Novel potassium channel opener compounds and related uses

Abstract

Described herein are potassium channel opener compounds, compositions, and related uses and preparations thereof for the treatment of a disease or disorder, such as congenital hyperinsulinism.

Description

[0001]Attorney Docket No.: R2054-7036WO NOVEL POTASSIUM CHANNEL OPENER COMPOUNDS AND RELATED USES CLAIM OF PRIORITY The instant application claims priority to U.S. Application No.63 / 636,075, filed on April 18, 2024; and U.S. Application No.63 / 636,079, filed on April 18, 2024. The contents of the 5 foregoing applications are incorporated herein by reference in their entirety. BACKGROUND ATP-gated, inward-rectifier potassium (KATP) channels, in part, modulate insulin secretion and glucose homeostasis in pancreatic β-cells. KATP channel dysfunction may effectively uncouple insulin secretion from plasma glucose levels and lead to metabolic disorders 10 such as hyperinsulinism (HI). Although KATPchannel-opener compounds have previously been developed for the treatment of HI, currently available therapies, e.g., diazoxide, can be non- selective, not generally well-tolerated, and have a myriad of serious potential side effects, including cardiac failure, pulmonary hypertension, and anaemia, inter alia. Other KATPchannel pathologies may be contributing etiological factors in the development of cancer, neurological 15 disorders, cardiovascular disorders, pulmonary disorders, integumentary disorders, sexual disorders, and urinary disorders. Therefore, there is a significant unmet need to develop compounds that are selective, potent, and well-tolerated. The present disclosure describes compounds that modulate the activity of SUR / Kir6 KATP channels and methods of using said compounds for the treatment of disorders, e.g., hyperinsulinism (HI), e.g., congenital 20 hyperinsulinism (CHI). DETAILED DESCRIPTION OF INVENTION KATPchannels are octameric, ATP-gated inward rectifier potassium channels expressed in various tissues, including the heart, smooth muscle, and pancreas. The octameric protein 25 complex comprises four inward-rectifier potassium ion channel protein family subunits, either Kir6.1 or Kir6.2, and / or four regulatory sulfonylurea receptor subunits, either SUR1, SUR2A, or SUR2B. The assembly of these subunits in different combinations result in tissue specific KATP channel isoforms. Human pancreatic β-cell KATP channels are SUR1 / Kir6.2 complexes, whereas SUR2A / Kir6.2 and SUR2B / Kir6.2 or Kir6.1 isoforms are expressed in cardiac and smooth 1 Attorney Docket No.: R2054-7036WO muscles, respectively. SUR proteins belong to the ATP binding cassette transporter (ABCC) subfamily and comprise 17 transmembrane helices (TM1 through TM17) clustered into three transmembrane domains (TMD0, TMD1, and TMD2), separated by two cytosolic nucleotide binding domains (NBDs), NBD1 and NBD2 for binding Mg-ATP. The Kir6.x subunit comprises 5 two membrane spanning, α-helical domains which provides a K+selectivity P-loop. Cryo-electron microscopy (cryo-EM) has been employed to investigate the interactions between SUR1 / Kir6.2 and drug targets previously characterized in the art, e.g., diazoxide and NN414. Several putative regions on SUR1, e.g., the A site, polar site (P site), and B site, as well as particular amino acid residues within these regions, have been postulated to participate in 10 modulation of channel activity. However, the direct mechanistic link between drug target interactions with these putative sites and a possible allosteric model of SUR1 / Kir6.2 channel modulation and even its clinically relevant manifestations in metabolic disorders such as CHI and related diseases has not fully elucidated (c.f., Wu et al., Mol Pharmacol.2022, 102: 234- 239). 15 Modulation of K+permeability, i.e., K+flux, of SUR / Kir6 channels is mediated by intracellular ATP stores and the activity of voltage gated Ca2+channels. Dimerization of the SUR nucleotide binding domains NBD1 and NBD2 activates SUR / Kir6 channels, whereas the binding of Mg-ATP to SUR NBD inhibits SUR / Kir6. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational change in 20 SUR1 / Kir6.2. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational change in SUR2A / Kir6.2. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational change in SUR2B / Kir6.2. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational 25 change in SUR2B / Kir6.1. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational change in SUR1 / Kir6.2, where a nucleotide (e.g., Mg-ATP) is already bound to a SUR1 NBD. In some embodiments, the featured compounds induce a confirmational change in SUR1 / Kir6.2, thereby allosterically regulating SUR1 / Kir6.2. 30 In some embodiments, the allostery comprises: (i) regulating the dimerization of the SUR1 nucleotide-binding domains NBD1 and NBD2; and / or (ii) modulating K+permeability, e.g., K+2 Attorney Docket No.: R2054-7036WO current, e.g., K+ efflux, e.g., in a pancreatic β-cell. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational change in SUR2 / Kir6.2 (e.g., SUR2A / Kir6.2 or SUR2B / Kir6.2) where a nucleotide (e.g., Mg- ATP) is already bound to a SUR2 NBD. In some embodiments, the featured compounds induce a 5 confirmational change in SUR2 / Kir6.2, thereby allosterically regulating SUR2 / Kir6.2. In some embodiments, the allostery comprises: (i) regulating the dimerization of the SUR2 nucleotide- binding domains NBD1 and NBD2; and / or (ii) modulating K+permeability, e.g., K+current, e.g., K+ efflux, e.g., in a pancreatic β-cell. In some embodiments, the compounds featured in the present disclosure interact with (e.g., bind to) and / or induce a confirmational change in 10 SUR2 / Kir6.1 (e.g., SUR2A / Kir6.1 or SUR2B / Kir6.1), where a nucleotide (e.g., Mg-ATP) is already bound to a SUR2 NBD. In some embodiments, the featured compounds induce a confirmational change in SUR2 / Kir6.1, thereby allosterically regulating SUR2 / Kir6.1. In some embodiments, the allostery comprises: (i) regulating the dimerization of the SUR2 nucleotide- binding domains NBD1 and NBD2; and / or (ii) modulating K+permeability, e.g., K+current, e.g., 15 K+ efflux, e.g., in a pancreatic β-cell. The compounds described herein may play a role in modulating the intracellular trafficking of the SUR / Kir6 channel (e.g., SUR1 / Kir6.2, SUR2A / Kir6.2, SUR2B / Kir6.2, SUR2B / Kir6 / 1). In an embodiment, the features compounds block or prevent trafficking of the channel or assembly of the channel components, e.g., at the cell surface. 20 A last aspect of the present disclosure relates to the use of the compounds or pharmaceutical compositions, or pharmaceutically acceptable salts thereof, for the treatment of subjects, particularly human subjects suffering from a disorder. Exemplary disorders contemplated may include a metabolic disorder (e.g., hyperinsulinism (HI), e.g., congenital hyperinsulinism, cancer, a neurological disorder, a cardiovascular disorder, a pulmonary disorder, 25 an integumentary disorder, a sexual disorder, a urinary disorder, or a symptom thereof. The compounds and pharmaceutical compositions, or their pharmaceutically acceptable salts, may be particularly useful in the treatment of metabolic disorders, especially hyperinsulinism (HI), congenital hyperinsulinism (CHI), persistent hyperinsulinism, or transient hyperinsulinism. In some embodiments, the metabolic disorder is a hyperinsulinism-related 30 syndrome, e.g., Beckwith-Wiedemann syndrome, hyperinsulinism-hyperammonaemia (HIHA) 3 Attorney Docket No.: R2054-7036WO syndrome, Sotos syndrome, Turner syndrome, Costello syndrome, Kabuki syndrome, and the like. The SUR1 / Kir6.2 KATPchannel is integral in modulating membrane potential as part of the calcium-mediated flux leading to insulin secretion in response to changes in plasma glucose 5 levels in pancreatic β-cells. Aberrant activity of inward-rectifier potassium channels, in particular the SUR1 / Kir6.2 isoform, may contribute to metabolic disease states such as obesity, type 2 diabetes, and local or peripheral insulin resistance, hypoglycemia, hyperglycemia, and hypertriglyceridemia. Changes in channel conductance, trafficking to / from the cell membrane, and / or changes in the cytosolic ATP / ADP concentration ratio may contribute to SUR1 / Kir6.2 10 pathology (cf. N.D. Rodriguez-Rivera et al. Int. J Mol. Sci.2024, 25(7), 4079). Hyperinsulinism (HI) is defined as elevated insulin levels in blood due to dysregulated release of insulin from β-cells, which leads to hypoglycemia. It can be genetic or acquired and transient or permanent. Hyperinsulinemiac hypoglycemia (HH) is described as a clinically, genetically, and morphologically heterozygous conditions where insulin secretion is persistent 15 despite low blood glucose levels. The most severe and permanent forms of HH are due to congenital hyperinsulinism. Congenital hyperinsulinism (CHI) is an inherited form of hyperinsulinemiac hypoglycemia (HH) due to mutations in genes involved in the regulation of insulin secretion. CHI is a permanent form of hypoglycemia in neonates, infants and children which causes 20 irreversible brain damage due to the secondary metabolic actions of insulin. The excessive release of insulin causes suppression of lipolysis and reduction in ketones which are alternative energy sources for the brain. The rise in insulin levels also inhibits secretion of glucagon which hinders fat breakdown again causing direct damage to the brain. Therefore, up to 48% of children having recurrent hypoglycemia suffer from brain damage. 25 The genetic basis of CHI has been related to 23 mutations in essential genes controlling insulin secretion and two of these genes, namely ABCC8 and KCNJ11, are genes encoding KATPchannel proteins SUR1 and Kir6.2, regulating the insulin release from pancreatic β-cells, among other proteins. Other SUR / Kir6 “channelopathies” may further play a role as an etiological factor in the 30 development of cancer, neurological disorders, cardiovascular disorders, pulmonary disorders, integumentary disorders, sexual disorders, and urinary disorders, inter alia. 4 Attorney Docket No.: R2054-7036WO Definitions Selected Chemical Definitions 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 5 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 Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, 10 Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to 15 the standard rules of chemical valency known in the chemical arts. When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C1-C6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1- C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6alkyl. 20 The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C1-C24alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 25 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-C6alkyl 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– 30 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. Each instance of an alkyl group may be 5 Attorney Docket No.: R2054-7036WO independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1–C10alkyl (e.g., –CH3). In certain embodiments, the alkyl group is substituted C1–C6 alkyl. 5 As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C2-C24alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2- C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6alkenyl”). In some10 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-C4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl 15 (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C1–C10alkenyl. In certain 20 embodiments, the alkenyl group is substituted C2–C6alkenyl. As used herein, the term “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C2-C24alkenyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In 25 some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). 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-C4 alkynyl groups include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1– butynyl (C4), 2–butynyl (C4), and the like. Each instance of an alkynyl group may be 30 independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 6 Attorney Docket No.: R2054-7036WO 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C2–6 alkynyl. As used herein, the term "haloalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one halogen selected 5 from the group consisting of F, Cl, Br, and I. The halogen(s) F, Cl, Br, and I may be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CCl3, -CH2-CF3, -CH2-CCl3,-CH2-CBr3,-CH2-CI3,-CH2-CH2-CH(CF3)-CH3, -CH2-CH2-CH(Br)- CH3, and -CH2-CH=CH-CH2-CF3. Each instance of a haloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted haloalkyl”) or substituted (a 10 “substituted haloalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms 15 may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O- CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to20 two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O- Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like, it will be understood that the terms heteroalkyl and –CH2O or –NRCRDare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding 25 specific heteroalkyl groups, such as –CH2O, –NRCRD, or the like. Each instance of a heteroalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent As used herein, “cycloalkyl” refers to a radical of a non–aromatic cyclic hydrocarbon group30 having from 3 to 10 ring carbon atoms (“C3-C10cycloalkyl”) and zero heteroatoms in the non– aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms 7 Attorney Docket No.: R2054-7036WO (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3- C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein 5 the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl 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-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl 10 (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl 15 (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of 20 attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl 25 group is a substituted C3-C10 cycloalkyl. Exemplary 3–membered cycloalkyl groups include cyclopropyl, 1,1-dimethylcyclopropyl, 2,2-dimethylcyclopropyl, isopropylcyclopropyl, cyclopropylmethanol, 1,1-difluoro-2-methyl- cyclopropyl, difluorocyclopropyl, ethynylcyclopropyl, methylcyclopropyl, 1-cyclopropylethan-1- ol, and N,1-dimethylcyclopropyl-1-carboxamide.Exemplary 4-membered cycloalkyl groups 30 include cyclobutyl, difluorocyclobutyl, methoxycyclobutyl, methoxymethylcyclobutyl, methylcyclobutyl, and 1,1-difluoro-3-methylcyclobutyl. Exemplary 5-membered cycloalklyl 8 Attorney Docket No.: R2054-7036WO groups include bicyclo[1.1.1]pentyl, spiro[2.2]pentyl, and hydroxybicyclo[1.1.1]]pentyl. Exemplary 6-membered cycloalkyl groups include spiro[2.3]hexyl and bicyclo[2.1.1]hexyl. “Heterocyclyl” as used herein refers to a radical of a 3– to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently 5 selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). 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 a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. 10 Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, 15 and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7- membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted 20 heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl. Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing25 one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5– membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and 30 oxazolidin–2–one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered 9 Attorney Docket No.: R2054-7036WO heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1- methylpyridin2-onyl), and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2- 5 methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4- onyl), dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without 10 limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5–membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6–bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5–membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5–bicyclic heterocyclyl ring) include, without limitation,15 octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7- diazaspiro[3.5]nonanyl). Exemplary 6–membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6–bicyclic heterocyclyl ring) include, without limitation, 20 tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6–membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6–membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8- bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9- 25 azabicyclo[3.3.1]nonanyl). As used herein, the terms “cyano” or “–CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N. As used herein, the terms “halogen” or “halo” refer to fluorine, chlorine, bromine or iodine. As used herein, the term “nitro” refers to a substitutent having two oxygen atoms bound to 30 a nitrogen atom, e.g., -NO2. As used herein, “oxo” refers to a carbonyl, i.e., -C(O)-. 10 Attorney Docket No.: R2054-7036WO The symbol “ ” as used herein in relation to a compound of Formula (I) refers to anattachment point to another moiety or functional group within the compound. Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, and heterocyclyl groups, as defined herein, are optionally substituted. In general, the term “substituted”, whether preceded by 5 the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions 10 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. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes 15 of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. Two or more substituents may optionally be joined to form cycloalkyl or heterocyclyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found 20 attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure 25 create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure. The compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to: cis- and trans-forms; E- and Z-forms; endo- and exo-forms; R-30 , S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate- forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial 11 Attorney Docket No.: R2054-7036WO forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the 5 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. In an embodiment, the stereochemistry depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography 10 (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, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, 15 Notre Dame, IN 1972). This disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of 20 the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by 25 weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising 30 an enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In certain embodiments, the enantiomerically pure R– 12 Attorney Docket No.: R2054-7036WO compound in such compositions can, for example, comprise, at least about 95% by weight R– compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. 5 In certain embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R–compound, by total weight of the compound. In some embodiments, a diastereomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising a 10 diastereometerically pure exo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure exo compound. In certain embodiments, the diastereometerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most about 5% by weight endo compound, by total weight of the compound. For example, a pharmaceutical composition comprising a 15 diastereometerically pure endo compound can comprise, for example, about 90% excipient and about 10% diastereometerically pure endo compound. In certain embodiments, the diastereometerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo compound, by total weight of the compound. 20 In some embodiments, an isomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising a isomerically pure exo compound can comprise, for example, about 90% excipient and about 10% isomerically pure exo compound. In certain embodiments, the isomerically pure exo compound in such compositions can, for example, comprise, at least about 95% by weight exo compound and at most 25 about 5% by weight endo compound, by total weight of the compound. For example, a pharmaceutical composition comprising an isomerically pure endo compound can comprise, for example, about 90% excipient and about 10% isomerically pure endo compound. In certain embodiments, the isomerically pure endo compound in such compositions can, for example, comprise, at least about 95% by weight endo compound and at most about 5% by weight exo 30 compound, by total weight of the compound. 13 Attorney Docket No.: R2054-7036WO In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); 5 C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18 O; N may be in any isotopic form, including14N and15N; F may be in any isotopic form, including18F,19F, and the like. The term “pharmaceutical composition” as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable. 10 The term “pharmaceutically acceptable” as used herein has its conventional meaning and refers to compounds, material, compositions and / or dosage forms, which are, within the scope of sound medical judgement suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and problem complications commensurate with a reasonable benefit / risk ratio. 15 The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, 20 either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of 25 pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, 30 phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like 14 Attorney Docket No.: R2054-7036WO glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other 5 pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. The term “tautomer” refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually 10 H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. 15 Other Definitions The following definitions are more general terms used throughout the present disclosure. The articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “and / or” means either “and” or “or” unless indicated otherwise. 20 The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. 25 “Acquire” or “acquiring” as used herein, refer to obtaining possession of a value, e.g., a numerical value, or image, or a physical entity (e.g., a sample), by “directly acquiring” or “indirectly acquiring” the value or physical entity. “Directly acquiring” means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. “Indirectly acquiring” refers to receiving the value or physical entity from another party or 30 source (e.g., a third-party laboratory that directly acquired the physical entity or value). Directly acquiring a value or physical entity includes performing a process that includes a physical 15 Attorney Docket No.: R2054-7036WO change in a physical substance or the use of a machine or device. Examples of directly acquiring a value include obtaining a sample from a human subject. Directly acquiring a value includes performing a process that uses a machine or device, e.g., mass spectrometer to acquire mass spectrometry data. 5 The terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof. As used herein, the terms “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound of Formula (I) refers to an amount sufficient to 10 elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of Formula (I) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, 15 in treating cancer, an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor. A “therapeutically effective amount” of a compound of Formula (I) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically 20 effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, 25 reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. “Prevention,” “prevent,” and “preventing” as used herein refers to a treatment that comprises administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I)) prior to the onset of a disease, disorder, or condition in order to 30 preclude the physical manifestation of said disease, disorder, or condition. In some embodiments, “prevention,” “prevent,” and “preventing” require that signs or symptoms of the 16 Attorney Docket No.: R2054-7036WO disease, disorder, or condition have not yet developed or have not yet been observed. In some embodiments, treatment comprises prevention and in other embodiments it does not. A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, 5 adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and / or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female 10 and at any stage of development. A non–human animal may be a transgenic animal. As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., administering a compound described herein (e.g., a 15 compound of Formula (I)). In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, reducing, or delaying the onset 20 of, an underlying cause of a disease, disorder, or condition. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease or disorder have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease, e.g., in preventive treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history 25 of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment comprises prevention and in other embodiments it does not. 30 The term “controlling” is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of the diseases and conditions affecting the 17 Attorney Docket No.: R2054-7036WO mammal. However, “controlling” does not necessarily indicate a total elimination of all disease and condition symptoms and is intended to include prophylactic treatment. The term “carrier” as used herein has its conventional meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient or vehicle with which a pharmaceutically 5 active ingredient is administered. The term “excipient” as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid formulation. The term “persistent or recurrent congenital hyperinsulinism (CHI)” comprises forms of 10 hyperinsulinism (HI) which can be formed in neonates and children due to any genetic mutations and which is persistent despite continuous glucose administration or due to any other metabolic disorder known or unknown to the skilled person. The term “transient CHI” comprises forms of HI which can be formed during foetal, neonatal and early childhood stages due to gene mutations and / or perinatal stress, such as 15 prematurity, intrauterine growth retardation, small for gestational age, or perinatal asphyxia or due to any other metabolic disorder known or unknown to the skilled person. KATPK+Channel Opener Compounds Described herein are compounds, compositions, and related uses and preparations thereof for the treatment of a disease or disorder, such as CHI. In a first aspect, the present disclosure 20 features a compound of Formula (I): A first aspect of the present disclosure relates to a compound having a structure of Formula (I): R5RxI), or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof,25 wherein: each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - 18 Attorney Docket No.: R2054-7036WO S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, 5 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; Rxand Ryare each independently absent, hydrogen, or C1-C6 alkyl; or Rxand R3, together with the atoms to which they are attached, form a heterocyclyl that is optionally substituted with one or more R4; or Ryand R3, together with the atoms to which they are attached, form a heterocyclyl that is optionally substituted with one or more R4; each R4is 10 independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 15 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted with one or more R7; or RBand RC, together with the atoms to which they are connected, form a heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 20 cycloalkyl, heterocyclyl, -ORA’, -N(RB’)(RC’), -C(O)N(RB’)(RC’), halo, oxo, nitro, or cyano; or two R7and the atom(s) to which they are attached form a cycloalkyl or heterocyclyl; each of RDand REis independently hydrogen, halogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with 25 one or more R7; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each of RB’and RC’is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or RB’and RC’, together with the atoms to which they are connected, form a heterocyclyl; x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2. 30 In some embodiments, the compound of Formula (I) is a compound of Formula (I-A): 19 Attorney Docket No.: R2054-7036WO R5RxR1N R3A),or a pharmaceutically acceptable sal rate, or isotope thereof, wherein: each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - 5 S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl and cycloalkyl are each substituted with one or more R4, and wherein alkenyl, alkynyl, heteroalkyl, haloalkyl, and 10 heterocyclyl are each optionally substituted with one or more R4; Rxand Ryare each independently absent, hydrogen, or C1-C6 alkyl; or Rxand R3, together with the atoms to which they are attached, form a heterocyclyl that is optionally substituted with one or more R4; or Ryand R3, together with the atoms to which they are attached, form a heterocyclyl that is optionally substituted with one or more R4; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, 15 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl is tertiary, wherein alkyl is substituted with one or more R7, and wherein alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2- 20 C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted with one or more R7; or RBand RC, together with the atoms to which they are connected, form a heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 25 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, -ORA’, -N(RB’)(RC’), -C(O)N(RB’)(RC’), halo, oxo, nitro, or cyano; or two R7and the atom(s) to which they are attached form a cycloalkyl or heterocyclyl; each of RDand REis independently hydrogen, halogen, oxo, ORA, C1-C6 alkyl, 20 Attorney Docket No.: R2054-7036WO C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each of RB’and RC’is 5 independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or RB’and RC’, together with the atoms to which they are connected, form a heterocyclyl; x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I-B): R5RxR1N R3B),10 or a pharmaceutically acceptable sal rate, or isotope thereof, wherein: each of R1, R2, R5, and R6is independently hydrogen, -ORA, or halo; R3is C1-C8 alkyl, cycloalkyl, ORA, or N(RB)(RC); Rxand Ryare each independently absent or hydrogen; RAis C1- C6 alkyl; RBis hydrogen; and RCis independently C1-C6 alkyl, C2-C6 alkenyl, or monocyclic cycloalkyl, wherein alkyl is a primary or secondary alkyl, and wherein alkyl is optionally 15 substituted with one or more -OH. In some embodiments, the compound of Formula (I) is a compound of Formula (I’): R5Rx’),or a pharmaceutically acceptable salt , tautomer, stereoisomer, hydrate, or isotope thereof, wherein: each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-20 C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, 21 Attorney Docket No.: R2054-7036WO heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 5 more R4; R’ is hydrogen or C1-C6 alkyl; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1- C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently 10 hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; 15 each of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2. In some embodiments, the compound of Formula (I) is a compound of Formula (I”): R5Rx1 320 ”)or a pharmaceutically acceptable salt drate, or isotope thereof, wherein each of R1, R2, R5, and R6are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and 25 heterocyclyl are each optionally substituted with one or more R7; R3is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally 22 Attorney Docket No.: R2054-7036WO substituted with one or more R4; R’ is hydrogen or alkyl; each R4is independently oxo, -S(RD)x, N(RB)(RC), alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with 5 one or more R7; each of RBand RCis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, halo, nitro, or cyano; 10 each of RDand REis independently hydrogen, oxo, ORA, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; wherein x is 0, 1, 2, 3, 4 or 5; and wherein y is 0, 1 or 2. In some embodiments, R1, R2, R5, and R6are independently hydrogen, C1-C6 alkyl, C2- 15 C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), 20 wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; R’ is hydrogen or C1-C6 alkyl; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 25 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally 30 substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; each of RDand REis independently 23 Attorney Docket No.: R2054-7036WO hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; wherein x is 0, 1, 2, 3, 4 or 5; and wherein y is 0, 1 or 2. 5 As generally described herein, R1and R2are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 heterocyclyl, C1- C6 haloalkyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, or cyano, each alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, and haloalkyl is each optionally substituted with one or more R7. 10 In some embodiments, R1, R2, R5and R6are each independently halo. In some embodiments, R1, R2, R5and R6are each independently fluorine, chlorine, bromine, or iodine. In some embodiments, R1is fluorine. In some embodiments, R1is chlorine. In some embodiments, R1is bromine. In some embodiments, R1is iodine. In some embodiments, R2is fluorine. In some embodiments, R2is chlorine. In some embodiments, R2is bromine. In some embodiments, R2is 15 iodine. In some embodiments, R5is fluorine. In some embodiments, R5is chlorine. In some embodiments, R5is bromine. In some embodiments, R5is iodine. In some embodiments, R6is fluorine. In some embodiments, R6is chlorine. In some embodiments, R6is bromine. In some embodiments, R6is iodine. In some embodiments, R1, R2, R5and R6are each independently fluorine or chlorine. In 20 some embodiments, R1is fluorine or chlorine. In some embodiments, R2is fluorine or chlorine. In some embodiments, R5is fluorine or chlorine. In some embodiments, R6is fluorine or chlorine. In some embodiments, R1and R2are each independently halo. In some embodiments, R1is fluorine and R2is fluorine. In some embodiments, R1is fluorine and R2is chlorine. In some 25 embodiments, R1is fluorine and R2is bromine. In some embodiments, R1is fluorine and R2is iodine. In some embodiments, R1is chlorine and R2is fluorine. In some embodiments, R1is chlorine and R2is chlorine. In some embodiments, R1is chlorine and R2is bromine. In some embodiments, R1is chlorine and R2is iodine. In some embodiments, R1is bromine and R2is fluorine. In some embodiments, R1is bromine and R2is chlorine. In some embodiments, R1is 30 bromine and R2is bromine. In some embodiments, R1is bromine and R2is iodine. In some embodiments, R1is iodine and R2is fluorine. In some embodiments, R1is iodine and R2is 24 Attorney Docket No.: R2054-7036WO chlorine. In some embodiments, R1is iodine and R2is bromine. In some embodiments, R1is fluorine and R2is iodine. In some embodiments, R1and R2are each independently halo or hydrogen. In some embodiments, R1is fluorine, chlorine, bromine, or iodine, and R2is hydrogen. In some 5 embodiments, R1is fluorine and R2is hydrogen. In some embodiments, R1is chlorine and R2is hydrogen. In some embodiments, R1is bromine and R2is hydrogen. In some embodiments, R1is iodine and R2is hydrogen. In some embodiments, R1is hydrogen, and R2is fluorine, chlorine, bromine, or iodide. In some embodiments, R1is hydrogen, and R2is fluorine. In some embodiments, R1is hydrogen, and R2is chlorine. In some embodiments, R1is hydrogen, and R210 is bromine. In some embodiments, R1is hydrogen, and R2is iodine. In some embodiments R1and R2are each independently halo or hydrogen and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine, chlorine, bromine, or iodine and R2, R5, and R6are hydrogen. In some embodiments, R1is fluorine, and R2, R5, and R6are each hydrogen. In some embodiments, R1is chlorine, and R2, R5, and R6are each hydrogen. 15 In some embodiments, R1is bromine, and R2, R5, and R6are hydrogen. In some embodiments, R1is iodine, and R2, R5, and R6are each hydrogen. In some embodiments, R2is fluorine, chlorine, bromine, or iodine and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is fluorine and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is chlorine and R1, R5, and R6are each 20 independently hydrogen. In some embodiments, R2is bromine and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is iodine and R1, R5, and R6are each independently hydrogen. In some embodiments, R1and R2are each independently halo, and R5and R6are each independently hydrogen. In some embodiments, R1and R2are each independently fluorine, 25 chlorine, bromine, or iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is iodine, and R5and R630 are each independently hydrogen. In some embodiments, R1is chlorine and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is 25 Attorney Docket No.: R2054-7036WO chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is fluorine, and R5and R6are each independently hydrogen. 5 In some embodiments, R1is bromine and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is chlorine, 10 and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R2and R6are each independently halo and R1and R5are each independently hydrogen. In some embodiments, R2and R6are each independently fluorine, 15 chlorine, bromine, or iodine and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is fluorine, and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is iodine, and R1and R520 are each independently hydrogen. In some embodiments, R2is chlorine and R6is fluorine, and R1and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is iodine, and R1and R5are each independently hydrogen. In some 25 embodiments, R2is bromine and R6is fluorine, and R1and R5are each independently hydrogen. In some embodiments, R2is bromine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is bromine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is bromine and R6is iodine, and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is fluorine, and R130 and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is 26 Attorney Docket No.: R2054-7036WO bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is iodine, and R1and R5are each independently hydrogen. In some embodiments, R1and R5are each independently halo and R2and R6are each independently hydrogen. In some embodiments, R1and R5are each independently fluorine, 5 chlorine, bromine, or iodine and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is chlorine, and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is iodine, and R2and R610 are each independently hydrogen. In some embodiments, R1is chlorine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is chlorine and R5is chlorine, and R2and R6are each independently hydrogen. In some embodiments, R1is chlorine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is chlorine and R5is iodine, and R2and R6are each independently hydrogen. In some 15 embodiments, R1is bromine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is bromine and R5is chlorine, and R2and R6are each independently hydrogen. In some embodiments, R1is bromine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is bromine and R5is iodine, and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is fluorine, and R220 and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is chlorine, and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is iodine, and R2and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently -ORA, wherein RAis 25 hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R1is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 30 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R2is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 27 Attorney Docket No.: R2054-7036WO alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R5is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 5 cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R6is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 10 more R7. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 alkoxy, each alkoxy optionally substituted with one or more R7. In some embodiments, R1is C1-C6 alkoxy, optionally substituted with one or more R7. In some embodiments, R2is C1-C6 alkoxy, optionally substituted with one or more R7. In some embodiments, R5is C1-C6 alkoxy, 15 optionally substituted with one or more R7. In some embodiments, R6is C1-C6 alkoxy, optionally substituted with one or more R7. In some embodiments, R1and R2are each independently hydrogen, halo, or -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, 20 cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and R5and R6are each independently halo or hydrogen. In some embodiments, R1and R2are each independently hydrogen, halo, or C1-C6 alkoxy, and R5and R6are each independently halo or hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is halo, and R5and R6are each 25 independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is fluorine, chlorine, bromine, or iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is bromine, and R5and R6are each 30 independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is iodine, and R5and R6are each independently hydrogen. 28 Attorney Docket No.: R2054-7036WO In some embodiments, R1is halo and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine, chlorine, bromine, or iodine, and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some 5 embodiments, R1is chlorine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently -S(RD)x, wherein RDis 10 independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 15 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R2is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 20 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R5is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 25 more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R6is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. 30 In some embodiments, R1, R2, R5, and R6are each independently -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R1is -S(RD)x, wherein RDis halo and x is 5. In some 29 Attorney Docket No.: R2054-7036WO embodiments, R2is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R5is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R6is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R1, R2, R5, and R6are each independently -SF5. In some 5 embodiments, R1is -SF5. In some embodiments, R2is -SF5. In some embodiments, R5is -SF5. In some embodiments, R6is -SF5. In some embodiments, R1and R2are each independently hydrogen, halo, or -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 10 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, or -S(RD)x, wherein RDis halo and x is 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, or -S(RD)x, wherein RDis 15 fluorine, chlorine, bromine, or iodine and x is 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is -SF5and R2, R5and R6are each independently hydrogen. In some embodiments, R2is -SF5and R1, R5and R6are each independently hydrogen. In some embodiments, R1, R2, R5and R6are each independently -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 20 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 25 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R2is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 30 more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R5is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 30 Attorney Docket No.: R2054-7036WO C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R6is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 5 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1, R2, R5and R6are each independently -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R1is -N=S(O)(RD)(RD), wherein RDis C1-C6 10 alkyl. In some embodiments, R2is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R5is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R6is - N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R1, R2, R5and R6are each independently -N=S(O)(CH3)2. In some embodiments, R1is -N=S(O)(CH3)2. In some embodiments, R2is -N=S(O)(CH3)2. In some 15 embodiments, R5is -N=S(O)(CH3)2. In some embodiments, R6is -N=S(O)(CH3)2. In some embodiments, R1and R2are each independently hydrogen, halo, or -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each 20 optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl, and R2, R5and R6are each independently hydrogen. In some embodiments, R2is - 25 N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl, and R1, R5and R6are each independently hydrogen. In some embodiments, R1is -N=S(O)(CH3)2, and R2, R5and R6are each independently hydrogen. In some embodiments, R2is -N=S(O)(CH3)2, and R1, R5and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently -P(O)(RE)y, wherein RE30 is independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 31 Attorney Docket No.: R2054-7036WO heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R1is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 5 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R2is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 10 more R7, and wherein y is 0, 1, or 2. In some embodiments, R5is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R6is independently -P(O)(RE)y, 15 wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R1, R2, R5, and R6are each independently -P(O)(RE)y, wherein RE20 is independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R1is independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R2is independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R5is independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R6is 25 independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R1, R2, R5, and R6are each independently P(O)(CH3)2. In some embodiments, R1is P(O)(CH3)2. In some embodiments, R2is P(O)(CH3)2. In some embodiments, R5is P(O)(CH3)2. In some embodiments, R6is P(O)(CH3)2. 30 In some embodiments, R1and R2are each independently hydrogen, halo, or -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 32 Attorney Docket No.: R2054-7036WO C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, or -P(O)(RE)y, wherein RE5 is independently hydrogen, halo, or C1-C6 alkyl and y is 2, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2, and R2, R5, and R6are each independently hydrogen. In some embodiments, R1is P(O)(CH3)2 and R2, R5, and R6are each independently hydrogen. In some embodiments, R2is -P(O)(RE)y, wherein REis independently 10 hydrogen, halo, or C1-C6 alkyl and y is 2, and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is P(O)(CH3)2 and R1, R5, and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently cyano. In some embodiments, R1is cyano. In some embodiments, R2is cyano. In some embodiments, R5is cyano. In some embodiments, R6is cyano. 15 In some embodiments, R1and R2are each independently hydrogen, halo, or cyano, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is independently cyano, and R2, R5, and R6are each independently hydrogen or halo. In some embodiments, R1is independently cyano, and R2, R5, and R6are each independently hydrogen. In some embodiments, R2is independently cyano, and R1, R5, and R6are each independently hydrogen or 20 halo. In some embodiments, R2is independently cyano, and R1, R5, and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently nitro. In some embodiments, R1is nitro. In some embodiments, R2is nitro. In some embodiments, R5is nitro. In some embodiments, R6is nitro. 25 In some embodiments, R1and R2are each independently hydrogen, halo, or nitro, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is independently nitro, and R2, R5, and R6are each independently hydrogen or halo. In some embodiments, R1is independently nitro, and R2, R5, and R6are each independently hydrogen. In some embodiments, R2is independently nitro, and R1, R5, and R6are each independently hydrogen or halo. In some 30 embodiments, R2is independently nitro, and R1, R5, and R6are each independently hydrogen. 33 Attorney Docket No.: R2054-7036WO In some embodiments, R1, R2, R5, and R6are each independently C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 heterocyclyl, or C1-C6 haloalkyl. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 alkyl or C3-C6 5 cycloalkyl, each alkyl or cycloalkyl optionally substituted with one or more R7. In some embodiments R1, R2, R5, and R6are each independently C1-C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, C3-C6 cycloalkyl is bicyclyl or spiro. In some embodiments, C3-C6 cycloalkyl is C3-C6 bicyclyl. In some embodiments, C3-C6 cycloalkyl is spiro. 10 In some embodiments, R1, R2, R5, and R6are each independently C3-C6 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C3-C6 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C3 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C5 bicyclyl, optionally substituted with one or 15 more R7. In some embodiments, R1is C6 bicyclyl, optionally substituted with one or more R7.In some embodiments, R2is C3-C6 bicyclyl. In some embodiments, R2is C3 bicyclyl, optionally substituted with one or more R7. In some embodiments, R2is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R2is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R2is C6 bicyclyl, optionally substituted with one or more R7.In 20 some embodiments, R5is C3-C6 bicyclyl. In some embodiments, R5is C3 bicyclyl, optionally substituted with one or more R7. In some embodiments, R5is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R5is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R5is C6 bicyclyl, optionally substituted with one or more R7.In some embodiments, R6is C3-C6 bicyclyl. In some embodiments, R6is C3 bicyclyl, optionally 25 substituted with one or more R7. In some embodiments, R6is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R6is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R6is C6 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5, and R6are each independently C5-C6 spiro, optionally substituted with one or more R7. In some embodiments, R1is C5 spiro, optionally substituted 30 with one or more R7. In some embodiments, R1is C6 spiro, optionally substituted with one or more R7. In some embodiments, R2is C5 spiro, optionally substituted with one or more R7. In 34 Attorney Docket No.: R2054-7036WO some embodiments, R2is C6 spiro, optionally substituted with one or more R7. In some embodiments, R5is C5 spiro, optionally substituted with one or more R7. In some embodiments, R5is C6 spiro, optionally substituted with one or more R7. In some embodiments, R6is C5 spiro, optionally substituted with one or more R7. In some embodiments, R6is C6 spiro, optionally 5 substituted with one or more R7. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7and with one or more heteroatoms selected from N, S, and O. In some embodiments R1, R2, R5, and R6are each independently C3-C6 heterocyclyl. In some embodiments, C3-C6 heterocyclyl is heterobicyclyl 10 or spiro. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl, each optionally substituted with one or more R7and one or more heteroatoms selected from N, S, and O. In some embodiments, R1, R2, R5, and R6are each independently C3-C6 heterocyclyl, each optionally substituted with one or more R7and one or more heteroatoms selected from N, S, and O. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or 15 C3-C6 heterocyclyl, each optionally substituted with one or more R7, wherein the heteroatom is nitrogen. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7, wherein the heteroatom is oxygen. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7, wherein the heteroatom is 20 sulphur. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some 25 embodiments, R5is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing heteroalkyl. In some embodiments, R1is an oxygen containing heteroalkyl, optionally substituted 30 with one or more R7. In some embodiments, R2is an oxygen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing heteroalkyl, 35 Attorney Docket No.: R2054-7036WO optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur 5 containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing heteroalkyl, optionally substituted with one or more R7. 10 In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C3 heterocyclyl, optionally substituted with one or 15 more R7. In some embodiments, R6is a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C4 heterocyclyl. In some embodiments, R1is a nitrogen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C4 20 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen 25 containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C5 heterocyclyl., optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C5 heterocyclyl, optionally substituted with one or more R7. 30 In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen 36 Attorney Docket No.: R2054-7036WO containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C6 heterocyclyl, optionally 5 substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C3 heterocyclyl, optionally substituted with one or 10 more R7. In some embodiments, R5is an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an 15 oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. 20 In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C5 heterocyclyl, optionally 25 substituted with one or more R7. In some embodiments, R6is an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some 30 embodiments, R2is an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C6 heterocyclyl, optionally 37 Attorney Docket No.: R2054-7036WO substituted with one or more R7. In some embodiments, R6is an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur 5 containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. 10 In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C4 heterocyclyl, optionally substituted with one or 15 more R7. In some embodiments, R6is a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, 20 R2is a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C5 heterocyclyl optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C6 25 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing C6 heterocyclyl, optionally 30 substituted with one or more R7. 38 Attorney Docket No.: R2054-7036WO In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or 5 more R7. In some embodiments, R5is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is an 10 oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. 15 In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C6 heterobicyclyl, optionally substituted with one or 20 more R7. In some embodiments, R6is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl optionally substituted with one or more R7. In some embodiments, R1is C1 alkyl, optionally 25 substituted with one or more R7. In some embodiments, R1is C2 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C3 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C5 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C6 alkyl, optionally substituted with one or more R7. In some embodiments, 30 In some embodiments, R1is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C3 alkenyl, optionally substituted with one or more R7. In some 39 Attorney Docket No.: R2054-7036WO embodiments, R1is C4 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C5 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C2 alkynyl, optionally substituted with one or more R7. In some 5 embodiments, R1is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C4 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C6 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C2 heteroalkyl, optionally substituted with one or more R7. In some 10 embodiments, R1is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C5 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C2 haloalkyl, optionally substituted with one or more R7. In some 15 embodiments, R1is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R1is C4 haloalkyl, optionally substituted with one or more R7. In some embodiments, R1is C5 haloalkyl, optionally substituted with one or more R7.In some embodiments, R1is C6 haloalkyl, optionally substituted with one or more R7. In some embodiments, R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 20 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl optionally substituted with one or more R7. In some embodiments, R2is C1 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 alkyl., optionally substituted with one or more R7. In some embodiments, R2is C3 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C4 alkyl, optionally substituted with one or more R7. In 25 some embodiments, R2is C5 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C6 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C3 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C4 alkenyl, optionally substituted with one or more R7. In some embodiments, R2 is C5 alkenyl, optionally 30 substituted with one or more R7. In some embodiments, R2is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C2 alkynyl, optionally substituted with one or 40 Attorney Docket No.: R2054-7036WO more R7. In some embodiments, R2is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C4 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C6 alkynyl, optionally substituted with one or more R7. In some 5 embodiments, R2is C1 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C5 heteroalkyl, optionally substituted with one or more R7. In some 10 embodiments, R2is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C1 haloalkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 haloalkyl, optionally substituted with one or more R7. In some embodiments, R2is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R2is C4 haloalkyl, optionally substituted with one or more R7. In some 15 embodiments, R2is C5 haloalkyl. In some embodiments, R2is C6 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl optionally substituted with one or more R7. In some embodiments, R5is C1 alkyl, optionally 20 substituted with one or more R7. In some embodiments, R5is C2 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C3 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C5 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C6 alkyl, optionally substituted with one or more R7. In some embodiments, 25 R5is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C3 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C4 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C5 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C2 alkynyl, optionally substituted with one or 30 more R7. In some embodiments, R5is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C4 alkynyl, optionally substituted with one or more R7. In some 41 Attorney Docket No.: R2054-7036WO embodiments, R5is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C6 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C1 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C2 heteroalkyl, optionally substituted with one or more R7. In some 5 embodiments, R5is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C5 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C1 haloalkyl, optionally substituted with one or more R7. In some 10 embodiments, R5is C2 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C4 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C5 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C6 haloalkyl, optionally substituted with one or more R7. 15 In some embodiments, R6is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl optionally substituted with one or more R7. In some embodiments, R6is C1 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C3 alkyl, optionally substituted with one or 20 more R7. In some embodiments, R6is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C5 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C6 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C3 alkenyl, optionally substituted with one or more R7. In some embodiments, R6 is C4 alkenyl, 25 optionally substituted with one or more R7. In some embodiments, R6is C5 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C2 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C4 alkynyl, optionally substituted with one or more R7. In some 30 embodiments, R6is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C6 alkynyl, optionally substituted with one or more R7. In some 42 Attorney Docket No.: R2054-7036WO embodiments, R6is C1 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C4 heteroalkyl, optionally substituted with one or more R7. In some 5 embodiments, R6is C5 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C1 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C3 haloalkyl, optionally substituted with one or more R7. In some 10 embodiments, R6is C4 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C5 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C6 haloalkyl, optionally substituted with one or more R7. In some embodiments, R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C1-C8 heteroalkyl, C1-C8 aryl, C1-C8 heteroaryl, C1-C8 haloalkyl, cycloalkyl, heterocyclyl, each 15 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4. In some embodiments, R3is C1-C8 alkyl optionally substituted with one or more R4. In some embodiments, R3is C1 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C2 alkyl, optionally substituted with one or more R4. In some embodiments, 20 R3is C3 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C4 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C5 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C6 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C7 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C8 alkyl, optionally substituted with one or more R4. 25 In some embodiments, R3is C1-C8 alkenyl optionally substituted with one or more R4. In some embodiments, R3is C2 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C3 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C4 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C5 alkenyl, optionally substituted with one or more R4. In some 30 embodiments, R3is C6 alkenyl, optionally substituted with one or more R4. In some 43 Attorney Docket No.: R2054-7036WO embodiments, R3is C7 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C8 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C1-C8 alkynyl optionally substituted with one or more R4. some embodiments, R3is C2 alkynyl, optionally substituted with one or more R4. In some 5 embodiments, R3is C3 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C4 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C5 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C6 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C7 alkynyl, optionally substituted with one or more R4. In some 10 embodiments, R3is C8 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C1-C8 heteroalkyl optionally substituted with one or more R4. In some embodiments, R3is C1 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C2 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C3 heteroalkyl, optionally substituted with one or more R4. In some 15 embodiments, R3is C4 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C5 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C6 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C7 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C8 heteroalkyl, optionally substituted with one or more R4. 20 In some embodiments, R3is C1-C8 heteroalkyl optionally substituted with one or more R4, wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is a nitrogen containing C1-C8 heteroalkyl optionally substituted with one or more R4. In some embodiments, R3is an oxygen containing C1-C8 heteroalkyl optionally substituted with one or more R4. In some embodiments, R3is a sulphur containing C1-C8 heteroalkyl optionally 25 substituted with one or more R4. In some embodiments, R3is C6-C8 bicyclyl, optionally substituted with one or more R4. In some embodiments, R3is C6 bicyclyl, optionally substituted with one or more R4. In some embodiments, R3is C7 bicyclyl, optionally substituted with one or more R4. In some embodiments, R3is C8 bicyclyl, optionally substituted with one or more R4. 44 Attorney Docket No.: R2054-7036WO In some embodiments, R3is spiro, optionally substituted with one or more R4. In some embodiments, R3is C5-C6 spiro, optionally substitute with one or more R4. In some embodiments, R3is C5 spiro. In some embodiments, R3is C6 spiro. In some embodiments, R3is C3-C8 heterocyclyl, optionally substituted with one or more 5 R4. In some embodiments, R3is C3 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C7 heterocyclyl, optionally substituted with one or more R4. In some 10 embodiments, R3is C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C3-C8 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C3 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C4 heterocyclyl, 15 optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C5 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C6 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C7 heterocyclyl, 20 optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C8 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is nitrogen containing C3-C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C3 25 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C7 heterocyclyl, optionally substituted with 30 one or more R4. In some embodiments, R3is nitrogen containing C8 heterocyclyl, optionally substituted with one or more R4. 45 Attorney Docket No.: R2054-7036WO In some embodiments, R3is oxygen containing C3-C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C3 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen 5 containing C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C7 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C8 heterocyclyl, optionally substituted with one or more R4. 10 In some embodiments, R3is sulphur containing C3-C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C3 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, 15 R3is sulphur containing C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C7 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, 20 C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, RAis C1-C6 alkyl, optionally substituted with one or more R7. In some embodiments, RAis selected from: 25 . odiments, RAis C1-C6 cycloalkyl, optionally substituted with one or more R7. In some embodiments, RAis selected from: 6 Attorney Docket No.: R2054-7036WO In some embodiments, R3is N(RB)(RC), wherein each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken 5 together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano. In some embodiments, both RBand RCare each independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein 10 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, RBand RCare each independently C1- C6 alkyl, optionally substituted with one or more R7. In some embodiments, one of RBor RCis independently C1-C6 alkyl and one of RCor RBis C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with one or more R7. In some embodiments, RBand RCare each 15 independently C3-C6 cycloalkyl, optionally substituted with one or more R7. In some embodiments, one of RBor RCis independently hydrogen and one of RCor RBis selected from: O , OH ,20 O , Attorney Docket No.: R2054-7036WO F OH OH , , O 5 substituted with one or more R7. In some embodiments RBand RCare taken together to form heterocyclyl, wherein N(RB)(RC) is selected from: OH . 10 In some embodiments, RBand RCare each independently C3-C8 aryl or C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCare taken together to form aryl or heteroaryl optionally substituted with one or more R7. In some embodiments, RBand RCare taken together to form nitrogen-containing heteroaryl optionally substituted with one or more R7. 15 In some embodiments, RBand RCis each independently C3-C8 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C4 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C5 aryl, optionally substituted with one or more R7. In some 20 embodiments, RBand RCis each independently C6 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C7 aryl, optionally substituted with 48 Attorney Docket No.: R2054-7036WO one or more R7. In some embodiments, RBand RCis each independently C8 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3 5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C4 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C7 heteroaryl, 10 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3-C8 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C3 heteroaryl, optionally substituted 15 with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C4 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C5 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some 20 embodiments, RBand RCis each independently C6 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C7 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C8 heteroaryl, optionally substituted with one or 25 more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C3 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C4 heteroaryl, 30 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C5 heteroaryl, optionally substituted with one or more R7. In 49 Attorney Docket No.: R2054-7036WO some embodiments, RBand RCis each independently nitrogen containing C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C7 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C8 heteroaryl, 5 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, wherein the number of nitrogen heteroatoms in the heteroaryl ring is 1, 2, or 3. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, 10 wherein the number of nitrogen heteroatoms in the heteroaryl ring is 1. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, wherein the number of nitrogen heteroatoms in the heteroaryl ring is 2. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, wherein the number of nitrogen heteroatoms in the 15 heteroaryl ring is 3. In some embodiments, RBand RCis each independently oxygen containing C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C3 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C4 heteroaryl, 20 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C7 heteroaryl, optionally substituted with one or more R7. In 25 some embodiments, RBand RCis each independently oxygen containing C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C3 heteroaryl, optionally substituted with one or more R7. In 30 some embodiments, RBand RCis each independently sulphur containing C4 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each 50 Attorney Docket No.: R2054-7036WO independently sulphur containing C5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C7 heteroaryl, optionally substituted with one or more R7. In 5 some embodiments, RBand RCis each independently sulphur containing C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, the compound of Formula (I) is a compound of Formula (I-a): R5H R1N R3a)or a pharmaceutically acceptable sal rate, or isotope thereof, 10 wherein each of R1, R2, R5, and R6are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein 15 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each R4is independently oxo, -S(RD)x, N(RB)(RC), alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each 20 of RBand RCis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, halo, nitro, or cyano; each of RDand REis 25 independently hydrogen, oxo, ORA, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl 51 Attorney Docket No.: R2054-7036WO are each optionally substituted with one or more R7; wherein x is 0, 1, 2, 3, 4 or 5; and wherein y is 0, 1 or 2. In some embodiments, each of R1, R2, R5, and R6are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5 C3-C6 heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each 10 optionally substituted with one or more R4; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis 15 independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA,20 halo, nitro, or cyano; each of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; wherein x is 0, 1, 2, 3, 4 or 5; and wherein y is 0, 1 or 2. 25 In some embodiments, R1, R2, R5, and R6are independendently hydrogen or halo. In some embodiments, R3is selected from the group consisting of: O , Attorney Docket No.: R2054-7036WO F H H H N N H H N H N N N F , , H , 5 , F , 10 , Attorney Docket No.: R2054-7036WO In some embodiments, the compound of Formula (I) is a compound of Formula (I-b): RxR1N R3b) or a pharmaceutically acceptable sal rate, or isotope thereof, n each of R1 5 wherei and R2is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, 10 alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; R’ is hydrogen or alkyl; each R4is independently oxo, -S(RD)x, N(RB)(RC), alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 15 more R7; each of RBand RCis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, halo, nitro, or cyano; each of RDand 20 REis independently hydrogen, oxo, ORA, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; wherein x is 0, 1, 2, 3, 4 or 5; and wherein y is 0, 1 or 2. In some embodiments, each of R1and R2is independently hydrogen, C1-C6 alkyl, C2-C6 25 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally 54 Attorney Docket No.: R2054-7036WO substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; R’ is hydrogen or C1-C6 alkyl; each R4is 5 independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 10 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; each of RDand REis independently 15 hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; wherein x is 0, 1, 2, 3, 4 or 5; and wherein y is 0, 1 or 2. In some embodiments, or a pharmaceutically acceptable salt, tautomer, stereoisomer, 20 hydrate, or isotope thereof, R1and R2are each independently hydrogen or halo. In some embodiments, R3is independently selected from the group consisting of: H H H Attorney Docket No.: R2054-7036WO OH H H H N H N N H HN OHNN H , 5 10 In some embodiments, the compound of Formula (I) is a compound of Formula (I-c): R5RxRBc) Attorney Docket No.: R2054-7036WO or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R1, R2, R5, R6, RX, RY, RA, RB, RC, and R7are defined as provided for in Formula (I). In some embodiments, one of RBor RCis independently hydrogen and the other of RCor RBis selected from the group consisting of: O 5 10 , , O 15 In some embodiments, the compound of Formula (I) is a compound of Formula (I-d): 57 Attorney Docket No.: R2054-7036WO R5RxRBR1N N R7md) or a pharmaceutically accep te, or isotope thereof, wherein R1, R2, R5, R6, RX, R , R , R , and R7are defined as provided for in Formula (I), m is an integer between 0 and 12; and n is an integer between 0 and 4. 5 In some embodiments, RBis independently hydrogen and RCis selected from the group consisting of: , 10 F Attorney Docket No.: R2054-7036WO In some embodiments, the compound of Formula (I) is a compound of Formula (I-e): RxRBR1N N R7-e) or a pharmaceutically acce te, or isotope thereof, 12 X 5 wherein R , R , R , RA, RB, and R7are defined as provided for in Formula (I), m is an integer between 0 and 12; and n is an integer between 0 and 4. In some embodiments, RBis independently hydrogen and RCis selected from the group consisting of:10, F Attorney Docket No.: R2054-7036WO O S , f): RxRBR1N N7-f) 5 or a pharmaceutically acce te, or isotope thereof, wherein R1, RX, RA, RB, and R7are defined as provided for in Formula (I), m is an integer between 0 and 12; and n is an integer between 0 and 4. In some embodiments, RBis independently hydrogen and RCis selected from the group consisting of: 10 , , Attorney Docket No.: R2054-7036WO F F F F OH F : 5 wherein R1, RX, RA, RB, and R7are defined as provided for in Formula (I), m is an integer between 0 and 12; and n is an integer between 0 and 4. In some embodiments, RBis independently hydrogen and RCis selected from the group 10 consisting of: O , , Attorney Docket No.: R2054-7036WO F F F F OH F Rxn R1N N75 g) or a pharmaceutically accep ate, or isotope thereof, wherein R1, R2, RX, RA, and R7are defined as provided for in Formula (I), m is an integer between 0 and 12; and n is an integer between 0 and 4. In some embodiments, the compound of Formula (I-g) is: OH xx10 . und that these compounds exhibit remarkable potency for binding selectively to SUR1 / Kir6.2 and inhibiting glucose stimulated insulin secretion. In view of the fact that the binding of these compounds to the target is so specific, reduced off target effects are observed. Moreover, the compounds 15 according to the present invention exhibit excellent bioavailability, stability and safety and can be administered orally. In an embodiment, the compounds of Formula (I) described herein exhibit improved properties over the compounds in the art. The known compounds cause serious side effects due 62 Attorney Docket No.: R2054-7036WO to lack of channel specificity. Moreover, the benefit for the patient group at large of compounds already known in the prior art is modest as the responsiveness of patients suffering from HI, in particularly CHI varies considerably within patients. It is assumed that this is due to their low specificity. In view of the high specificity of the compounds of the present invention 5 responsiveness of patients suffering from HI, in particular CHI will be considerably better. In an embodiment, the compound of Formula (I) is selected from Table 1: Table 1: Exemplary Compounds of Formula (I). CmpdChemicCmpd No.al StructureNo.Chemical Structure Attorney Docket No.: R2054-7036WO CmpdCheCmpd No.mical StructureNo.Chemical Structure 64 Attorney Docket No.: R2054-7036WO CmpdChemiCmpd No.cal StructureNo.Chemical StructureH H H H 65 Attorney Docket No.: R2054-7036WO CmpdChemiCmpd No.cal StructureNo.Chemical StructureH H H H O 66 Attorney Docket No.: R2054-7036WO CmpdChemiCmpd No.cal StructureNo.Chemical StructureH H H H 67 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H H 68 Attorney Docket No.: R2054-7036WO CmpdChemiCmpd No.cal StructureNo.Chemical StructureH H H H 69 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureO H H 70 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H 71 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H N 72 Attorney Docket No.: R2054-7036WO CmpdChemiCmpd No.cal StructureNo.Chemical StructureH H H H 73 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H 74 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H H 75 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H 76 Attorney Docket No.: R2054-7036WO CmpdChemCmpd No.ical StructureNo.Chemical StructureH H 77 Attorney Docket No.: R2054-7036WO CmpdChemicCmpd No.al StructureNo.Chemical StructureF NNH278ClN F S OOH N N 279 N F SOHO OHO N NH 280 N F S OOF H Cl N N 505 NH S OOF H Cl N N 506 NH S OOF H Cl N N 507 N S OOHThe present disclosure features compounds found, for example, in Table 1, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 1, or an isomer, tautomer, or pharmaceutically acceptable salt 5 thereof. In some embodiments, the compound of the present disclosure is compound 2, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 3, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is 78 Attorney Docket No. R2054-7036WO compound 4, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 5, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 6, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In 5 some embodiments, the compound of the present disclosure is compound 7, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 8, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 9, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 10 compound of the present disclosure is compound 10, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 11, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 12, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 15 disclosure is compound 13, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 14, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 15, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 16, or 20 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 17, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 18, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 19, or an isomer, tautomer, 25 or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 20, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 21, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 22, or an isomer, tautomer, or pharmaceutically acceptable 30 salt thereof. In some embodiments, the compound of the present disclosure is compound 23, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 79 Attorney Docket No. R2054-7036WO compound of the present disclosure is compound 24, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 25, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 26, or an isomer, tautomer, 5 or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 27, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 28, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 29, or an isomer, tautomer, or pharmaceutically acceptable 10 salt thereof. In some embodiments, the compound of the present disclosure is compound 30, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 31, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 32, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some 15 embodiments, the compound of the present disclosure is compound 33, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 34, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 35, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 20 the present disclosure is compound 36, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 37, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 38, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is 25 compound 39, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 40, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 41, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 42, or an isomer, 30 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 43, or an isomer, tautomer, or pharmaceutically acceptable 80 Attorney Docket No. R2054-7036WO salt thereof. In some embodiments, the compound of the present disclosure is compound 44, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 45, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is 5 compound 46, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 47, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 48, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 49, or an isomer, 10 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 50, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 51, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 52, or an isomer, tautomer, or pharmaceutically 15 acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 53, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 54, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 55, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 20 In some embodiments, the compound of the present disclosure is compound 56, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 57, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 58, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 25 compound of the present disclosure is compound 59, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 60, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 61, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 30 disclosure is compound 62, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 63, or an isomer, 81 Attorney Docket No. R2054-7036WO tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 64, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 65, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 5 compound of the present disclosure is compound 66, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 67, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 68, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 10 disclosure is compound 69, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 70, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 71, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 72, or 15 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 73, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 74, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 75, or an isomer, tautomer, 20 or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 76, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 77, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 78, or an isomer, tautomer, or pharmaceutically acceptable 25 salt thereof. In some embodiments, the compound of the present disclosure is compound 79, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 80, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 81, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some 30 embodiments, the compound of the present disclosure is compound 82, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 82 Attorney Docket No. R2054-7036WO disclosure is compound 83, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 84, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 85, or an isomer, tautomer, or pharmaceutically acceptable 5 salt thereof. In some embodiments, the compound of the present disclosure is compound 86, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 87, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 88, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some 10 embodiments, the compound of the present disclosure is compound 89, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 90, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 91, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 15 the present disclosure is compound 92, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 93, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 94, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is 20 compound 95, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 96, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 97, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 98, or an isomer, 25 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 99, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 100, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 101, or an isomer, tautomer, or 30 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 102, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 83 Attorney Docket No. R2054-7036WO In some embodiments, the compound of the present disclosure is compound 103, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 104, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 105, or 5 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 106, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 107, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 108, or an isomer, 10 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 109, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 110, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 111, or an isomer, tautomer, or 15 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 112, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 113, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 114, or an isomer, tautomer, or pharmaceutically acceptable 20 salt thereof. In some embodiments, the compound of the present disclosure is compound 115, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 116, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 117, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 25 In some embodiments, the compound of the present disclosure is compound 118, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 119, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 120, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 30 compound of the present disclosure is compound 121, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 84 Attorney Docket No. R2054-7036WO disclosure is compound 122, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 123, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 124, or an isomer, tautomer, or pharmaceutically acceptable 5 salt thereof. In some embodiments, the compound of the present disclosure is compound 125, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 126, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 127, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 10 In some embodiments, the compound of the present disclosure is compound 128, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 129, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 130, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 15 compound of the present disclosure is compound 131, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 132, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 133, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 20 the present disclosure is compound 134, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 135, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 136, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 25 disclosure is compound 137, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 138, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 139, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 140, or 30 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 141, or an isomer, tautomer, or 85 Attorney Docket No. R2054-7036WO pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 142, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 143, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 5 the present disclosure is compound 144, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 145, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 146, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 10 disclosure is compound 147, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 148, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 149, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 150, or 15 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 151, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 152, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 153, or an isomer, 20 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 154, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 155, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 156, or an isomer, tautomer, or 25 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 157, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 158, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 159, or an isomer, tautomer, or pharmaceutically acceptable 30 salt thereof. In some embodiments, the compound of the present disclosure is compound 160, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 86 Attorney Docket No. R2054-7036WO compound of the present disclosure is compound 161, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 162, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 163, or an isomer, 5 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 164, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 165, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 166, or an isomer, tautomer, or 10 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 167, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 168, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 169, or an isomer, tautomer, or pharmaceutically acceptable 15 salt thereof. In some embodiments, the compound of the present disclosure is compound 170, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 171, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 172, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 20 In some embodiments, the compound of the present disclosure is compound 173, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 174, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 175, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 25 compound of the present disclosure is compound 176, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 177, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 178, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 30 the present disclosure is compound 179, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 180, or 87 Attorney Docket No. R2054-7036WO an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 181, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 182, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 5 In some embodiments, the compound of the present disclosure is compound 183, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 184, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 185, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 10 compound of the present disclosure is compound 186, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 187, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 188, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 15 the present disclosure is compound 189, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 190, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 191, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 20 disclosure is compound 192, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 193, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 194, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 195, or 25 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 196, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 197, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 198, or an isomer, 30 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 199, or an isomer, tautomer, or pharmaceutically acceptable 88 Attorney Docket No. R2054-7036WO salt thereof. In some embodiments, the compound of the present disclosure is compound 200, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 201, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 5 disclosure is compound 202, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 203, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 204, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 205, or 10 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 206, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 207, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 208, or an isomer, 15 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 209, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 210, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 211, or an isomer, tautomer, or 20 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 212, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 213, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 214, or an isomer, tautomer, or pharmaceutically acceptable 25 salt thereof. In some embodiments, the compound of the present disclosure is compound 215, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 216, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 217, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 30 In some embodiments, the compound of the present disclosure is compound 218, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 89 Attorney Docket No. R2054-7036WO the present disclosure is compound 219, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 220, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 221, or an isomer, tautomer, or 5 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 222, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 223, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 224, or an isomer, tautomer, or pharmaceutically acceptable 10 salt thereof. In some embodiments, the compound of the present disclosure is compound 225, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 226, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 227, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 15 In some embodiments, the compound of the present disclosure is compound 228, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 229, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 230, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 20 compound of the present disclosure is compound 231, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 232, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 233, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 25 the present disclosure is compound 234, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 235, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 236, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 30 disclosure is compound 237, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 238, or an isomer, 90 Attorney Docket No. R2054-7036WO tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 239, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 240, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 5 compound of the present disclosure is compound 241, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 242, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 243, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 10 the present disclosure is compound 244, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 245, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 246, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 15 disclosure is compound 247, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 248, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 249, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 250, or 20 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 251, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 252, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 253, or an isomer, 25 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 254, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 255, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 256, or an isomer, tautomer, or 30 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 257, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 91 Attorney Docket No. R2054-7036WO In some embodiments, the compound of the present disclosure is compound 258, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 259, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 260, or 5 an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 261, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 262, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 263, or an isomer, 10 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 264, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 265, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 266, or an isomer, tautomer, or 15 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 267, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 268, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 269, or an isomer, tautomer, or pharmaceutically acceptable 20 salt thereof. In some embodiments, the compound of the present disclosure is compound 270, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 271, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 272, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 25 In some embodiments, the compound of the present disclosure is compound 273, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 274, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 275, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 30 compound of the present disclosure is compound 276, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 92 Attorney Docket No. R2054-7036WO disclosure is compound 277, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 278, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 279, or an isomer, tautomer, or pharmaceutically acceptable 5 salt thereof. In some embodiments, the compound of the present disclosure is compound 280, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 505, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 506, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 10 In some embodiments, the compound of the present disclosure is compound 507, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is drawn as one tautomer, but the present disclosure is intended to encompass all tautomeric forms of the compounds. For example, in an embodiment, compounds 276, 505, 506, and 507 are tautomers of each other. In some 15 embodiments, a set of tautomers may rapidly interconvert when dissolved. In other embodiments, a mixture of tautomers may be resolved into individual tautomers. In some embodiments, two tautomers equilibrate to a ratio of about 99:1, 95:5, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, 5:95, or 1:99. A second aspect of the present disclosure relates to a compound having a structure of 20 Formula (II): R51 3I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein: B is N(Ry), C(Ry), or C(Ry)2; D is N(Rx) or C(Rx); E is C or S; one of the bonds connecting D to C(R3) and B to C(R3) is a double bond, and the other bond is a single bond; each 25 of the bonds connecting E to B and E to Rzis independently a single bond or double bond; each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, -S(RD)x, - 93 Attorney Docket No. R2054-7036WO P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, 5 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each of Rxand Ryis independently absent or hydrogen; Rzis independently RF, =N-CN, -N(RG), or -N(RG)2; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, 10 wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to 15 form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; each of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or20 more R7; each of RFand RGis independently hydrogen, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7;RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; x is 0, 1, 2, 3, 4 or 5; 25 and y is 0, 1 or 2. In some embodiments, the compound of Formula (II) is a compound of Formula (II-A): R5A), Attorney Docket No. R2054-7036WO or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein: B is N(Ry), C(Ry), or C(Ry)2; D is N(Rx) or C(Rx); one of the bonds connecting D to C(R3) and B to C(R3) is a double bond, and the other bond is a single bond; each of the bonds connecting S to B and S to Rzis independently a single bond or double bond; each of R1, R2, R5, 5 and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, -S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, 10 cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each of Rxand Ryis independently absent or hydrogen; Rzis independently RF, =N-CN, -N(RG), or - N(RG)2; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1- 15 C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each 20 optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; each of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 25 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RFand RGis independently hydrogen, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7;RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 30 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2. 95 Attorney Docket No. R2054-7036WO In some embodiments, the compound of Formula (II) is a compound of Formula (II-B): R5RxR1N R3B), or a pharmaceutically acceptable salt, t ydrate, or isotope thereof, wherein: each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- 5 C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, 10 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each of Rxand Ryis independently absent or hydrogen; Rzis independently RF, =N-CN, -N(RG), or -N(RG)2; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, 15 wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to 20 form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; each of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or25 more R7; each of RFand RGis independently hydrogen, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each 96 Attorney Docket No. R2054-7036WO optionally substituted with one or more R7;RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2. In some embodiments, the compound of Formula II is a compound of Formula (II’): R5RxR1N R35’),or a pharmaceutically acceptable sal rate, or isotope thereof, wherein: each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, 10 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; Rzis independently RF, =N-CN, or -N(RG), each Rzconnected to S via a single or 15 double bond; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 20 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; each 25 of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 97 Attorney Docket No. R2054-7036WO heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2. In some embodiments, the compound of Formula II is a compound of Formula (II”): R5RxR1N R3”)5 or a pharmaceutically acceptable sal rate, or isotope thereof, herein B is N or C(R’); each of R1 w , R2, R5, and R6are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl; haloalkyl, -ORA, halo, nitro, cyano, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, 10 heterocyclyl, haloalkyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; Rzis independently RF, =N-CN, or -N(RG), each Rzconnected to S via a single or double bond; R’ is hydrogen or alkyl; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; RAis 15 hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 20 more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; each of RFand RGis independently hydrogen, oxo, ORA, alkyl, alkenyl, C1-C6 alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, or acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are 25 each optionally substituted with one or more R7; and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, B is N or C(R’); each of R1, R2, R5, and R6are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, 98 Attorney Docket No. R2054-7036WO C3-C6 heterocyclyl; C1-C6 haloalkyl, -ORA, halo, nitro, cyano, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C1-C8 alkynyl, C1-C8 heteroalkyl, C3-C8 heterocyclyl, C1-C8 haloalkyl, or N(RB)(RC), wherein alkyl, alkenyl, 5 alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; Rzis independently RF, =N-CN, or -N(RG), each Rzconnected to S via a single or double bond; R’ is hydrogen or alkyl; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1- C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 10 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with 15 one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; each of RFand RGis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or C1-C6 acetyl, 20 wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7; and wherein x is 0, 1, 2, 3, 4 or 5. As generally described herein, R1, R2, R5and R6are each independently hydrogen, C1- C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, cyano. 25 In some embodiments, R1, R2, R5and R6are each independently halo. In some embodiments, R1, R2, R5and R6are each independently fluorine, chlorine, bromine, or iodine. In some embodiments, R1is fluorine. In some embodiments, R1is chlorine. In some embodiments, R1is bromine. In some embodiments, R1is iodine. In some embodiments, R2is fluorine. In some embodiments, R2is chlorine. In some embodiments, R2is bromine. In some embodiments, R2is 30 iodine. In some embodiments, R5is fluorine. In some embodiments, R5is chlorine. In some embodiments, R5is bromine. In some embodiments, R5is iodine. In some embodiments, R6is 99 Attorney Docket No. R2054-7036WO fluorine. In some embodiments, R6is chlorine. In some embodiments, R6is bromine. In some embodiments, R6is iodine. In some embodiments, R1, R2, R5and R6are each independently fluorine or chlorine. In some embodiments, R1is fluorine or chlorine. In some embodiments, R2is fluorine or chlorine. 5 In some embodiments, R5is fluorine or chlorine. In some embodiments, R6is fluorine or chlorine. In some embodiments, R1and R2are each independently halo. In some embodiments, R1is fluorine and R2is fluorine. In some embodiments, R1is fluorine and R2is chlorine. In some embodiments, R1is fluorine and R2is bromine. In some embodiments, R1is fluorine and R2is 10 iodine. In some embodiments, R1is chlorine and R2is fluorine. In some embodiments, R1is chlorine and R2is chlorine. In some embodiments, R1is chlorine and R2is bromine. In some embodiments, R1is chlorine and R2is iodine. In some embodiments, R1is bromine and R2is fluorine. In some embodiments, R1is bromine and R2is chlorine. In some embodiments, R1is bromine and R2is bromine. In some embodiments, R1is bromine and R2is iodine. In some 15 embodiments, R1is iodine and R2is fluorine. In some embodiments, R1is iodine and R2is chlorine. In some embodiments, R1is iodine and R2is bromine. In some embodiments, R1is fluorine and R2is iodine. In some embodiments, R1and R2are each independently halo or hydrogen. In some embodiments, R1is fluorine, chlorine, bromine, or iodine, and R2is hydrogen. In some 20 embodiments, R1is fluorine and R2is hydrogen. In some embodiments, R1is chlorine and R2is hydrogen. In some embodiments, R1is bromine and R2is hydrogen. In some embodiments, R1is iodine and R2is hydrogen. In some embodiments, R1is hydrogen, and R2is fluorine, chlorine, bromine, or iodide. In some embodiments, R1is hydrogen, and R2is fluorine. In some embodiments, R1is hydrogen, and R2is chlorine. In some embodiments, R1is hydrogen, and R225 is bromine. In some embodiments, R1is hydrogen, and R2is iodine. In some embodiments R1and R2are each independently halo or hydrogen and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine, chlorine, bromine, or iodine and R2, R5, and R6are hydrogen. In some embodiments, R1is fluorine, and R2, R5, and R6are each hydrogen. In some embodiments, R1is chlorine, and R2, R5, and R6are each hydrogen. 30 In some embodiments, R1is bromine, and R2, R5, and R6are hydrogen. In some embodiments, R1is iodine, and R2, R5, and R6are each hydrogen. 100 Attorney Docket No. R2054-7036WO In some embodiments, R2is fluorine, chlorine, bromine, or iodine and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is fluorine and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is chlorine and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is bromine and R1, R5, and R6are each 5 independently hydrogen. In some embodiments, R2is iodine and R1, R5, and R6are each independently hydrogen. In some embodiments, R1and R2are each independently halo, and R5and R6are each independently hydrogen. In some embodiments, R1and R2are each independently fluorine, chlorine, bromine, or iodine, and R5and R6are each independently hydrogen. In some 10 embodiments, R1is fluorine and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is fluorine, and R515 and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is chlorine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is fluorine, and R5and R6are each independently hydrogen. 20 In some embodiments, R1is bromine and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is chlorine, 25 and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is iodine, and R5and R6are each independently hydrogen. In some embodiments, R2and R6are each independently halo and R1and R5are each independently hydrogen. In some embodiments, R2and R6are each independently fluorine, 30 chlorine, bromine, or iodine and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is fluorine, and R1and R5are each independently hydrogen. 101 Attorney Docket No. R2054-7036WO In some embodiments, R2is fluorine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is fluorine and R6is iodine, and R1and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is fluorine, and R15 and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is chlorine and R6is iodine, and R1and R5are each independently hydrogen. In some embodiments, R2is bromine and R6is fluorine, and R1and R5are each independently hydrogen. 10 In some embodiments, R2is bromine and R6is chlorine, and R1and R5are each independently hydrogen. In some embodiments, R2is bromine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is bromine and R6is iodine, and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is fluorine, and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is chlorine, 15 and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is bromine, and R1and R5are each independently hydrogen. In some embodiments, R2is iodine and R6is iodine, and R1and R5are each independently hydrogen. In some embodiments, R1and R5are each independently halo and R2and R6are each independently hydrogen. In some embodiments, R1and R5are each independently fluorine, 20 chlorine, bromine, or iodine and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is chlorine, and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is fluorine and R5is iodine, and R2and R625 are each independently hydrogen. In some embodiments, R1is chlorine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is chlorine and R5is chlorine, and R2and R6are each independently hydrogen. In some embodiments, R1is chlorine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is chlorine and R5is iodine, and R2and R6are each independently hydrogen. In some 30 embodiments, R1is bromine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is bromine and R5is chlorine, and R2and R6are each independently 102 Attorney Docket No. R2054-7036WO hydrogen. In some embodiments, R1is bromine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is bromine and R5is iodine, and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is fluorine, and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is chlorine, 5 and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is bromine, and R2and R6are each independently hydrogen. In some embodiments, R1is iodine and R5is iodine, and R2and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 10 cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R1is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 15 more R7. In some embodiments, R2is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R5is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 20 cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, R6is -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 25 more R7. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 alkoxy, each alkoxy optionally substituted with one or more R7. In some embodiments, R1is C1-C6 alkoxy, optionally substituted with one or more R7. In some embodiments, R2is C1-C6 alkoxy, optionally substituted with one or more R7. In some embodiments, R5is C1-C6 alkoxy, 30 optionally substituted with one or more R7. In some embodiments, R6is C1-C6 alkoxy, optionally substituted with one or more R7. 103 Attorney Docket No. R2054-7036WO In some embodiments, R1and R2are each independently hydrogen, halo, or -ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and R5and R65 are each independently halo or hydrogen. In some embodiments, R1and R2are each independently hydrogen, halo, or C1-C6 alkoxy, and R5and R6are each independently halo or hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is halo, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is fluorine, chlorine, 10 bromine, or iodine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is fluorine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is chlorine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is bromine, and R5and R6are each independently hydrogen. In some embodiments, R1is C1-C6 alkoxy and R2is iodine, and R5and 15 R6are each independently hydrogen. In some embodiments, R1is halo and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine, chlorine, bromine, or iodine, and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is fluorine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some 20 embodiments, R1is chlorine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is bromine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1is iodine and R2is C1-C6 alkoxy, and R5and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently -S(RD)x, wherein RDis 25 independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 30 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 104 Attorney Docket No. R2054-7036WO more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R2is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 5 more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R5is -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R6is -S(RD)x, wherein RDis 10 independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1, R2, R5, and R6are each independently -S(RD)x, wherein RDis 15 halo and x is 5. In some embodiments, R1is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R2is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R5is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R6is -S(RD)x, wherein RDis halo and x is 5. In some embodiments, R1, R2, R5, and R6are each independently -SF5. In some 20 embodiments, R1is -SF5. In some embodiments, R2is -SF5. In some embodiments, R5is -SF5. In some embodiments, R6is -SF5. In some embodiments, R1and R2are each independently hydrogen, halo, or -S(RD)x, wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 25 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, or -S(RD)x, wherein RDis halo and x is 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, or -S(RD)x, wherein RDis 30 fluorine, chlorine, bromine, or iodine and x is 5, and R5and R6are each independently hydrogen 105 Attorney Docket No. R2054-7036WO or halo. In some embodiments, R1is -SF5 and R2, R5and R6are each independently hydrogen. In some embodiments, R2is -SF5 and R1, R5and R6are each independently hydrogen. In some embodiments, R1, R2, R5and R6are each independently -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 5 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 10 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R2is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 15 more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R5is -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R6is -N=S(O)(RD)(RD), 20 wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, R1, R2, R5and R6are each independently -N=S(O)(RD)(RD), 25 wherein RDis C1-C6 alkyl. In some embodiments, R1is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R2is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R5is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R6is - N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl. In some embodiments, R1, R2, R5and R6are each independently -N=S(O)(CH3)2. In some 30 embodiments, R1is -N=S(O)(CH3)2. In some embodiments, R2is -N=S(O)(CH3)2. In some embodiments, R5is -N=S(O)(CH3)2. In some embodiments, R6is -N=S(O)(CH3)2. 106 Attorney Docket No. R2054-7036WO In some embodiments, R1and R2are each independently hydrogen, halo, or -N=S(O)(RD)(RD), wherein RDis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each 5 optionally substituted with one or more R7and wherein x is 0, 1, 2, 3, 4 or 5, and R5and R6are each independently hydrogen or halo. In some embodiments, R1and R2are each independently hydrogen, halo, -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is -N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl, and R2, R5and R6are each independently hydrogen. In some embodiments, R2is - 10 N=S(O)(RD)(RD), wherein RDis C1-C6 alkyl, and R1, R5and R6are each independently hydrogen. In some embodiments, R1is -N=S(O)(CH3)2, and R2, R5and R6are each independently hydrogen. In some embodiments, R2is -N=S(O)(CH3)2, and R1, R5and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently -P(O)(RE)y, wherein RE15 is independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R1is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 20 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R2is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, 25 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R5is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 30 more R7, and wherein y is 0, 1, or 2. In some embodiments, R6is independently -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 107 Attorney Docket No. R2054-7036WO C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2. In some embodiments, R1, R2, R5, and R6are each independently -P(O)(RE)y, wherein RE5 is independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R1is independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R2is independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R5is independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R6is 10 independently -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2. In some embodiments, R1, R2, R5, and R6are each independently P(O)(CH3)2. In some embodiments, R1is P(O)(CH3)2. In some embodiments, R2is P(O)(CH3)2. In some embodiments, R5is P(O)(CH3)2. In some embodiments, R6is P(O)(CH3)2. 15 In some embodiments, R1and R2are each independently hydrogen, halo, or -P(O)(RE)y, wherein REis independently hydrogen, =O, O(RA), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7, and wherein y is 0, 1, or 2, and R5and R6are each independently hydrogen or halo. In 20 some embodiments, R1and R2are each independently hydrogen, halo, or -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2, and R2, R5, and R6are each independently hydrogen. In some embodiments, R1is P(O)(CH3)2 and R2, R5, and R6are each 25 independently hydrogen. In some embodiments, R2is -P(O)(RE)y, wherein REis independently hydrogen, halo, or C1-C6 alkyl and y is 2, and R1, R5, and R6are each independently hydrogen. In some embodiments, R2is1, R5, and R6are each independently hydrogen. In some embodiment R6are each independently cyano. In some embodiments, R1is cyano. In nts, R2is cyano. In some embodiments, R5is 30 cyano. In some embodiments, R6is cyano. 108 Attorney Docket No. R2054-7036WO In some embodiments, R1and R2are each independently hydrogen, halo, or cyano, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is independently cyano, and R2, R5, and R6are each independently hydrogen or halo. In some embodiments, R1is independently cyano, and R2, R5, and R6are each independently hydrogen. In some 5 embodiments, R2is independently cyano, and R1, R5, and R6are each independently hydrogen or halo. In some embodiments, R2is independently cyano, and R1, R5, and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently nitro. In some embodiments, R1is nitro. In some embodiments, R2is nitro. In some embodiments, R5is nitro. 10 In some embodiments, R6is nitro. In some embodiments, R1and R2are each independently hydrogen, halo, or nitro, and R5and R6are each independently hydrogen or halo. In some embodiments, R1is independently nitro, and R2, R5, and R6are each independently hydrogen or halo. In some embodiments, R1is independently nitro, and R2, R5, and R6are each independently hydrogen. In some embodiments, 15 R2is independently nitro, and R1, R5, and R6are each independently hydrogen or halo. In some embodiments, R2is independently nitro, and R1, R5, and R6are each independently hydrogen. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 heterocyclyl, or C1-C6 haloalkyl. 20 In some embodiments, R1, R2, R5, and R6are each independently C1-C6 alkyl or C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with one or more R7. In some embodiments R1, R2, R5, and R6are each independently C1-C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, C3-C6 cycloalkyl is bicyclyl or spiro. In some embodiments, C3-C6 cycloalkyl is C3-C6 bicyclyl. In some embodiments, C3-C6 25 cycloalkyl is spiro. In some embodiments, R1, R2, R5, and R6are each independently C3-C6 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C3-C6 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C3 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C4 bicyclyl, optionally substituted 30 with one or more R7. In some embodiments, R1is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C6 bicyclyl, optionally substituted with one or more R7.In 109 Attorney Docket No. R2054-7036WO some embodiments, R2is C3-C6 bicyclyl. In some embodiments, R2is C3 bicyclyl, optionally substituted with one or more R7. In some embodiments, R2is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R2is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R2is C6 bicyclyl, optionally substituted with one or more R7.In 5 some embodiments, R5is C3-C6 bicyclyl. In some embodiments, R5is C3 bicyclyl, optionally substituted with one or more R7. In some embodiments, R5is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R5is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R5is C6 bicyclyl, optionally substituted with one or more R7.In some embodiments, R6is C3-C6 bicyclyl. In some embodiments, R6is C3 bicyclyl, optionally 10 substituted with one or more R7. In some embodiments, R6is C4 bicyclyl, optionally substituted with one or more R7. In some embodiments, R6is C5 bicyclyl, optionally substituted with one or more R7. In some embodiments, R6is C6 bicyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5, and R6are each independently C5-C6 spiro, optionally substituted with one or more R7. In some embodiments, R1is C5 spiro, optionally substituted 15 with one or more R7. In some embodiments, R1is C6 spiro, optionally substituted with one or more R7. In some embodiments, R2is C5 spiro, optionally substituted with one or more R7. In some embodiments, R2is C6 spiro, optionally substituted with one or more R7. In some embodiments, R5is C5 spiro, optionally substituted with one or more R7. In some embodiments, R5is C6 spiro, optionally substituted with one or more R7. In some embodiments, R6is C5 spiro, 20 optionally substituted with one or more R7. In some embodiments, R6is C6 spiro, optionally substituted with one or more R7. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7and with one or more heteroatoms selected from N, S, and O. In some embodiments R1, R2, R5, and R6are each 25 independently C3-C6 heterocyclyl. In some embodiments, C3-C6 heterocyclyl is heterobicyclyl or spiro. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl, each optionally substituted with one or more R7and one or more heteroatoms selected from N, S, and O. In some embodiments, R1, R2, R5, and R6are each independently C3-C6 heterocyclyl, each optionally substituted with one or more R7and one or more heteroatoms selected from N, S, 30 and O. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7, wherein the heteroatom is 110 Attorney Docket No. R2054-7036WO nitrogen. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7, wherein the heteroatom is oxygen. In some embodiments, R1, R2, R5, and R6are each independently C1-C6 heteroalkyl or C3-C6 heterocyclyl, each optionally substituted with one or more R7, wherein the heteroatom is 5 sulphur. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some 10 embodiments, R5is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing heteroalkyl. In some embodiments, R1is an oxygen containing heteroalkyl, optionally substituted 15 with one or more R7. In some embodiments, R2is an oxygen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing 20 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing heteroalkyl, optionally substituted with one or 25 more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some 30 embodiments, R5is a nitrogen containing C3 heterocyclyl, optionally substituted with one or 111 Attorney Docket No. R2054-7036WO more R7. In some embodiments, R6is a nitrogen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C4 heterocyclyl. In some embodiments, R1is a nitrogen containing C4 heterocyclyl, optionally 5 substituted with one or more R7. In some embodiments, R2is a nitrogen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C5 10 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C5 heterocyclyl., optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C5 heterocyclyl, optionally 15 substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some 20 embodiments, R5is a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an 25 oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C3 heterocyclyl, optionally substituted with one or more R7. 30 In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an 112 Attorney Docket No. R2054-7036WO oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C4 5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C5 heterocyclyl, optionally substituted with one or 10 more R7. In some embodiments, R5is an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is an 15 oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C6 heterocyclyl, optionally substituted with one or more R7. 20 In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C3 heterocyclyl, optionally substituted with one or 25 more R7. In some embodiments, R6is a sulphur containing C3 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, 30 R2is a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C4 heterocyclyl, optionally substituted with one or 113 Attorney Docket No. R2054-7036WO more R7. In some embodiments, R6is a sulphur containing C4 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur 5 containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C5 heterocyclyl optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing C5 heterocyclyl, optionally substituted with one or more R7. 10 In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R5is a sulphur containing C6 heterocyclyl, optionally substituted with one or 15 more R7. In some embodiments, R6is a sulphur containing C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some 20 embodiments, R2is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R5is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R6is a nitrogen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1, R2, R5and R6are each independently an oxygen containing 25 C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R2is an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R5is an oxygen containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R6is an oxygen containing C6 30 heterobicyclyl, optionally substituted with one or more R7. 114 Attorney Docket No. R2054-7036WO In some embodiments, R1, R2, R5and R6are each independently a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R2is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some 5 embodiments, R5is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R6is a sulphur containing C6 heterobicyclyl, optionally substituted with one or more R7. In some embodiments, R1is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl 10 optionally substituted with one or more R7. In some embodiments, R1is C1 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C2 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C3 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R1is C5 alkyl, optionally substituted with one or more R7. In some 15 embodiments, R1is C6 alkyl, optionally substituted with one or more R7. In some embodiments, In some embodiments, R1is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C3 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C4 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C5 alkenyl, optionally substituted with one or more R7. In some 20 embodiments, R1is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R1is C2 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C4 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C5 alkynyl, optionally substituted with one or more R7. In some 25 embodiments, R1is C6 alkynyl, optionally substituted with one or more R7. In some embodiments, R1is C2 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C5 heteroalkyl, optionally substituted with one or more R7. In some 30 embodiments, R1is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R1is C2 haloalkyl, optionally substituted with one or more R7. In some 115 Attorney Docket No. R2054-7036WO embodiments, R1is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R1is C4 haloalkyl, optionally substituted with one or more R7. In some embodiments, R1is C5 haloalkyl, optionally substituted with one or more R7.In some embodiments, R1is C6 haloalkyl, optionally substituted with one or more R7. 5 In some embodiments, R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl optionally substituted with one or more R7. In some embodiments, R2is C1 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 alkyl., optionally substituted with one or more R7. In some embodiments, R2is C3 alkyl, optionally substituted with one or 10 more R7. In some embodiments, R2is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C5 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C6 alkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C3 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C4 alkenyl, 15 optionally substituted with one or more R7. In some embodiments, R2 is C5 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R2is C2 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C4 alkynyl, optionally substituted with one or more R7. In some 20 embodiments, R2is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C6 alkynyl, optionally substituted with one or more R7. In some embodiments, R2is C1 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C3 heteroalkyl, optionally substituted with one or more R7. In some 25 embodiments, R2is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C5 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R2is C1 haloalkyl, optionally substituted with one or more R7. In some embodiments, R2is C2 haloalkyl, optionally substituted with one or more R7. In some 30 embodiments, R2is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R2is C4 haloalkyl, optionally substituted with one or more R7. In some 116 Attorney Docket No. R2054-7036WO embodiments, R2is C5 haloalkyl. In some embodiments, R2is C6 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl 5 optionally substituted with one or more R7. In some embodiments, R5is C1 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C2 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C3 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C5 alkyl, optionally substituted with one or more R7. In some 10 embodiments, R5is C6 alkyl, optionally substituted with one or more R7. In some embodiments, R5is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C3 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C4 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C5 alkenyl, optionally substituted with one or more R7. In some embodiments, R5is C6 alkenyl, optionally substituted 15 with one or more R7. In some embodiments, R5is C2 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C3 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C4 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R5is C6 alkynyl, optionally substituted with one or more R7. In some 20 embodiments, R5is C1 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C2 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C5 heteroalkyl, optionally substituted with one or more R7. In some 25 embodiments, R5is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R5is C1 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C2 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C4 haloalkyl, optionally substituted with one or more R7. In some 30 embodiments, R5is C5 haloalkyl, optionally substituted with one or more R7. In some embodiments, R5is C6 haloalkyl, optionally substituted with one or more R7. 117 Attorney Docket No. R2054-7036WO In some embodiments, R6is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl optionally substituted with one or more R7. In some embodiments, R6is C1 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 alkyl, optionally substituted 5 with one or more R7. In some embodiments, R6is C3 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C4 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C5 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C6 alkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C3 10 alkenyl, optionally substituted with one or more R7. In some embodiments, R6 is C4 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C5 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C6 alkenyl, optionally substituted with one or more R7. In some embodiments, R6is C2 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C3 alkynyl, optionally substituted with one or more R7. In 15 some embodiments, R6is C4 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C5 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C6 alkynyl, optionally substituted with one or more R7. In some embodiments, R6is C1 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C2 heteroalkyl, optionally substituted with one or more R7. In some 20 embodiments, R6is C3 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C4 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C5 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C6 heteroalkyl, optionally substituted with one or more R7. In some embodiments, R6is C1 haloalkyl, optionally substituted with one or more R7. In some 25 embodiments, R6is C2 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C3 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C4 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C5 haloalkyl, optionally substituted with one or more R7. In some embodiments, R6is C6 haloalkyl, optionally substituted with one or more R7. 30 In some embodiments, R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C1-C8 heteroalkyl, C1-C8 aryl, C1-C8 heteroaryl, C1-C8 haloalkyl, cycloalkyl, heterocyclyl, each 118 Attorney Docket No. R2054-7036WO alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4. In some embodiments, R3is C1-C8 alkyl optionally substituted with one or more R4. In some embodiments, R3is C1 alkyl, optionally substituted with one or more R4. In some 5 embodiments, R3is C2 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C3 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C4 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C5 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C6 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C7 alkyl, optionally substituted with one or 10 more R4. In some embodiments, R3is C8 alkyl, optionally substituted with one or more R4. In some embodiments, R3is C1-C8 alkenyl optionally substituted with one or more R4. In some embodiments, R3is C2 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C3 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C4 alkenyl, optionally substituted with one or more R4. In some 15 embodiments, R3is C5 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C6 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C7 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C8 alkenyl, optionally substituted with one or more R4. In some embodiments, R3is C1-C8 alkynyl optionally substituted with one or more R4. 20 some embodiments, R3is C2 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C3 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C4 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C5 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C6 alkynyl, optionally substituted with one or more R4. In some 25 embodiments, R3is C7 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C8 alkynyl, optionally substituted with one or more R4. In some embodiments, R3is C1-C8 heteroalkyl optionally substituted with one or more R4. In some embodiments, R3is C1 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C2 heteroalkyl, optionally substituted with one or more R4. In some 30 embodiments, R3is C3 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C4 heteroalkyl, optionally substituted with one or more R4. In some 119 Attorney Docket No. R2054-7036WO embodiments, R3is C5 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C6 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C7 heteroalkyl, optionally substituted with one or more R4. In some embodiments, R3is C8 heteroalkyl, optionally substituted with one or more R4. 5 In some embodiments, R3is C1-C8 heteroalkyl optionally substituted with one or more R4, wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is a nitrogen containing C1-C8 heteroalkyl optionally substituted with one or more R4. In some embodiments, R3is an oxygen containing C1-C8 heteroalkyl optionally substituted with one or more R4. In some embodiments, R3is a sulphur containing C1-C8 heteroalkyl optionally 10 substituted with one or more R4. In some embodiments, R3is C6-C8 bicyclyl, optionally substituted with one or more R4. In some embodiments, R3is C6 bicyclyl, optionally substituted with one or more R4. In some embodiments, R3is C7 bicyclyl, optionally substituted with one or more R4. In some embodiments, R3is C8 bicyclyl, optionally substituted with one or more R4. 15 In some embodiments, R3is spiro, optionally substituted with one or more R4. In some embodiments, R3is C5-C6 spiro, optionally substitute with one or more R4. In some embodiments, R3is C5 spiro. In some embodiments, R3is C6 spiro. In some embodiments, R3is C3-C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C3 heterocyclyl, optionally substituted with one or more R4. In 20 some embodiments, R3is C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C7 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is C8 heterocyclyl, optionally substituted with one or more R4. 25 In some embodiments, R3is C3-C8 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C3 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C4 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected 30 from N, S, and O. In some embodiments, R3is C5 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some 120 Attorney Docket No. R2054-7036WO embodiments, R3is C6 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C7 heterocyclyl, optionally substituted with one or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is C8 heterocyclyl, optionally substituted with one 5 or more R4, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, R3is nitrogen containing C3-C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C3 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, 10 R3is nitrogen containing C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C7 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is nitrogen containing C8 heterocyclyl, optionally substituted with one or more R4. 15 In some embodiments, R3is oxygen containing C3-C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C3 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, 20 R3is oxygen containing C6 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C7 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is oxygen containing C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C3-C8 heterocyclyl, optionally 25 substituted with one or more R4. In some embodiments, R3is sulphur containing C3 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C4 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C5 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is sulphur containing C6 heterocyclyl, optionally substituted with one or more R4. In some 30 embodiments, R3is sulphur containing C7 heterocyclyl, optionally substituted with one or more 121 Attorney Docket No. R2054-7036WO R4. In some embodiments, R3is sulphur containing C8 heterocyclyl, optionally substituted with one or more R4. In some embodiments, R3is ORA, wherein RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, 5 alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7. In some embodiments, RAis C1-C6 alkyl, optionally substituted with one or more R7. n some embodiments, RAis C1-C6 cycloalkyl, optionally substituted with one or more R7. 10 In some embodiments, R3is N(RB)(RC), wherein each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, 15 C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano. In some embodiments, both RBand RCare each independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally20 substituted with one or more R7. In some embodiments, RBand RCare each independently C1- C6 alkyl, optionally substituted with one or more R7. In some embodiments, one of RBor RCis independently C1-C6 alkyl and one of RCor RBis C3-C6 cycloalkyl, each alkyl or cycloalkyl optionally substituted with one or more R7. In some embodiments, RBand RCare each independently C3-C6 cycloalkyl, optionally substituted with one or more R7. 25 In some embodiments, one of RBor RCis independently hydrogen and one of RCor RBis selected from: In some embodiments, RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7. In some embodiments, RBand RCare each independently C3-C8 aryl or C3-C8 30 heteroaryl, optionally substituted with one or more R7. 122 Attorney Docket No. R2054-7036WO In some embodiments, RBand RCare taken together to form aryl or heteroaryl optionally substituted with one or more R7. In some embodiments, RBand RCare taken together to form nitrogen-containing heteroaryl optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3-C8 aryl, optionally 5 substituted with one or more R7. In some embodiments, RBand RCis each independently C3 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C4 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C5 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C6 aryl, optionally substituted with one or more 10 R7. In some embodiments, RBand RCis each independently C7 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C8 aryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3 15 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C4 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C7 heteroaryl, 20 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently C3-C8 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C3 heteroaryl, optionally substituted 25 with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C4 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C5 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some 30 embodiments, RBand RCis each independently C6 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some 123 Attorney Docket No. R2054-7036WO embodiments, RBand RCis each independently C7 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. In some embodiments, RBand RCis each independently C8 heteroaryl, optionally substituted with one or more R7, and wherein one or more heteroatoms is selected from N, S, and O. 5 In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C3 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C4 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each 10 independently nitrogen containing C5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C7 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C8 heteroaryl, 15 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, wherein the number of nitrogen heteroatoms in the heteroaryl ring is 1, 2, or 3. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, 20 wherein the number of nitrogen heteroatoms in the heteroaryl ring is 1. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, wherein the number of nitrogen heteroatoms in the heteroaryl ring is 2. In some embodiments, RBand RCis each independently nitrogen containing C3-C8 heteroaryl, optionally substituted with one or more R7, wherein the number of nitrogen heteroatoms in the 25 heteroaryl ring is 3. In some embodiments, RBand RCis each independently oxygen containing C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C3 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C4 heteroaryl, 30 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C5 heteroaryl, optionally substituted with one or more R7. In 124 Attorney Docket No. R2054-7036WO some embodiments, RBand RCis each independently oxygen containing C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C7 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently oxygen containing C8 heteroaryl, 5 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C3-C8 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C3 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C4 heteroaryl, 10 optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C5 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C6 heteroaryl, optionally substituted with one or more R7. In some embodiments, RBand RCis each independently sulphur containing C7 heteroaryl, optionally substituted with one or more R7. In 15 some embodiments, RBand RCis each independently sulphur containing C8 heteroaryl, optionally substituted with one or more R7. As generally described herein, Rzis independently RF, oxo, =N-CN, -N(RG). In some embodiments, Rzis independently RF. In some embodiments, Rzis independently independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 20 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or C1-C6 acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7. In some embodiments, Rzis independently hydrogen. In some embodiments, Rzis independently oxo. In some embodiments, Rzis independently ORA. In some embodiments, Rzis 25 independently C1-C6 alkyl, optionally substituted with one or more R7. In some embodiments, Rzis independently C3-C6 cycloalkyl, optionally substituted with one or more R7. In some embodiments, Rzis independently C2-C6 alkenyl, optionally substituted with one or more R7. In some embodiments, Rzis independently C2-C6 alkenyl, optionally substituted with one or more R7. In some embodiments, Rzis independently C1-C6 heteroalkyl, optionally substituted with 30 one or more R7. In some embodiments, Rzis independently C1-C6 haloalkyl, optionally substituted with one or more R7. In some embodiments, Rzis independently C3-C6 heterocyclyl, 125 Attorney Docket No. R2054-7036WO optionally substituted with one or more R7. In some embodiments, Rzis independently C1-C6 acetyl, optionally substituted with one or more R7. In some embodiments, Rzis independently C1-C6 alkyl. In some embodiments, Rzis independently C1 alkyl. In some embodiments, Rzis independently C2 alkyl. In some 5 embodiments, Rzis independently C3 alkyl. In some embodiments, Rzis independently C4 alkyl. In some embodiments, Rzis independently C5 alkyl. In some embodiments, Rzis independently C6 alkyl. In some embodiments Rzis methyl. In some embodiments, Rzis independently C3-C6 cycloalkyl. In some embodiments, Rzis independently C3 cycloalkyl. In some embodiments, Rzis independently C4 cycloalkyl. In 10 some embodiments, Rzis independently C5 cycloalkyl. In some embodiments, Rzis independently C6 cycloalkyl. In some embodiments, Rzis independently C2-C6 alkenyl. In some embodiments, Rzis independently C2 alkenyl. In some embodiments, Rzis independently C3 alkenyl. In some embodiments, Rzis independently C4 alkenyl. In some embodiments, Rzis independently C5 15 alkenyl. In some embodiments, Rzis independently C6 alkenyl. In some embodiments, Rzis independently C2-C6 alkynyl. In some embodiments, Rzis independently C2 alkynyl. In some embodiments, Rzis independently C3 alkynyl. In some embodiments, Rzis independently C4 alkynyl. In some embodiments, Rzis independently C5 alkynyl. In some embodiments, Rzis independently C6 alkynyl. 20 In some embodiments, Rzis independently C1-C6 heteroalkyl. In some embodiments, Rzis independently C1 heteroalkyl. In some embodiments, Rzis independently C2 heteroalkyl. In some embodiments, Rzis independently C3 heteroalkyl. In some embodiments, Rzis independently C4 heteroalkyl. In some embodiments, Rzis independently C5 heteroalkyl. In some embodiments, Rzis independently C6 heteroalkyl. 25 In some embodiments, Rzis independently C1-C6 haloalkyl. In some embodiments, Rzis independently C1 haloalkyl. In some embodiments, Rzis independently C2 haloalkyl. In some embodiments, Rzis independently C3 haloalkyl. In some embodiments, Rzis independently C4 haloalkyl. In some embodiments, Rzis independently C5 haloalkyl. In some embodiments, Rzis independently C6 haloalkyl. 30 In some embodiments, Rzis independently C3-C6 heterocyclyl. In some embodiments, Rzis independently C3 heterocyclyl. In some embodiments, Rzis independently C4 heterocyclyl. 126 Attorney Docket No. R2054-7036WO In some embodiments, Rzis independently C5 heterocyclyl. In some embodiments, Rzis independently C6 heterocyclyl. In some embodiments, Rzis independently C1-C6 acetyl. In some embodiments, Rzis independently C1 acetyl. In some embodiments, Rzis independently C2 acetyl. In some 5 embodiments, Rzis independently C3 acetyl. In some embodiments, Rzis independently C4 acetyl. In some embodiments, Rzis independently C5 acetyl. In some embodiments, Rzis independently C6 acetyl. In some embodiments, Rzis acyl. In some embodiments, Rzis independently N(RG). In some embodiments, RGis independently independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 10 C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or C1-C6 acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7. In some embodiments, RGis independently hydrogen. In some embodiments, RG is independently oxo. In some embodiments, RGis independently ORA. In some embodiments, RG15 is independently C1-C6 alkyl, optionally substituted with one or more R7. In some embodiments, RGis independently C3-C6 cycloalkyl, optionally substituted with one or more R7. In some embodiments, RGis independently C2-C6 alkenyl, optionally substituted with one or more R7. In some embodiments, RGis independently C2-C6 alkenyl, optionally substituted with one or more R7. In some embodiments, RGis independently C1-C6 heteroalkyl, optionally 20 substituted with one or more R7. In some embodiments, RGis independently C1-C6 haloalkyl, optionally substituted with one or more R7. In some embodiments, RGis independently C3-C6 heterocyclyl, optionally substituted with one or more R7. In some embodiments, RGis independently C1-C6 acetyl, optionally substituted with one or more R7. In some embodiments, RGis independently C1-C6 alkyl. In some embodiments, RGis 25 independently C1 alkyl. In some embodiments, RGis independently C2 alkyl. In some embodiments, RGis independently C3 alkyl. In some embodiments, RGis independently C4 alkyl. In some embodiments, RGis independently C5 alkyl. In some embodiments, RGis independently C6 alkyl. In some embodiments RGis methyl. In some embodiments, RGis independently C3-C6 cycloalkyl. In some embodiments, RG30 is independently C3 cycloalkyl. In some embodiments, RGis independently C4 cycloalkyl. In 127 Attorney Docket No. R2054-7036WO some embodiments, RGis independently C5 cycloalkyl. In some embodiments, RGis independently C6 cycloalkyl. In some embodiments, RGis independently C2-C6 alkenyl. In some embodiments, RGis independently C2 alkenyl. In some embodiments, RGis independently C3 alkenyl. In some 5 embodiments, RGis independently C4 alkenyl. In some embodiments, RGis independently C5 alkenyl. In some embodiments, RGis independently C6 alkenyl. In some embodiments, RGis independently C2-C6 alkynyl. In some embodiments, RGis independently C2 alkynyl. In some embodiments, RGis independently C3 alkynyl. In some embodiments, RGis independently C4 alkynyl. In some embodiments, RGis independently C5 10 alkynyl. In some embodiments, RGis independently C6 alkynyl. In some embodiments, RGis independently C1-C6 heteroalkyl. In some embodiments, RGis independently C1 heteroalkyl. In some embodiments, RGis independently C2 heteroalkyl. In some embodiments, RGis independently C3 heteroalkyl. In some embodiments, RGis independently C4 heteroalkyl. In some embodiments, RGis independently C5 heteroalkyl. In 15 some embodiments, RGis independently C6 heteroalkyl. In some embodiments, RGis independently C1-C6 haloalkyl. In some embodiments, RGis independently C1 haloalkyl. In some embodiments, RGis independently C2 haloalkyl. In some embodiments, RGis independently C3 haloalkyl. In some embodiments, RGis independently C4 haloalkyl. In some embodiments, RGis independently C5 haloalkyl. In some embodiments, RGis 20 independently C6 haloalkyl. In some embodiments, RGis independently C3-C6 heterocyclyl. In some embodiments, RGis independently C3 heterocyclyl. In some embodiments, RGis independently C4 heterocyclyl. In some embodiments, RGis independently C5 heterocyclyl. In some embodiments, RGis independently C6 heterocyclyl. 25 In some embodiments, RGis independently C1-C6 acetyl. In some embodiments, RGis independently C1 acetyl. In some embodiments, RGis independently C2 acetyl. In some embodiments, RGis independently C3 acetyl. In some embodiments, RGis independently C4 acetyl. In some embodiments, RGis independently C5 acetyl. In some embodiments, RGis independently C6 acetyl. In some embodiments, RGis acyl. 30 In some embodiments, the compound of Formula (II) is a compound of Formula (II-a): 128 Attorney Docket No. R2054-7036WO R5RxR1N R3-a)or a pharmaceutically acceptable sal rate, or isotope thereof, wherein each of R1, R2, R5, and R6a re independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl; haloalkyl, -ORA, halo, nitro, cyano, each alkyl, alkenyl, 5 alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, haloalkyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; Rzis independently RF, =N-CN, or -N(RG), each Rzconnected to S via a single or double bond; each R4is independently oxo, -S(RD)x, 10 N(RB)(RC), alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; RAis hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, 15 alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; each of RFand RGis independently hydrogen, oxo, ORA, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, 20 heterocyclyl, or acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7; and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, each of R1, R2, R5, and R6are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 heterocyclyl; 25 C1-C6 haloalkyl, -ORA, halo, nitro, cyano, each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C1-C8 alkynyl, C1-C8 heteroalkyl, C3-C8 heterocyclyl, 129 Attorney Docket No. R2054-7036WO C1-C8 haloalkyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; Rzis independently RF, =N-CN, or -N(RG), each Rzconnected to S via a single or double bond; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 5 cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; RAis hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, 10 heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; each of RFand RGis independently hydrogen, oxo, ORA, C1-C6 alkyl, 15 C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, or C1-C6 acetyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7; and wherein x is 0, 1, 2, 3, 4 or 5. In some embodiments, the compound of Formula (II) is a compound of Formula (II-b): R51H320 b)or a pharmaceutically acceptable sal rate, or isotope thereof, wherein R1, R2, R5and R6are each independently hydrogen, and halo; Rzis N(RF)(RG), alkyl, lkenyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; RF25 and RGare each independently absent, hydrogen, nitro, nitroso, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, acyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 130 Attorney Docket No. R2054-7036WO more R7 as valency permits; or wherein RFand RGare taken together to form heterocyclyl optionally substituted with one or more R7as valency permits; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; and R3is selected from the group consisting of: H H H F H H N N N N F N 5 . In some embodiments, R1, R2, R5and R6are each independently hydrogen, and halo; Rzis N(RF)(RG), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each 10 optionally substituted with one or more R7; RFand RGare each independently absent, hydrogen, nitro, nitroso, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 acyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7as valency permits; or wherein RFand RGare taken together to form heterocyclyl optionally15 substituted with one or more R7as valency permits; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; and R3 is selected from the group consisting of: H H H F H H N N N N F N . 20 In another embodiment, the compound of Formula (II) is a compound of Formula (II-c): R5Rx-c) or a pharmaceutically acce r, hydrate, or iosotope thereof, wherein R1, R2, R5and R6are each independently hydrogen, alkyl, or halo; Rzis N(RD)(RE); RDand REare each independently absent, hydrogen, nitro, nitroso, cyano, alkyl, 131 Attorney Docket No. R2054-7036WO alkenyl, alkynyl, heteroalkyl, haloalkyl, acyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7as valency permits; or wherein RDand REare taken together to form heterocyclyl optionally substituted with one or more R7as valency permits; each R7is alkyl, alkenyl, alkynyl, 5 heteroalkyl, haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; and R3is selected from the group consisting of: H H H F H N N N N F . d D are independently N; wherein A and D and B and S are connected via a double bond or a single bond; or A and B are connected by a 10 double bond or single bond; R1, R2, R5and R6are each independently hydrogen, fluorine chlorine; bromine; and iodine; Rzis N(RD)(RE); RDand REare each independently absent, hydrogen, nitro, nitroso, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 acyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 15 more R7as valency permits; or wherein RDand REare taken together to form heterocyclyl optionally substituted with one or more R7as valency permits; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano; and R3is selected from the group consisting of: H H H F H N N N N F . 20 In another embodiment, the compound of Formula (II) is a compound of Formula (II-d): R5RxR1D R3d) or a pharmaceutically acceptable salt, ta hydrate, or isotope thereof, wherein A is C; each of B and D are independently N; wherein A and D and B and S are 25 connected via a double bond or a single bond; or A and B are connected by a double bond or 132 Attorney Docket No. R2054-7036WO single bond; R1, R2, R5and R6are each independently hydrogen, fluorine chlorine and halo; Rzis alkyl, heteroalkyl, or haloalkyl, wherein alkyl, heteroalkyl, or haloalkyl, are each optionally substituted with one or more R7; each R7is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, -ORA, halo, nitro, or cyano; and R3is selected from the group consisting of: H H N N 5 . ents, A is C; each of B and D are independently N; wherein A and D and B and S are connected via a double bond or a single bond; or A and B are connected by a double bond or single bond; R1, R2, R5and R6are each independently hydrogen, fluorine chlorine and halo; Rz is C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, wherein alkyl, 10 heteroalkyl, or haloalkyl, are each optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; and R3is selected from the group consisting of: H H N N . ments, the compounds of Formula (II) described herein exhibit improved 15 properties over the compounds in the art. The known compounds cause serious side effects due to lack of channel specificity. Moreover, the benefit for the patient group at large of compounds already known in the prior art is modest as the responsiveness of patients suffering from HI, in particularly CHI varies considerably within patients. It is assumed that this is due to their low specificity. In view of the high specificity of the compounds of the present invention 20 responsiveness of patients suffering from HI, in particular CHI will be considerably better. With respect to the compounds according to the present invention it is noted that they include all their acid addition and base salts, tautomeric forms, metabolites, or prodrugs. The present invention further includes unsolvated forms, solvated forms including hydrated forms of the compounds of the present invention. 25 Preferred compounds according to the present invention are wherein said compounds are according to general formula (I) such that: - A is carbon (C); - B and D are Nitrogen (N); and 133 Attorney Docket No. R2054-7036WO - wherein A and B or A and D are connected via a double or single bond; and - wherein R1 and R2 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine; and - wherein A and B form a double bond and Rxis H or wherein A and D form a double bond 5 and Ry is H. In relation to these compounds the present inventors have surprisingly found that these compounds exhibit remarkable potency for binding selectively to SUR / Kir6 potassium channel and inhibiting glucose stimulated insulin secretion. In view of the fact that the binding of these compounds to the target is so specific, reduced off target effects are observed. Moreover, the 10 compounds according to the present invention exhibit excellent bioavailability, stability and safety and can be administered orally. In an embodiment, the compound of Formula (II) is selected from Table 2: Table 2: Exemplary Compounds of Formula (II). Cmpd Cmpd Chemical Structure Chemical Structure 134 Attorney Docket No. R2054-7036WO Cmpd Cmpd Chemical Structure Chemical Structure No. No. 135 Attorney Docket No. R2054-7036WO Cmpd Cmpd Chemical Structure Chemical Structure No. No. e presen sc osure ea ures compoun s found, for example, in Table 2, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 281, or an isomer, tautomer, or pharmaceutically acceptable 5 salt thereof. In some embodiments, the compound of the present disclosure is compound 282, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 283, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 284, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 10 In some embodiments, the compound of the present disclosure is compound 285, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 286, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 287, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 136 Attorney Docket No. R2054-7036WO compound of the present disclosure is compound 288, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 289, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 290, or an isomer, 5 tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 291, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 292, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 293, or an isomer, tautomer, or 10 pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 294, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 295, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 296, or an isomer, tautomer, or pharmaceutically acceptable 15 salt thereof. In some embodiments, the compound of the present disclosure is compound 297, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 298, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 299, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 20 In some embodiments, the compound of the present disclosure is compound 300, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 301, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 302, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 25 compound of the present disclosure is compound 303, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 304, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 305, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 30 the present disclosure is compound 306, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 307, or 137 Attorney Docket No. R2054-7036WO an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 308, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 309, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. 5 In some embodiments, the compound of the present disclosure is compound 310, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 311, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 312, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the 10 compound of the present disclosure is compound 313, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 314, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 500, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of 15 the present disclosure is compound 501, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 502, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is compound 503, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present 20 disclosure is compound 504, or an isomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula II is drawn as one tautomer, but the present disclosure is intended to encompass all tautomeric forms of the compounds. For example, in an embodiment, compound 500 is a tautomer of compound 288. In an embodiment, compound 501 is a tautomer of compound 289. In an embodiment, compound 502 is a tautomer of compound 25 309. In an embodiment, compound 503 is a tautomer of compound 312. In an embodiment, compound 504 is a tautomer of compound 314. In some embodiments, a set of tautomers may rapidly interconvert when dissolved. In other embodiments, a mixture of tautomers may be resolved into individual tautomers. In some embodiments, two tautomers equilibrate to a ratio of about 99:1, 95:5, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, 5:95, or 1:99. 30 In a third aspect, the present disclosure features a compound of Formula (III): 138 Attorney Docket No. R2054-7036WO R5R1Z DR3Y A I), or a pharmaceutically acceptable salt, r, hydrate, or isotope thereof, wherein: A is C; B is N(Rx), and D is C (Ry)2, N(Ry), O, S, -ON(H)-, or -N(H)O-; or D is N(Ry), and B is C(Rx)2, N(Rx), O, S, -ON(H)-, or -N(H)O-; wherein one of the bonds connecting A to B 5 and A to D is a double bond, and the other bond is a single bond; each of W, X, Y, and Z are independently N or C; each of R1, R2, R5, and R6are independently absent, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; each of Rxand Ryare independently absent, hydrogen, C1-C6 alkyl, halogen, or -CN, wherein the alkyl is optionally substituted with one or more R3; R3is C1-C6 alkyl, C2-C6 10 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each R4is independently C1-C6 alkyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, 15 wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to 20 form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl; and n is 0, 1, or 2. In some embodiments, the compound of Formula (III) is a compound of Formula (III-A): 139 Attorney Docket No. R2054-7036WO R5R1Z DR3Y A ),or a pharmaceutically acceptable s ydrate, or isotope thereof, wherein: A is C; B is N(Rx), and D is C(Ry)2, N(Ry), O, -ON(H)-, or -N(H)O-; or D is N(Ry), and B is C(Rx)2, N(Rx), O, S, -ON(H)-, or -N(H)O-; wherein one of the bonds connecting A to B and 5 A to D is a double bond, and the other bond is a single bond; each of W, X, Y, and Z are independently N or C, wherein X and Z shall not be N when R3is N(H)(primary alkyl) or N(H)(secondary alkyl); each of R1, R2, R5, and R6are independently absent, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; each of Rxand Ryare independently absent, hydrogen, C1-C6 alkyl, halogen, or -CN, 10 wherein the alkyl is optionally substituted with one or more R3; R3is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each R4is independently C1-C6 alkyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, 15 C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl 20 are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl; and n is 0, 1, or 2. 25 In some embodiments, the compound of Formula (III) is a compound of Formula (III-B): 140 Attorney Docket No. R2054-7036WO R5R1Z DR3Y A ), or a pharmaceutically accepta isomer, hydrate, or isotope thereof, w...

Claims

Attorney Docket No. R2054-7036WO CLAIMS 1. A compound having the structure of Formula (I): R5RxR1N R3I),5 or a pharmaceutically acceptable salt,drate, or isotope thereof, wherein: each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, 10 heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 15 more R4; Rxand Ryare each independently absent, hydrogen or C1-C6 alkyl; or Rxand R3, together with the atoms to which they are attached, form a heterocyclyl that is optionally substituted with one or more R4; or Ryand R3, together with the atoms to which they are attached, form a heterocyclyl that is 20 optionally substituted with one or more R4; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, 25 cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; 341Attorney Docket No. R2054-7036WO each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted with one or more R7; or 5 RBand RC, together with the atom(s) to which they are connected form a heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, -ORA’, -N(RB’)(RC’), -C(O)N(RB’)(RC’), halo, oxo, nitro, or cyano; or 10 two R7and the atom(s) to which they are attached form a cycloalkyl or heterocyclyl; each of RDand REis independently hydrogen, halogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; 15 RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each of RB’and RC’is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or RB’and RC’, together with the atoms to which they are connected, a heterocyclyl; 20 x is 0, 1, 2, 3, 4 or 5; and y is 0, 1 or 2.

2. The compound of claim 1, wherein each of R1and R2is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or 25 cyano.

3. The compound of claim 1, wherein each of R1and R2is independently hydrogen, fluorine, chlorine, bromine, iodine, or cyano. 30 4. The compound of claim 1, wherein each of R1and R2is independently hydrogen, fluorine, or chlorine. 342Attorney Docket No. R2054-7036WO 5. The compound of claim 1, wherein R1is hydrogen and R2is fluorine, chlorine, bromine, iodine, nitro, or cyano. 5 6. The compound of claim 1, wherein R2is fluorine, chlorine, bromine, iodine, nitro, or cyano and R2is fluorine, chlorine, bromine, iodine, nitro, or cyano.

7. The compound of claim 1, wherein R1is hydrogen and R2is fluorine. 10 8. The compound of claim 1, wherein R1is hydrogen and R2is chlorine.

9. The compound of claim 1, wherein R1is chlorine and R2is fluorine.

10. The compound of claim 1, wherein each of R1and R2is independently fluorine. 15 11. The compound of claim 1, wherein R5is H.

12. The compound of claim 1, wherein R6is H. 20 13. The compound of claim 1, wherein R3is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), each of which is optionally substituted with optionally substituted with one or more R7.

14. The compound of claim 1, wherein R3is C1-C6 heteroalkyl optionally substituted with 25 one or more R7.

15. The compound of claim 1, wherein R3is C1-C6 haloalkyl, optionally substituted with one or more R7. 30 16. The compound of claim 1, wherein R3is cycloalkyl, optionally substituted with one or more R7. 343Attorney Docket No. R2054-7036WO 17. The compound of claim 1, wherein R3is heterocyclyl, optionally substituted with one or more R7. 5 18. The compound of claim 1, wherein R3is N(RB)(RC).

19. The compound of claim 18, wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7(e.g., a 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, or a bridged heterocyclyl). 10 20. The compound of claim 18, wherein RBis hydrogen.

21. The compound of claim 18, wherein RCis C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each optionally substituted with 15 one or more R7.

22. The compound of claim 18, wherein RCis C1-C6 alkyl optionally substituted with one or more R7. 20 23. The compound of claim 18, wherein RCis C1-C6 heteroalkyl optionally substituted with one or more R7.

24. The compound of claim 18, wherein RCis C1-C6 haloalkyl optionally substituted with one or more R7. 25 25. The compound of claim 18, wherein RCis cycloalkyl optionally substituted with one or more R7(e.g., monocyclic cycloalkyl, bicyclic cycloalkyl).

26. The compound of claim 18, wherein RCis heterocyclyl optionally substituted with one or 30 more R7. 344Attorney Docket No. R2054-7036WO 27. The compound of claim 21, wherein R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano. 5 28. The compound of claim 1, wherein R3is selected from the group consisting of: O H O H 7NN N R7ndO 10 29. The compound of claim 1, wherein R3is selected from the group consisting of O,Attorney Docket No. R2054-7036WO OH H H H H N N H NN OHN , 5 , ,10 30. The compound of claim 1, wherein the compound is a compound of Formula (I-a): R5H a),Attorney Docket No. R2054-7036WO or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein each of R1, R2, R3, R5, R6and Ryare as defined in claim 1.

31. The compound of claim 1, wherein the compound is a compound of Formula (I-b): RxR1N R35 b), or a pharmaceutically acceptable sal rate, or isotope thereof, erein each of R1wh , R2, R3, Rx, and Ryare as defined in claim 1.

32. The compound of claim 1, wherein the compound is a compound of Formula (I-c): R5RxRBR1N N10 c),or a pharmaceutically acceptabdrate, or isotope thereof, wherein R1, R2, R5, R6, RX, RY, RA, RB, RC, and R7are as defined in claim 1.

33. The compound of claim 1, wherein the compound is a compound of Formula (I-d): R5RxRB15 d), or a pharmaceutically accete, or isotope thereof, wherein R1, R2, R5, R6, RX, RY, RA, RB, and R7are defined as in claim 1; m is an integer between 0 and 12; and n is an integer between 0 and 4. 347Attorney Docket No. R2054-7036WO 34. The compound of claim 1, wherein the compound is a compound of Formula (I-e): RxRBR1N N R7e), or a pharmaceutically acce te, or isotope thereof, rein R1, R2, RXwhe , RA, RB, and R7are in claim 1; m is an integer between 0 and 12; and n is an 5 integer between 0 and 4.

35. The compound of claim 1, wherein the compound is a compound of Formula (I-f): RxRBR1N N f), 10 or a pharmaceutically accete, or isotope thereof, wherein R1, RX, RA, RB, and R7are defined as in claim 1; m is an integer between 0 and 12; and n is an integer between 0 and 4.

36. The compound of claim 1, wherein the compound is a compound of Formula (I-g): Rxn 15 g), or a pharmaceutically accepte, or isotope thereof, wherein R1, R2, RX, RA, and R7are defined as in claim 1; m is an integer between 0 and 12; and n is an integer between 0 and 4. 348Attorney Docket No. R2054-7036WO 37. The compound of claim 1, wherein the compound is provided in Table 1 or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically 5 acceptable excipient.

39. A method for treating a disease or disorder in a subject with a compound of claim 1, or a pharmaceutically acceptable thereof, or a pharmaceutical composition of claim 38. 10 40. The method of claim 39, wherein the disease or disorder is selected from a metabolic disorder (e.g., CHI), cancer, a neurological disorder, a cardiovascular disorder, a pulmonary disorder, an integumentary disorder, a sexual disorder, a urinary disorder, or a symptom thereof.

41. The method of claim 39, wherein the disease or disorder is a metabolic disorder. 15 42. The method of claim 39, wherein the metabolic disorder is hyperinsulinism, e.g., congenital hyperinsulinism (CHI).

43. The method of claim 39, wherein the subject has been diagnosed or identified with 20 having the disease or disorder.

44. The method of claim 39, wherein the subject is a mammal (e.g., a human).

45. The method of claim 39, wherein the compound or pharmaceutical composition is 25 formulated for oral or intravenous administration.

46. The method of claim 45, wherein the compound or pharmaceutical composition is a solid dosage form, in particular an oral dosage form, such as a tablet or capsule. 30 47. A compound having the structure of Formula (II): 349Attorney Docket No. R2054-7036WO R5R1D R3I), or a pharmaceutically acceptable salt,drate, or isotope thereof, wherein: B is N(Ry), C(Ry), or C(Ry)2; 5 D is N(Rx) or C(Rx); E is C or S; one of the bonds connecting D to C(R3) and B to C(R3) is a double bond, and the other bond is a single bond; each of the bonds connecting E to B and E to Rzis independently a single bond or double 10 bond; each of R1, R2, R5, and R6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -ORA, - S(RD)x, -P(O)(RE)y, -N=S(O)(RD)(RD), halo, nitro, cyano, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or 15 more R7; R3is C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, C2-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, ORA, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; 20 each of Rxand Ryis independently absent or hydrogen; Rzis independently RF, =N-CN, -N(RG), or -N(RG)2; each R4is independently oxo, -S(RD)x, N(RB)(RC), C1-C6 alkyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 25 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; 350Attorney Docket No. R2054-7036WO each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or 5 wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; each of RDand REis independently hydrogen, oxo, ORA, C1-C6 alkyl, C2-C6 alkenyl, 10 C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RFand RGis independently hydrogen, ORA, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or acetyl, wherein alkyl, 15 alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and acetyl are each optionally substituted with one or more R7; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; x is 0, 1, 2, 3, 4 or 5; and 20 y is 0, 1 or 2.

48. The compound of claim 47, wherein each of R1and R2is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano. 25 49. The compound of claim 47, wherein each of R1and R2is independently hydrogen, fluorine, chlorine, bromine, iodine, or cyano.

50. The compound of claim 47, wherein each of R1and R2is independently hydrogen, 30 fluorine, or chlorine. 351Attorney Docket No. R2054-7036WO 51. The compound of claim 47, wherein R1is hydrogen and R2is fluorine, chlorine, bromine, iodine, nitro, or cyano.

52. The compound of claim 47, wherein R2is fluorine, chlorine, bromine, iodine, nitro, or 5 cyano and R2is fluorine, chlorine, bromine, iodine, nitro, or cyano.

53. The compound of claim 47, wherein R1is hydrogen and R2is fluorine.

54. The compound of claim 47, wherein R1is hydrogen and R2is chlorine. 10 55. The compound of claim 47, wherein R1is chlorine and R2is fluorine.

56. The compound of claim 47, wherein each of R1and R2is independently fluorine. 15 57. The compound of claim 47, wherein R5is H.

58. The compound of claim 47, wherein R6is H.

59. The compound of claim 47, wherein R3is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 20 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), each of which is optionally substituted with optionally substituted with one or more R7.

60. The compound of claim 47, wherein R3is C1-C6 heteroalkyl optionally substituted with one or more R7. 25 61. The compound of claim 47, wherein R3is C1-C6 haloalkyl, optionally substituted with one or more R7.

62. The compound of claim 47, wherein R3is cycloalkyl, optionally substituted with one or 30 more R7.352Attorney Docket No. R2054-7036WO 63. The compound of claim 47, wherein R3is heterocyclyl, optionally substituted with one or more R7.

64. The compound of claim 47, wherein R3is N(RB)(RC). 5 65. The compound of claim 64, wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7(e.g., a 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, or a bridged heterocyclyl). 10 66. The compound of claim 64, wherein RBis hydrogen.

67. The compound of claim 63, wherein RCis C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each optionally substituted with one or more R7. 15 68. The compound of claim 64, wherein RCis C1-C6 alkyl optionally substituted with one or more R7.

69. The compound of claim 64, wherein RCis C1-C6 heteroalkyl optionally substituted with 20 one or more R7.

70. The compound of claim 64, wherein RCis C1-C6 haloalkyl optionally substituted with one or more R7. 25 71. The compound of claim 64, wherein RCis cycloalkyl optionally substituted with one or more R7(e.g., monocyclic cycloalkyl, bicyclic cycloalkyl).

72. The compound of claim 63, wherein RCis heterocyclyl optionally substituted with one or more R7. 30 353Attorney Docket No. R2054-7036WO 73. The compound of claim 67, wherein R7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano.

74. The compound of claim 47, wherein R3is selected from the group consisting of: O H O H 7N R7N N 5 ndO 10 , H ,Attorney Docket No. R2054-7036WO H N H H H O H H N N N , 5 ,76. The compound of claim 47, wherein the compound is a compound of Formula (II-a): R5H10 a),or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein each of R1, R2, R3, R5, R6and Ryare as defined in claim 47. 355Attorney Docket No. R2054-7036WO 77. The compound of claim 47, wherein the compound is a compound of Formula (II-b): RxR1N R3b), or a pharmaceutically acceptable sa rate, or isotope thereof, 5 wherein each of R1, R2, R3, Rx, and Ryare as defined in claim 47.

78. The compound of claim 47, wherein the compound is a compound of Formula (II-c): RxR1N R3c),or a pharmaceutically acceptable sarate, or isotope thereof, 10 wherein each of R1, R2, R3, R5, R6, Rx, Ry, and RGare as defined in claim 47 79. The compound of claim 47, wherein the compound is a compound of Formula (II-e): R51e),or a pharmaceutically acceptable sarate, or isotope thereof, 15 wherein each of R1, R2, R3, R5, R6, Ry, and RZare as defined in claim.

80. The compound of claim 47, wherein the compound is a compound of Formula (II-f): 356Attorney Docket No. R2054-7036WO R5RxR1R3f), or a pharmaceutically acceptable sal rate, or isotope thereof, wherein each of R1, R2, R3, R5, R6, Rx, Ry, and R are as defined in claim. 5 81. The compound of claim 47, wherein the compound is a compound of Formula (II-g): R5R1N R3g),or a pharmaceutically acceptable sa rate, or isotope thereof,wherein each of R1, R2, R3, R5, R6, Ry, and RZare as defined in claim. 10 82. The compound of claim 47, wherein the compound is a compound of Formula (II-h): R51 3h), or a pharmaceutically acceptable sarate, or isotope thereof, wherein each of R1, R2, R3, R5, R6, Ry, and RZare as defined in claim. 15 83. The compound of claim 47, wherein the compound is a compound of Formula (II-i): 357Attorney Docket No. R2054-7036WO R5R1D R3i),or a pharmaceutically acceptable sal rate, or isotope thereof, wherein each of R1, R2, R3, R5, R6, B, D, and R are as defined in claim. 5 84. The compound of claim 47, wherein the compound is a compound of Formula (II-j): R5R1D R3j),or a pharmaceutically acceptable sal rate, or isotope thereof,wherein each of R1, R2, R3, R5, R6, B, D, and RZare as defined in claim. 10 85. A compound having the structure of Formula (III): R5R1Z DR3I), or a pharmaceutically acceptable salt,r, hydrate, or isotope thereof, wherein: A is C; 15 B is N(Rx), and D is C(Ry)2, N(Ry), O, S, -ON(H)-, or -N(H)O-; or D is N(Ry), and B is C(Rx)2, N(Rx), O, S, -ON(H)-, or -N(H)O-; wherein one of the bonds connecting A to B and A to D is a double bond, and the other bond is a single bond; each of W, X, Y, and Z are independently N or C; 358Attorney Docket No. R2054-7036WO each of R1, R2, R5, and R6are independently absent, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or cyano; each of Rxand Ryare independently absent, hydrogen, C1-C6 alkyl, halogen, or -CN, wherein the alkyl is optionally substituted with one or more R3; 5 R3is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each R4is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; 10 RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, 15 alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 20 haloalkyl, -ORA’, halo, nitro, or cyano; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl; and n is 0, 1, or 2. 25 86. The compound of claim 85, wherein each of R1and R2is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano.

87. The compound of claim 86, wherein each of R1and R2is independently hydrogen, 30 fluorine, chlorine, bromine, iodine, or cyano. 359Attorney Docket No. R2054-7036WO 88. The compound of claim 86, wherein each of R1and R2is independently hydrogen, fluorine, or chlorine.

89. The compound of claim 86, wherein R1is hydrogen and R2is fluorine, chlorine, bromine, 5 iodine, nitro, or cyano.

90. The compound of claim 85, wherein R2is fluorine, chlorine, bromine, iodine, nitro, or cyano and R2is fluorine, chlorine, bromine, iodine, nitro, or cyano. 10 91. The compound of claim 85, wherein R1is hydrogen and R2is fluorine.

92. The compound of claim 85, wherein R1is hydrogen and R2is chlorine.

93. The compound of claim 85, wherein R1is chlorine and R2is fluorine. 15 94. The compound of claim 85, wherein each of R1and R2is independently fluorine.

95. The compound of claim 85, wherein R5is H. 20 96. The compound of claim 85, wherein R6is H.

97. The compound of claim 85, wherein R3is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), each of which is optionally substituted with optionally substituted with one or more R7. 25 98. The compound of claim 85, wherein R3is C1-C6 heteroalkyl optionally substituted with one or more R7.

99. The compound of claim 85, wherein R3is C1-C6 haloalkyl, optionally substituted with 30 one or more R7.360Attorney Docket No. R2054-7036WO 100. The compound of claim 85, wherein R3is cycloalkyl, optionally substituted with one or more R7.

101. The compound of claim 85, wherein R3is heterocyclyl, optionally substituted with one or 5 more R7.

102. The compound of claim 85, wherein R3is N(RB)(RC).

103. The compound of claim 102, wherein RBand RCare taken together to form heterocyclyl 10 optionally substituted with one or more R7(e.g., a 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, or a bridged heterocyclyl).

104. The compound of claim 102, wherein RBis hydrogen. 15 105. The compound of claim 102, wherein RCis C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each optionally substituted with one or more R7.

106. The compound of claim 102, wherein RCis C1-C6 alkyl optionally substituted with one 20 or more R7.

107. The compound of claim 102, wherein RCis C1-C6 heteroalkyl optionally substituted with one or more R7. 25 108. The compound of claim 102, wherein RCis C1-C6 haloalkyl optionally substituted with one or more R7.

109. The compound of claim 102, wherein RCis cycloalkyl optionally substituted with one or more R7(e.g., monocyclic cycloalkyl, bicyclic cycloalkyl). 30 361Attorney Docket No. R2054-7036WO 110. The compound of claim 102, wherein RCis heterocyclyl optionally substituted with one or more R7.

111. The compound of claim 110, wherein R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 5 C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano.

112. The compound of claim 85, wherein R3is selected from the group consisting of: O H O H 7N 7N N nd10113. The compound of claim 85, wherein R3is selected from the group consisting of: O , 15Attorney Docket No. R2054-7036WO OH H H H H N N H NN OHN , 5 , ,10 114. The compound of claim 85, wherein the compound is a compound of Formula (III-e): 363Attorney Docket No. R2054-7036WO R5R1Z NR3Y A e), or a pharmaceutically acceptable salt hydrate, or isotope thereof, wherein A, B, W, X, Y, Z, R1, R2, R3,R , and R are as defined in claim 83. 5 115. The compound of claim 85, wherein the compound is a compound of Formula (III-b’): R5R1D R3A ’), or a pharmaceutically acceptable sal hydrate, or isotope thereof,wherein A, B, D, R1, R3, R5, and R6are as defined in claim 83. 10 116. The compound of claim 85, wherein the compound is a compound of Formula (III-f): R5H R1Z NR3f), or a pharmaceutically acceptable salt, hydrate, or isotope thereof, wherein A, B, W, X, Y, Z, R1, R2, R3, R5, and R6are as defined in claim 83. 15 117. The compound of claim 85, wherein the compound is a compound of Formula (III-g): R5R1Z D'R3g),Attorney Docket No. R2054-7036WO or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, W, X, Y, Z, R1, R2, R3, R5, and R6are as defined in claim 83, and D’ is C(Ry)2, O, S, - ON(H)-, or -N(H)O-. 5 118. The compound of claim 85, wherein the compound is a compound of Formula (III-h): R5H R1Z NR3Y A h), or a pharmaceutically acceptable sal hydrate, or isotope thereof, n A, W, X, Y, Z, R1, R2wherei , R3, R5, and R6are as defined in claim 83, and B’ is O, S, -ON(H)-, or -N(H)O-. 10 119. A compound having the structure of Formula (IV): R5 5'Rx1'RRZ DR3), or a pharmaceutically acceptable ser, hydrate, or isotope thereof, 15 wherein: A is C; each of B and D are independently N; each of R1, R1’, R2, R2’, R5, R5’, R6, and R6’ are independently absent, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, halo, nitro, or 20 cyano, each alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl and haloalkyl optionally substituted with one or more R7; or two of R1, R1’, R2, R2’, R5, R5’, R6, and R6’, together with the atom(s) they are connected to, form a cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more R7; 25 wherein A and B form a double bond, Rxis hydrogen, and Ryis absent; or 365Attorney Docket No. R2054-7036WO wherein A and D form a double bond, Ryis hydrogen, and Rxis absent; each of W, X, Y, and Z are independently in each instance C, N, or O; R3is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, 5 cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; each R4is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or halo; RAis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, 10 cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; each of RBand RCis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R7; or 15 wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7; each R7is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA’, halo, nitro, or cyano; RA’is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroalkyl, haloalkyl, 20 cycloalkyl, or heterocyclyl; and n is 1 or 2.

120. The compound of claim 119, wherein each of R1, R1’, R2, R2’, R5, R5’, R6, and R6’ is independently absent, hydrogen, C1-C6 alkyl, or halogen. 25 121. The compound of claim 119, wherein The compound of claim 116, wherein each of R1, R1’, R2, R2’, R5, R5’, R6, and R6’ is independently hydrogen, C1-C6 alkyl, or halogen.

122. The compound of claim 119, wherein each of R1, R1’, R5, R5’, R6, and R6’ is 30 independently hydrogen. 366Attorney Docket No. R2054-7036WO 123. The compound of claim 119, wherein each of R1, R1’, R5, R5’, R6, and R6’ is independently hydrogen, and each of R2and R2’ is hydrogen, C1-C6 alkyl, or halogen.

124. The compound of claim 119, wherein R3is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 5 C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB)(RC), each of which is optionally substituted with optionally substituted with one or more R7.125 The compound of claim 119, wherein R3is C1-C6 heteroalkyl optionally substituted with one or more R7.10 126. The compound of claim 119, wherein R3is C1-C6 haloalkyl, optionally substituted with one or more R7.

127. The compound of claim 119, wherein R3is cycloalkyl, optionally substituted with one or 15 more R7.

128. The compound of claim 119, wherein R3is heterocyclyl, optionally substituted with one or more R7. 20 129. The compound of claim 119, wherein R3is N(RB)(RC).

130. The compound of claim 119, wherein RBand RCare taken together to form heterocyclyl optionally substituted with one or more R7(e.g., a 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, or a bridged heterocyclyl). 25 131. The compound of claim 119, wherein RBis hydrogen.

132. The compound of claim 119, wherein RCis C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each optionally substituted with 30 one or more R7. 367Attorney Docket No. R2054-7036WO 133. The compound of claim 119, wherein RCis C1-C6 alkyl optionally substituted with one or more R7.

134. The compound of claim 119, wherein RCis C1-C6 heteroalkyl optionally substituted with 5 one or more R7.

135. The compound of claim 119, wherein RCis C1-C6 haloalkyl optionally substituted with one or more R7. 10 136. The compound of claim 119, wherein RCis cycloalkyl optionally substituted with one or more R7(e.g., monocyclic cycloalkyl, bicyclic cycloalkyl).

137. The compound of claim 119, wherein RCis heterocyclyl optionally substituted with one or more R7. 15 138. The compound of claim 137, wherein R7is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -ORA, fluorine, chlorine, bromine, iodine, nitro, or cyano.

139. The compound of claim 119, wherein R3is selected from the group consisting of: O H H N 20 ndAttorney Docket No. R2054-7036WO 140. The compound of claim 119, wherein R3is selected from the group consisting of: O , 5 , 10 , ,Attorney Docket No. R2054-7036WO H N N H O H N ,141. The compound of claim 119, wherein the compound is a compound of Formula (IV-a): R5R5'RxR1'N31R R A 5 a), or a pharmaceutically acceptable salt drate, or isotope thereof,wherein A, R1, R1’, R2, R2’, R3, R5, R5’, R6, R6’, Rx, and Ryare as defined in claim 116. 10 142. The compound of claim 47, wherein the compound is provided in Table 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof.

143. The compound of claim 85, wherein the compound is provided in Table 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. 15 144. The compound of claim 119, wherein the compound is provided in Table 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof.

145. A pharmaceutical composition comprising a compound of claim 46 and a 20 pharmaceutically acceptable excipient.

146. A method for treating a disease or disorder in a subject with a compound of claim 1, or a pharmaceutically acceptable thereof, or a pharmaceutical composition of claim 145. 370Attorney Docket No. R2054-7036WO 147. The method of claim 146, wherein the disease or disorder is selected from a metabolic disorder (e.g., CHI), cancer, a neurological disorder, a cardiovascular disorder, a pulmonary disorder, an integumentary disorder, a sexual disorder, a urinary disorder, or a symptom thereof. 5 148. The method of claim 147, wherein the disease or disorder is a metabolic disorder.

149. The method of claim 147, wherein the metabolic disorder is hyperinsulinism, e.g., congenital hyperinsulinism (CHI). 10 150. The method of claim 147, wherein the subject has been diagnosed or identified with having the disease or disorder.

151. The method of claim 147, wherein the subject is a mammal (e.g., a human). 15 152. The method of claim 147, wherein the compound or pharmaceutical composition is formulated for oral or intravenous administration.

153. The method of claim 147, wherein the compound or pharmaceutical composition is a solid dosage form, in particular an oral dosage form, such as a tablet or capsule. 20 154. A compound having the structure of Formula (V): E R1L ), or a pharmaceutically acceptable salt, ter, hydrate, or isotope thereof, wherein: 25 E is O, S, or N(CN); L is absent or S(O)2; when L is SO2, R1is C3-C7 alkyl, and R2is phenyl or heteroaryl, each of which is optionally substituted with one R4; or N when L is absent and E is N(CN), R1is C3-C7 alky ;371Attorney Docket No. R2054-7036WO when L is absent and E is not N(CN), R1is C3-C7 alkyl, benzyl, or phenyl, wherein R6R6'E' 8 phenyl is substituted with on ; R4is C1-C6 alkyl or a halo, cyano, or nitro; E’ is O or S; R66’and R are each C1-C3 alkyl; or 5 R6and R6’, together with the carbon atom they are attached to, form a cycloalkyl; one of R7and R8is H, and the other of R7and R8is halo or -N(H)C(O)-X-(C1-C6 alkyl); and X is O or CH2.

155. The compound of claim 154, having the structure of Formula (V-A): E R1L N N R210 H H (V-A), or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein: E is O, S, or N(CN); L is absent or S(O)2; when L is SO2, R1is C3-C7 alkyl, and R2is phenyl or heteroaryl, each of which is 15 substituted with one R4; or N when L is absent, E is N(CN), R1is C3-C7 alky kyl or amino; andR5is C1-C2 haloalkyl, halo, cyano, or nitro. 20 156. The compound of claim 154, having the structure of Formula (V-B): E R1L ), or a pharmaceutically acceptable salt,, r, hydrate, or isotope thereof, wherein: 372Attorney Docket No. R2054-7036WO E is O, S; L is absent; R1is C3-C7 alkyl, benzyl, or phenyl, wherein phenyl is substituted with one R5; R6R6'E' ; l, halo, cyano, or nitro;5 E’ is O or S; R6and R6’are each C1-C3 alkyl; or R6and R6’, together with the carbon atom they are attached to, form a cycloalkyl; one of R7and R8is H, and the other of R7and R8is halo or -N(H)C(O)-X-(C1-C6 alkyl); and X is O or CH2. 10 157. A compound having the structure of Formula (VI): R1R2N N I), or a pharmaceutically acceptable, , , hydrate, or isotope thereof, wherein: R1is H or OH; R2is H or C1-C6 alkyl; and 15 R3is C1-C6 alkyl or -C(O)O-(C1-C6 alkyl).

158. The compound of claim 157, wherein R1is H.

159. The compound of claim 157, wherein R1is OH. 20 160. The compound of claim 157, wherein R2is H.

161. The compound of claim 157, wherein R2is C1-C6 alkyl. 25 162. The compound of claim 157, wherein R3is C1-C6 alkyl. 373Attorney Docket No. R2054-7036WO 163. The compound of claim 157, wherein R3is -C(O)O-(C1-C6 alkyl).

164. The compound of 154, wherein the compound is provided in Table 5, or a 5 pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof.

165. The compound of 157, wherein the compound is provided in Table 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. 10 374

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