg, crude). Building Block Example 14: Synthesis of 7-bromo-3-(methoxymethyl)isobenzofuran-1(3H)-one (BB14)

[0580] Step 1: To a solution of 2,6-dibromobenzoic acid (2.00 g, 7.15 mmol) and 4,4,5,5-tetramethyl-2- vinyl-1,3,2-dioxaborolane (5.50 g, 35.7 mmol) in toluene (30 mL), ethanol (10 mL) and water (1.0 mL) was added Pd(PPh3)4(826 mg, 715 μmol) and K2CO3(2.96 g, 21.4 mmol). The reaction was stirred at 100°C for 2 hours, cooled down to room temperature, filtered through celite and the filter cake was washed with dichloromethane. The filtrate was then concentrated under reduced pressure, and the residue was purified by flash C18 gel chromatography eluting with 0% to 10% acetonitrile in 0.5% aqueous formic acid to afford 2-bromo-6-vinylbenzoic acid (800 mg, 49% yield). LCMS: m / z [M+H]+= 229.1.

[0581] Step 2: To a solution of 2-bromo-6-vinyl-benzoic acid (750 mg, 3.30 mmol) in chloroform (30 mL) was added MCPBA (684.02 mg, 3.96 mmol). The reaction was stirred for 16 hours at room temperature, followed by the addition of PTSA (188.50 mg, 990.95 μmol). The reaction was stirred at 80°C for 8 hours, cooled down to room temperature, diluted with dichloromethane (100 mL), and washed with saturated aqueous Na2CO3and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0% to 60% EtOAc in petroleum ether to afford 7-bromo-3-(hydroxymethyl)isobenzofuran- 1(3H)-one (460 mg, 57% yield). LCMS: m / z [M+H]+= 245.0.

[0582] Step 3: To a solution of 7-bromo-3-(hydroxymethyl)isobenzofuran-1(3H)-one (400 mg, 1.65 mmol) and HBF4•Et2O (1.45 g, 16.5 mmol) in dichloromethane (8.0 mL) was added diazomethyl(trimethyl)silane (940 mg, 8.23 mmol). The reaction was stirred for 3 hours at room temperature, diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0% to 100% EtOAc in petroleum ether to afford 7-bromo-3- (methoxymethyl)isobenzofuran-1(3H)-one (Building Block 14) (165 mg, 39% yield).1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 7.6 Hz, 1H), 7.62-7.57 (m 2H), 5.64 – 5.57 (m, 1H), 3.78 (dd, J = 11.2, 3.2 Hz, 1H), 3.65 (dd, J = 11.2, 4.8 Hz, 1H), 3.13 (s, 3H). Building Block Example 15: Synthesis of 4-chloro-7-cyclopropylfuro[3,4-b]pyridin-5(7H)-one (BB15)

[0583] Step 1: A mixture of methyl 2,4-dichloronicotinate (5.00 g, 24.3 mmol), potassium vinyltrifluoroborate (3.58 g, 26.7 mmol), sodium carbonate (5.14 g, 48.5 mmol) and Pd(PPh3)4(2.80 g, 2.43 mmol) in toluene (50 mL), ethanol (50 mL) and water (25 mL) was degassed and purged 3 times with N2. The reaction was stirred at 110°C for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 5% to 30% EtOAc in petroleum ether to afford methyl 4-chloro-2-vinylnicotinate (3.80 g, 79% yield).

[0584] Step 2: To a solution of methyl 4-chloro-2-vinylnicotinate (1.80 g, 9.11 mmol) in 2-MeTHF (80 mL) and water (40 mL), was added a solution of K2OsO4dihydrate (1.01 g, 2.73 mmol) and NaIO4(5.84 g, 27.3 mmol) in water (40 mL) at 0 °C. The reaction was stirred at room temperature for 1 hour, quenched with water and extracted with 2-MeTHF. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 5% to 30% EtOAc in petroleum ether to afford methyl 4-chloro-2-formylnicotinate (600 mg, 3.01 mmol).

[0585] Step 3: To a solution of methyl 4-chloro-2-formylnicotinate (500 mg, 2.51 mmol) in THF (10 mL) under N2was added cyclopropylmagnesium bromide (3.76 mL, 3.76 mmol, 1M in THF) at -65 °C. The solution was stirred at -65°C for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 5% to 30% EtOAc in petroleum ether to afford 4-chloro-7-cyclopropylfuro[3,4-b]pyridin- 5(7H)-one (Building Block 15) (200 mg, 38% yield).1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 5.4 Hz, 1H), 7.46 (d, J = 5.4 Hz, 1H), 5.04 (d, J = 7.2 Hz, 1H), 1.33 - 1.22 (m, 1H), 0.85 - 0.63 (m, 4H). Building Block Example 16: Synthesis of 7-bromo-4-methoxyfuro[3,4-c]pyridin-1(3H)-one (BB16)

[0586] Step 1: A solution of 5-bromo-2-chloro-pyridine-3-carboxylic acid (5.00 g, 21.2 mmol) in thionyl chloride (30 mL) was heated at 80 °C for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene (2 x 10 mL). The residue was dissolved in DCM (50 mL), and N,O-dimethylhydroxylamine hydrochloride (2.70 g, 27.5 mmol) and triethylamine (8.60 g, 84.6 mmol) was added at 0 ℃. The resulted mixture was stirred at 0 ℃ for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography, eluting with 20% EtOAc in petroleum ether, to give 5-bromo-2-chloro-N-methoxy-N-methyl-pyridine-3-carboxamide (5.2 g, 88% yield). LCMS: m / z [M+H]+= 279.0.

[0587] Step 2: To a solution of 5-bromo-2-chloro-N-methoxy-N-methyl-pyridine-3-carboxamide (5.10 g, 18.3 mmol) in THF (50 mL) was added LiAlH4(277 mg, 7.30 mmol, 1M in THF) dropwise at 0 ℃, after addition, the reaction mixture was warmed to 25 ℃ and stirred for 16 hours, then the mixture was cooled to 0 °C, quenched with addition of 1 M KHSO4solution carefully, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a crude residue, which was purified by silica gel chromatography, eluting with 20% EtOAc in petroleum ether, to give 5-bromo-2-chloro-pyridine-3-carbaldehyde (2.6 g, 65% yield). LCMS: m / z [M+H]+= 219.9.

[0588] Step 3: To a solution of 5-bromo-2-chloro-pyridine-3-carbaldehyde (2.50 g, 11.3 mmol) in MeOH (20 mL) was added sodium methoxide (1.20 g, 22.7 mmol), and the resulting mixture was stirred at 70 ℃ for 3 hours. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in DCM, washed with NH4Cl (aq.). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuum under reduced pressure to give a crude residue, which was purified by silica gel chromatography, eluting with 20% EtOAc in petroleum ether, to give 5-bromo-2-methoxynicotinaldehyde (1.6 g, 65% yield). LCMS: m / z [M+H]+= 216.0.

[0589] Step 4: To a solution of 5-bromo-2-methoxynicotinaldehyde (1.60 g, 7.41 mmol) in MeOH (20 mL) was added trimethyl orthoformate (3.10 g, 29.6 mmol) and PTSA (63.8 mg, 0.37 mmol). The reaction was stirred at 70℃ for 2 hours and then concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated aqueous NaHCO3, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 20% EtOAc in petroleum ether to give 5-bromo-3-(dimethoxymethyl)-2-methoxypyridine (1.30 g, 67% yield). LCMS: m / z [M+H]+= 262.0 / 264.1.

[0590] Step 5: To a solution of 5-bromo-3-(dimethoxymethyl)-2-methoxypyridine (1.30 g, 4.96 mmol) in THF (20 mL) was added LDA (3.72 mL, 7.44 mmol, 2.0 M in THF) dropwise at -78℃ under N2. The reaction was stirred at -78℃ for 30 minutes, followed by the addition of ethyl chloroformate (1.61 g, 14.88 mmol). The mixture was warmed to room temperature, stirred for 2 hours, quenched with saturated aqueous NaHCO3, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in reduced pressure. The residue was purified by flash silica gel chromatography eluting with 20% EtOAc in petroleum ether to give ethyl 5-bromo-3-(dimethoxymethyl)-2-methoxyisonicotinate (1.0 g, 60% yield). LCMS: m / z [M+H]+= 334.1 / 336.1.

[0591] Step 6: To a solution of ethyl 5-bromo-3-(dimethoxymethyl)-2-methoxyisonicotinate (1.0 g, 2.99 mmol) in acetonitrile (10 mL) and water (0.5 mL) was added LiBF4(309 mg, 3.29 mmol). The resulting mixture was stirred at 90℃ for 2 hours, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography eluting with 20% EtOAc in petroleum ether to give ethyl 5-bromo-3-formyl-2-methoxyisonicotinate (300 mg, 35% yield). LCMS: m / z [M+H]+= 288.0 / 290.0.

[0592] Step 7: To a solution of ethyl 5-bromo-3-formyl-2-methoxyisonicotinate (250 mg, 0.870 mmol) in ethanol (10 mL) was added NaBH4(49.0 mg, 1.30 mmol). The resulting mixture was stirred at 0℃ for 2 hours and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 20% EtOAc in petroleum ether, to give 7-bromo-4-methoxyfuro[3,4- c]pyridin-1(3H)-one (Building Block 16) (150 mg, 71% yield). LCMS: m / z [M+H]+= 243.9, 246.0. Building Block Example 17: Synthesis of 7-bromo-3-((dimethylamino)methyl)isobenzofuran-1(3H)- one (BB17)

[0593] Step 1: To a solution of 7-bromoisobenzofuran-1(3H)-one (600 mg, 2.82 mmol) in THF (8.0 mL) at -78°C under N2was added 1.0 M LiHMDS in THF (2.96 mL, 2.96 mmol). The reaction was stirred at -78°C for 10 minutes, followed by the addition of N-methyl-N-methylenemethanaminium iodide (573 mg, 3.10 mmol). The mixture was stirred at -78°C for 1 hour, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 0% to 100% EtOAc in petroleum ether, to afford 7-bromo-3- ((dimethyla...

Claims

1. CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted 6-membered aryl or optionally substituted 6-membered heteroaryl, and wherein the aryl or heteroaryl is monocyclic or further comprises fused thereto an optionally substituted 5-6 membered heterocyclyl; G1is CH, CF, or N; RCis C2-5alkyl, C2-5alkenyl, C2-5haloalkyl, C2-5haloalkenyl, -C1alkylene-C3carbocyclyl, or -C1haloalkylene-C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, or 2 halo; X is O, S, or NH; RD1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl or haloalkyl is substituted with 0 or 1 RD1Agroups, wherein RD1Ais -OH, -ORD1B, -NH2, -NH(RD1B), -N(RD1B)2, -SH, -SRD1B, -CN, -C(=O)RD1B, -C(=O)ORD1B, -C(=O)NH(RD1B), -C(=O)N(RD1B)2, -S(=O)RD1B, or -S(=O)2RD1B, wherein each instance of RD1Bis independently C1-3alkyl or C1-3haloalkyl; or RD1is a group of formula Ring E:wherein: Ring E is a C3-8carbocyclyl or a 4-8 membered heterocyclyl; each instance of REis independently halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, 4 membered heterocyclyl, -OH, -ORE1, -NH2, -NH(RE1), -N(RE1)2, -SH, -SRE1, -CN, -NHC(=O)RE1, -NHC(=O)ORE1, -N(RE1)C(=O)ORE1, -NHC(=O)NH(RE1), -NHC(=O)N(RE1)2, -N(RE1)C(=O)NH(RE1), -N(RE1)C(=O)N(RE1)2, -OC(=O)RE1, -OC(=O)ORE1, -OC(=O)NH(RE1), -OC(=O)N(RE1)2, -C(=O)RE1, -C(=O)ORE1, -C(=O)NH(RE1), -C(=O)N(RE1)2, -S(=O)RE1, or -S(=O)2RE1, or two REgroups attached to the same carbon atom are joined to form a C3-4carbocyclyl, and wherein each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; each instance of RE1is independently C1-6alkyl, C1-6haloalkyl, -L1-C3-5carbocyclyl or -L1-(4-5 membered heterocyclyl), or two instances of RE1attached to the same nitrogen atom are joined to form a 4-5 membered heterocyclyl; wherein L1is absent, C1-3alkylene or C1-3haloalkylene; each instance of alkyl, haloalkyl, carbocyclyl, and heterocyclyl is independently substituted with 0, 1, or 2 RE2; and each instance of carbocyclyl and heterocyclyl is further independently substituted with 0, 1, or 2 RE3;each instance of RE2is independently halo, -OH, -ORE3, -NH2, -NH(RE3), -N(RE3)2, -SH, -SRE3, -CN, -C(=O)RE3, -C(=O)ORE3, -C(=O)NH(RE3), -C(=O)N(RE3)2, -S(=O)RE3, or -S(=O)2RE3; each instance of RE3is independently C1-3alkyl or C1-3haloalkyl; y is 0, 1, 2, or 3; RD2is halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo; and RD3is hydrogen, halo, C1-3alkyl, C1-3haloalkyl, or C3carbocyclyl, wherein the carbocyclyl is substituted with 0, 1, 2, or 3 halo.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G1is N.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein RCis C2-5alkyl or C2-5haloalkyl.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein RCis selected from the group consisting of:

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein RD2is halo, C1alkyl, C1haloalkyl, or C3carbocyclyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein RD2is bromo, chloro, -CH3, -CHF2, or cyclopropyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein RD3is hydrogen.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein RD3is fluoro.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, whereinRD1is Ring E of formula.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E selected from the group consisting of:wherein y is 0, 1, 2 or 3, as valency permits.

12. The compound of claim 10 or 11, or a pharmaceutically acceptable salt thereof, wherein RD1is Ring E of formula:, , , , , , ,13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, whereinRing D of formula:is a group of formula:

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Ring A is a monocyclic 6-membered aryl or monocyclic 6-membered heteroaryl, and wherein Ring A is substituted with one or more of the following groups: -CN; and / or halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered aryl or 6-membered heteroaryl, and wherein the aryl or heteroaryl further comprises fused thereto a 5-6 membered heterocyclyl ring, and further wherein Ring A is unsubstituted or substituted with one or more of the following groups: halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and / or halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl;and / or C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two non-hydrogen groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl.

16. The compound of any one claims 1-15, or a pharmaceutically acceptable salt thereof, wherein: (i) Ring A is a group of formula: to provide a compound of Formula (II):or a pharmaceutically acceptable salt thereof; or (ii) Ring A is a group of formula:to provide a compound of Formula (III):or a pharmaceutically acceptable salt thereof; wherein: G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; G7is CRA7or N; provided no more than two of G2, G3, and G4or no more than two of G2, G3, and G7are N; each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5- membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each of RA5and RA7is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, -OR’’, -SR’’, -NHR”, -N(R”)2, C3-4carbocyclyl, 4-10 membered heterocyclyl, or 5-membered heteroaryl, wherein each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NH2, -NHR**, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ is independently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and x is 1 or 2.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II), or a pharmaceutically acceptable salt thereof, and the group of formula (a-1) is of formula:

18. The compound of claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein RA5or RA7is of formula: -F, -Cl,19. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III), or a pharmaceutically acceptable salt thereof, and the group of formula (a-2) is of formula:

20. The compound of claim 16 or 19, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III) or a pharmaceutically acceptable salt thereof, and wherein the group of formula (a-2) is of formula:

21. The compound of any one of claims 1-16, 19, and 20, wherein the compound is of Formula (III- C), (III-D), or (III-E):or a pharmaceutically acceptable salt thereof, wherein: G2is CRA2or N; G3is CRA3or N; each of RA2and RA3is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5-membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; each instance of RA6is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-4carbocyclyl, 4-5 membered heterocyclyl, 6-membered aryl, or 5-membered heteroaryl, or two RA6groups attached to the same carbon atom are joined to form a C3-4carbocyclyl, wherein each instance of alkyl and haloalkyl is independently substituted with 0 or 1 -CN, -OR’’’, -SR’’’, or -N(R’’’)2, wherein each instance of R’’’ isindependently hydrogen, C1-3alkyl, or C1-3haloalkyl, or two R’’’ groups together with the nitrogen to which they are attached form a 3-5 membered heterocyclyl or 5-membered heteroaryl; and wherein each instance of carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent, C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NHR**, -NH2, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

22. The compound of any one of claims 1-18, wherein the compound is of Formula (II’):or a pharmaceutically acceptable salt thereof, wherein: G2is CRA2or N; G3is CRA3or N; G4is CRA4or N; provided no more than two of G2, G3, and G4are N; each of RA2, RA3, and RA4is independently hydrogen, halo, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, -CN, -OR’, -SR’, or -N(R’)2, wherein each instance of R’ is independently hydrogen, C1-3alkyl, C1-3haloalkyl, C3-8carbocyclyl, 4-8 membered heterocyclyl, or two R’ groups together with the nitrogen to which they are attached form a 4-8 membered heterocyclyl or 5- membered heteroaryl; wherein each instance of carbocyclyl, heterocyclyl or heteroaryl is independently substituted with 0 or 1 C1-3alkyl or C1-3haloalkyl; and each instance of R’’ is independently C1-3alkyl, C1-3haloalkyl, -L2-C3-10carbocyclyl, -L2-(4-10 membered heterocyclyl), -L2-(6-membered aryl), or -L2-(5-membered heteroaryl), wherein L2is absent,C1-3alkylene or C1-3haloalkylene, or two R’’ groups together with the nitrogen to which they are attached form a 4-10 membered heterocyclyl; wherein each instance of alkyl, haloalkyl, alkylene, haloalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, or 3 R* groups, wherein each instance of R* is independently =O, =NH, =NR**, halo, C1-3alkyl, C1-3haloalkyl, -C1-3alkylene-OR**, -C1-3haloalkylene-OR**, -C1-3alkylene-NHR**, -C1-3haloalkylene-NHR**, -C1-3alkylene-N(R**)2, -C1-3haloalkylene-N(R**)2, -OR**, -NHR**, -NH2, -N(R**)2, -NH(C=O)R**, -N(R**)(C=O)R**, -NH(C=O)OR**, -N(R**)(C=O)OR**, -(C=O)NHR**, -(C=O)N(R**)2, -(C=O)R**, -(C=O)OR**, -C1-3alkylene-C3-4carbocyclyl, or -C3-4carbocyclyl, as valency permits; wherein each instance of R** is independently C1-6alkyl, C1-6haloalkyl, -C1-3alkylene-OR#, or -C1-3haloalkylene-OR#, and wherein each instance of R#is independently C1-3alkyl or C1-3haloalkyl; or two R** groups together with the nitrogen to which they are attached form a 4-5 membered heterocyclyl.

23. The compound of any one of claims 1-22 selected from the compounds set forth in Tables 1A, 1B, 2A, 2B, and 2C, or a pharmaceutically acceptable salt of any of the foregoing.

24. A pharmaceutical composition comprising the compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

25. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24.

26. A method of inhibiting Caspase-4 activity in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24.

27. A method of inhibiting Caspase-4 activity in a cell, the method comprising contacting the cell with a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof.

28. A method for preparing a compound of Formula (I) of any one of claims 1-23, or a salt thereof, wherein X, RD1, RD2, RD3, RC, G1, and Ring A are as defined in any one of claims 1-23, the method comprising: (i) treating a compound of Formula (F1), or salt thereof, with a compound of Formula (H1), or salt thereof, wherein Hal3is halogen or other leaving group, and each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl:to provide the compound of Formula (I), or salt thereof; or (ii) treating a compound of Formula (E1), or salt thereof, with a compound of Formula (H2), or salt thereof, wherein Hal1is halogen or other leaving group, and each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl:to provide the compound of Formula (I), or salt thereof.

29. A compound of Formula (E2):or salt thereof, wherein G1, RD2, RD3, and RCare as defined in any one of claims 1-23, and Hal1is halogen or other leaving group and Hal2is halogen.

30. A compound of Formula (E1):or salt thereof, wherein G1, X, RD1, RD2, RD3, and RCare as defined in any one of claims 1-23, and Hal1is halogen or other leaving group.

31. A compound of Formula (F1):or salt thereof, wherein G1, X, RD1, RD2, RD3, and RCare as defined in any one of claims 1-23, and each instance of RBis independently hydrogen or C1-4alkyl, or each -ORB, together with the boron atom to which each are attached, are joined to form a 5-6 membered heterocyclyl substituted with 0, 1, 2, 3, or 4 C1-4alkyl.

32. A method of inhibiting Caspase-4 comprising contacting a compound, or a pharmaceutically acceptable salt thereof, with human Caspase-4, wherein the compound, or a pharmaceutically acceptable salt thereof, binds to amino acid residue Arg364 of the allosteric binding pocket of human Caspase-4, and wherein the compound has a human Caspase-4 inhibitory activity of less than 100 nM, a human Caspase- 5 inhibitory activity of less than 100 nM, and a human Caspase-1 inhibitory activity of greater than 10,000 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

33. A compound, or a pharmaceutically acceptable salt thereof, which binds to amino acid residue Arg364 of the allosteric binding pocket of human Caspase-4, and has a human Caspase-4 inhibitory activity of less than 100 nM, a human Caspase-5 inhibitory activity of less than 100 nM, and a human Caspase-1 inhibitory activity of greater than 10,000 nM, as determined by Homogeneous Time Resolved Fluorescence (HTRF).

34. The method or compound of claims 32 or 33, wherein the compound is any one of claims 1-23, or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising the compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

36. A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 35.

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