Ion channel binders and uses thereof

Abstract

The present disclosure provides new ion channel binding compounds and uses thereof. Further provided are methods of treating diseases and disorders including painful conditions and neurological diseases.

Description

ION CHANNEL BINDERS AND USES THEREOF RELATED APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional applications, U.S.S.N.63 / 508,130, filed June 14, 2023, and U.S.S.N.63 / 508,430, filed June 15, 2023, each of which is incorporated herein by reference. GOVERNMENTSUPPORT

[0002] This invention was made with government support under NS036855, NS110860, NS127216 and NS105076 awarded by National Institutes of Health (NIH) and under W81XWH-20-1-0077 awarded by U.S. Army Medical Research and Materiel Command (MRMC). The government has certain rights in this invention. BACKGROUND

[0003] In the US, ~20% of adults live with chronic pain and almost 25 million Americans have persistent pain so severe that it limits their life or work activities. The economic cost of chronic pain totals up to $635 billion annually in both medical expenses and lost productivity. Acute pain also represents a substantial market for new, non-opioid drugs. In the US, 40 to 50 million major surgeries take place each year, virtually all requiring significant courses of treatment with analgesics, and there are many traumatic injuries that also require analgesia, ideally with no abuse liability or serious adverse effects. SUMMARY

[0004] Cannabidiol (CBD) is approved by the U.S. FDA for the treatment of refractoryCBD epilepsy associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Preclinical work and a clinical trial suggest that CBD may also be slightly effective for pain. It was found that CBD almost certainly derives its pain-relieving effects by both inhibiting sodium channels and activating Kv7.2 / 7.3 channels. Clinical CBD use is, however,severely limited due to its poor bioavailability, poor patient tolerability, and potential for drug-drug interactions. In addition, its very high lipophilicity makes in vitro studies difficult.

[0005] Thus, it was hypothesized that a novel drug candidate based on the CBD scaffold that selectively inhibits Nav1.8 and activates the Kv7.2 / 3 heteromeric channel would reduce nociceptor excitability and produce analgesia with minimal activity on other excitable cells and have no or little abuse liability. Further, new CBD analogs would allow for the tuning of bioavailability, tolerability, and lipophilicity, and limiting drug-drug interactions.

[0006] Provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, X, R2, R3, and R4are as defined herein.

[0007] In another aspect, provided herein are compounds of Formula (II):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, X, R2, R3, and R4are as defined herein.

[0008] In another aspect, provided herein are compounds of Formula (III):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, Ring A, X, R2, R3, and R4are as defined herein.

[0009] In another aspect, provided herein are compounds of Formula (IV):(IV), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, Ring B, X, q, R2, R3, and R4are as defined herein.

[0010] In another aspect, provided herein are compounds of Formula (V):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R5, X, R2, R3, and R4are as defined herein.

[0011] In another aspect, provided herein are compounds of Formula (VI):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, X, m, R2, R3, and R4are as defined herein.

[0012] In another aspect, provided herein are compounds of Formula (VII):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X, Z, g, and R4are as defined herein.

[0013] In another aspect, provided herein are compounds of Formula (I′′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, X, Z, g, and R4are as defined herein.

[0014] In another aspect, provided herein are compounds of Formula (II′′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, X, Z, g, and R4are as defined herein.

[0015] In another aspect, provided herein are compounds of Formula (III′′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, Ring A, X, Z, g, and R4are as defined herein.

[0016] In another aspect, provided herein are compounds of Formula (IV′′):(IV′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, Ring B, q, X, Z, g, and R4are as defined herein.

[0017] In another aspect, provided herein are compounds of Formula (V′ :(V′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R5, X, Z, g, and R4are as defined herein.

[0018] In another aspect, provided herein are compounds of Formula (VI′′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, n, m, X, Z, g, and R4are as defined herein.

[0019] In another aspect, provided herein are compounds of Formula (VII′):(VII′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X, Z, g, and R4are as defined herein.

[0020] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof); and optionally a pharmaceutically acceptable excipient.

[0021] In a further aspect, provided herein are methods of modulating CB1 receptors, the method comprising contacting a CB1 receptor with a compound described here (e.g., Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), or a pharmaceutical composition described herein.

[0022] In another aspect, provided herein are methods of modulating voltage gated potassium channels, the method comprising contacting a voltage gated potassium channel with a compound described here (e.g., Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), or a pharmaceutical composition described herein.

[0023] In a further aspect, provided herein are methods of modulating voltage gated sodium channels, the method comprising contacting a voltage gated sodium channel with a compound described herein (e.g., Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), or a pharmaceutical composition described herein.

[0024] In another aspect, provided herein are methods of treating or preventing a disease or disorder in a subject, the method comprising administering an effective amount of a compound described herein (e.g., a compound of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), or a pharmaceutical composition described herein, to the subject. In some embodiments, the disease or disorder is pain. In some embodiments, the disease or disorder is a neurological disease.

[0025] In another aspect, provided herein are kits comprising a compound as described herein (e.g., a compound of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof) or composition described herein and instructions for administering to a subject the compound or composition.

[0026] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, andadvantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. BRIEFDESCRIPTION OF THEDRAWINGS

[0027] FIG.1 shows the ability of KNA compounds at 10 micromolar to inhibit human Nav1.7 channels, inhibit human Nav1.8 channels, or to enhance or inhibit human Kv7.2 / 7.3 channels. Mean +- standard deviation.

[0028] FIG.2 shows the ability of KNA compounds at 3 micromolar to inhibit human Nav1.7 channels, inhibit human Nav1.8 channels, or to enhance or inhibit human Kv7.2 / 7.3 channels. Mean + / - standard deviation.

[0029] FIGs.3A-3B show the ability of KNA-273 and KNA-301 compounds at 1 micromolar to inhibit excitability of mouse nociceptive dorsal root ganglion neurons. Top panels show effect on ionic currents under voltage clamp, showing effective inhibition of inward sodium current. Bottom panels show inhibition of action potential firing evoked by a ramp of current.

[0030] FIG.4 shows the ability of selected KNA compounds at 1 micromolar to inhibit excitability of mouse nociceptive dorsal root ganglion neurons. DEFINITIONS

[0031] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0032] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0033] In a formula, is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.

[0034] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0035] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0036] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0037] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10alkyl (such as unsubstituted C1-6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10alkyl (such as substituted C1-6 alkyl, e.g., −CF3, Bn).

[0038] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0039] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-20 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-18 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-16alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-14alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 ormore heteroatoms within the parent chain (“heteroC1-12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-20alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl.

[0040] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3or) may be an (E)- or (Z)- double bond.

[0041] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0042] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10alkynyl.

[0043] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC2-6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.

[0044] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl 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 C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) orpolycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0045] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0046] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 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 polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclicsystem (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl 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, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0047] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0048] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include,without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0049] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or moresubstituents. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0050] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0051] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0052] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0053] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0054] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0055] The term “unsaturated bond” refers to a double or triple bond.

[0056] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0057] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0058] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0059] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” acyl, “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group 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 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, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes 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. The invention is not intended to be limited in any manner by the exemplary substituents described herein.

[0060] Exemplary carbon atom substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb,,−OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6 alkyl, −ON(C1-6 alkyl)2, −N(C1-6 alkyl)2, −N(C1-6 alkyl)3+X−, −NH(C1-6 alkyl)2+X−, −NH2(C1-6 alkyl)+X−, −NH3+X−, −N(OC1-6 alkyl)(C1-6 alkyl), −N(OH)(C1-6 alkyl), −NH(OH), −SH, −SC1-6alkyl, −SS(C1-6alkyl), −C(=O)(C1-6alkyl), −CO2H, −CO2(C1-6alkyl), −OC(=O)(C1-6 alkyl), −OCO2(C1-6 alkyl), −C(=O)NH2, −C(=O)N(C1-6 alkyl)2, −OC(=O)NH(C1-6alkyl), −NHC(=O)(C1-6alkyl), −N(C1-6alkyl)C(=O)( C1-6alkyl), −NHCO2(C1-6 alkyl),alkyl)2, −NHC(=O)NH(C1-6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1-6alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6alkyl)2, −C(=NH)NH(C1-6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6 alkyl)2, −OC(=NH)NH(C1-6alkyl), −OC(=NH)NH2, −NHC(=NH)N(C1-6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6 alkyl), −SO2N(C1-6 alkyl)2, −SO2NH(C1-6 alkyl), −SO2NH2, −SO2(C1-6 alkyl), −SO2O(C1-6alkyl), −OSO2(C1-6alkyl), −SO(C1-6alkyl), −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, −C(=O)S(C1-6 alkyl), −C(=S)SC1-6 alkyl, −SC(=S)SC1-6alkyl, −P(=O)(OC1-6alkyl)2, −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0061] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0062] The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa,, wherein X−, Raa, Rbb, and Rccare as defined herein.

[0063] The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0064] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0065] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0066] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3 and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0067] The term “acyl” refers to a group having the general formula −C(=O)RX1,, −C(=NRX1)SRX1, and −C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di- heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic,heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).

[0068] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen (i.e., –C(=O)-).

[0069] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0070] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0071] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein.

[0072] In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rcc, and Rddare as defined herein. Nitrogen protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0073] For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o- nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N¢- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide.

[0074] Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1- methylethyl carbamate (t-Bumeoc), 2-(2¢- and 4¢-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3- dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4- dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4- dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1- methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4- (trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0075] Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4¢,8¢- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0076] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)- acyl derivative, N¢-p-toluenesulfonylaminoacyl derivative, N¢-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl- 4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N,N’- isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0077] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa,, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0078] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″- tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1- bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethylcarbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0079] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein Ra, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdEdition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0080] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−,HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−,B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0081] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O- dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, - ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g.,,, wherein Raa, Rbb, and Rccare as defined herein).

[0082] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0083] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0084] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, Figures, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

[0085] The following definitions are more general terms used throughout the present application.

[0086] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts.

[0087] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate,sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0088] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0089] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R×x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R×0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R×2 H2O) and hexahydrates (R×6 H2O)).

[0090] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0091] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0092] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [ The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0094] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-8 alkyl,C2-8alkenyl, C2-8alkynyl, aryl, C7-12substituted aryl, and C7-12arylalkyl esters of the compounds described herein may be preferred.

[0095] The terms “composition” and “formulation” are used interchangeably.

[0096] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The subject may also be a plant. In certain embodiments, the plant is a land plant. In certain embodiments, the plant is a non-vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.

[0097] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0098] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound and / or composition of the disclosure is delivered. A tissuemay be an abnormal or unhealthy tissue. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy.

[0099] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into a biological system.

[0100] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0101] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0102] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0103] An “effective amount” of a compound described herein refers to an amount sufficient to elicit a desired outcome (e.g., modulating voltage gated sodium or potassium channels). An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint (e.g., extent of inhibition or activation), severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject, and the nature of the biological sample. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactically effective amount. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0104] A “therapeutically effective amount” of a compound described herein 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. 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, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for modulating voltage gated sodium or potassium channels. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or disorder (e.g., a neurological disease or pain). In certain embodiments, a therapeutically effective amount is an amount sufficient for modulating voltage gated sodium or potassium channels and treating a disease or disorder (e.g., a neurological disease or pain).

[0105] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for modulating voltage gated sodium or potassium channels. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease or disorder (e.g., a neurological disease or pain). In certain embodiments, a prophylactically effective amount is an amount sufficient for modulating voltage gated sodium or potassium channels and preventing a disease or disorder (e.g., a neurological disease or pain).

[0106] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerativediseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy- induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other“tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune- mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis;porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0107] The term “neurodevelopmental disorder” refers to a disorder or condition that begins to emerge during the development of the nervous system. In some embodiments, a neurodevelopmental disorder negatively impacts personal, social, academic, and / or occupational function. Neurodevelopmental disorders may include intellectual disabilities, communication disorders, autism, attention-deficit / hyperactivity disorder (ADHD), motor disorders, and learning disorders. In some embodiments, the neurodevelopmental disorder is autism, fragile X syndrome, tuberous sclerosis, Turner Syndrome, 22q Deletion Syndrome, Prader-Willi and Angelman Syndrome, Williams syndrome, lysosomal storage diseases, dyslexia, specific language impairment, or fetal alcohol syndrome.

[0108] “Pain” or a “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain),noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo–skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0109] In certain embodiments, the painful condition is neuropathic pain. The term "neuropathic pain" refers to pain resulting from injury to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is the pain caused by acute tissue injury involving small cutaneous nerves or small nerves in muscle or connective tissue. Neuropathic pain typically is long-lasting or chronic and often develops days or months following an initial acute tissue injury. Neuropathic pain can involve persistent, spontaneous pain as well as allodynia, which is a painful response to a stimulus that normally is not painful. Neuropathic pain also can be characterized by hyperalgesia, in which there is an accentuated response to a painful stimulus that usually is trivial, such as a pin prick. Neuropathic pain conditions can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain conditions include, but are not limited to, diabetic neuropathy (e.g., peripheral diabetic neuropathy); sciatica; non-specific lower back pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma (e.g., amputation; surgery, invasive medical procedures, toxins, burns, infection), pain resulting from cancer or chemotherapy (e.g., chemotherapy- induced pain such as chemotherapy- induced peripheral neuropathy), and pain resulting from an inflammatory condition (e.g., a chronic inflammatory condition). Neuropathic pain canresult from a peripheral nerve disorder such as neuroma; nerve compression; nerve crush, nerve stretch or incomplete nerve transsection; mononeuropathy or polyneuropathy. Neuropathic pain can also result from a disorder such as dorsal root ganglion compression; inflammation of the spinal cord; contusion, tumor or hemisection of the spinal cord; tumors of the brainstem, thalamus or cortex; or trauma to the brainstem, thalamus or cortex.

[0110] The symptoms of neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

[0449] In certain embodiments, the painful condition is non-inflammatory pain. The types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction in the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), deafferentation pain (e.g., pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (e.g., certain types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain felt in response to tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (e.g., pain where no physical cause may exist), and wandering pain (e.g., wherein the pain repeatedly changes location in the body).

[0111] In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) is associated with an inflammatory condition and / or an immune disorder.

[0112] A “sodium channel” is a membrane protein that forms ion channels, conducting sodium ions (Na+) through a cell’s plasma membrane. In neurons, sodium channels are responsible for the rising phase of action potentials. In some embodiments, the sodium channel is a NaV1.6, NaV1.7, NaV1.8, and NaV1.9 channel.

[0113] A “potassium channel” is a membrane protein that forms ion channels, conducting potassium ions (K+) through a cell’s plasma membrane. In neurons, potassium channels are responsible for the rising phase of action potentials. In some embodiments, the potassium channel is a KV7.2 or KV7.3 channel.

[0114] The term “mutation” in the context of a gene refers to a substitution, insertion, deletion, or combination thereof. In some embodiments, the mutation is a substitution. In some embodiments, the mutation is an insertion. In some embodiments, the mutation is a deletion. In some embodiments, the mutation is a missense mutation. In some embodiments, the mutation is a frameshift mutation. In some embodiments, the mutation is a nonsense mutation. DETAILED DESCRIPTION

[0115] Disclosed herein are compounds (e.g., compounds of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), or (I)-(VII), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof), compositions (e.g., pharmaceutical compositions comprising compounds of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′) or (I)-(VII)), kits, methods, and uses.

[0116] Provided herein are compounds of Formulae (I′′)-(IV′′), (VI′′), (I′)-(VII′), and (I)- (VII), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0117] In one aspect, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; orR2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0118] In some embodiments, the compound of Formula (I) is of Formula (I-A):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0119] In one aspect, provided herein are compounds of Formula (II):(II),or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0120] In some embodiments, the compound of Formula (II) is of Formula (II-A):(II-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0121] In another aspect, provided herein are compounds of Formula (III):(III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl; R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN;each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0122] In some embodiments, the compound of Formula (III) is of Formula (III-A):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0123] In another aspect, provided herein are compounds of Formula (IV):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, or substituted or unsubstituted heteroaryl ring; is a single or double bond, as valency permits; q is 1 or 2 R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2,, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group.

[0124] In some embodiments, the compound of Formula (IV) is of Formula (IV-A):(IV-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0125] In some embodiments, the compound of Formula (IV) is of Formula (IV-B):(IV-B), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0126] In some embodiments, the compound of Formula (IV) is of Formula (IV-C):(IV-C), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0127] In another aspect, provided herein are compounds of Formula (V):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R5is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2Rs, -CN, or -NO3; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen;R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group.

[0128] In some embodiments, the compound of Formula (V) is of Formula (V-A):(V-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0129] In another aspect, provided herein are compounds of Formula (VI):(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: m is 0, 1, or 2; is a single or double bond;R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

[0130] In some embodiments, the compound of Formula (VI) is of Formula (VI-A)(VI-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0131] In another aspect, provided herein are compounds of Formula (VII):(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

[0132] In some embodiments, the compound of Formula (VII) is of Formula (VII-A):(VII-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0133] In one aspect, provided herein are compounds of Formula (I′):(I′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O;R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl,, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0134] In one aspect, provided herein are compounds of Formula (II′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen;is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0135] In another aspect, provided herein are compounds of Formula ():or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl; R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group;provided that the compound is not of the formula: .(IV′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, or substituted or unsubstituted heteroaryl ring; is a single or double bond, as valency permits; q is 1 or 2 R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond;Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

[0137] In another aspect, provided herein are compounds of Formula (V′):(V′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R5is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2Rs, -CN, or -NO3; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond;Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

[0138] In another aspect, provided herein are compounds of Formula (VI′):(VI′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: m is 0, 1, or 2; is a single or double bond; R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2,, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

[0139] In one aspect, provided herein are compounds of Formula (I′′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:each instance of R1is independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ,n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0140] In one aspect, provided herein are compounds of Formula (II′′):(II′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of R1is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ,n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring;each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0141] In another aspect, provided herein are compounds of Formula (III′′):(III′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl; each instance of R1is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ,-SO2RS, -NRNSO2RS, -CN, -NO3, -NO2, or two instances of R1attached to the same carbon atom are taken together to form =O; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; orR2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0142] In another aspect, provided herein are compounds of Formula (IV′′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, or substituted or unsubstituted heteroaryl ring; is a single or double bond, as valency permits; q is 1 or 2 each instance of R1is independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ,n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group.

[0143] In another aspect, provided herein are compounds of Formula (VI′′):(VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: m is 0, 1, or 2; is a single or double bond; each instance of R1is independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,- SO2RS, -NRNSO2RS, -CN, -NO3, -NO2, or two instances of R1attached to the same carbon atom are taken together to form =O; or two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN;each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

[0144] In another aspect, provided herein are compounds of Formula (VII′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; orR2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -SRS, -SO2RS, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group.

[0145] In some embodiments, a compound of Formula (I′′) is of Formula (I′) or (I). In some embodiments, a compound of Formula (I′) is of Formula (I).

[0146] In some embodiments, a compound of Formula (II′′) is of Formula (II′) or (II). In some embodiments, a compound of Formula (II′) is of Formula (II).

[0147] In some embodiments, a compound of Formula (III′′) is of Formula (III′) or (III). In some embodiments, a compound of Formula (III′) is of Formula (III).

[0148] In some embodiments, a compound of Formula (IV′′) is of Formula (IV′) or (IV). In some embodiments, a compound of Formula (IV′) is of Formula (IV).

[0149] In some embodiments, a compound of Formula (V′) is of Formula (V).

[0150] In some embodiments, a compound of Formula (VI′′) is of Formula (VI′) or (VI). In some embodiments, a compound of Formula (VI′) is of Formula (VI).

[0151] In some embodiments, a compound of Formula (VII′) is of Formula (VII).

[0152] In some embodiments, provided herein are compounds of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), and (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, provided herein are compounds of Formula (I′′)-(IV′′), (VI′′), (I′)- (VII′), and (I)-(VII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, or stereoisomer thereof. In some embodiments, provided herein are compounds of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), and (I)-(VII), or a pharmaceuticallyacceptable salt, tautomer, or stereoisomer thereof. In some embodiments, provided herein are compounds of Formula (I′′)-(IV′′), (VI′′), (I′)-(VII′), and (I)-(VII), or a pharmaceutically acceptable salt thereof. R1As provided herein, each instance of R1is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, -NO2, or two instances of R1attached to the same carbon atom are taken together to form =O; or two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. In some embodiments, R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2. In some embodiments, R1is C1-6 alkyl substituted with halogen, carbocyclyl, -OH, -NH2, -CN, or -SO2CH3. In some embodiments, R1is -CF3,some embodiments, R1is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0153] In some embodiments, R1is hydrogen.

[0154] In some embodiments, R1is substituted or unsubstituted C1-6 alkyl. In some embodiments, R1is substituted or unsubstituted C2-6 alkenyl. In some embodiments, R1is substituted or unsubstituted C2-6 alkynyl. In some embodiments, R1is -CF3, -(CH3)2(CH2OH), -CH2NH2, -CH2CN, or -CH2SO2CH3.

[0155] In some embodiments, R1is halogen. In some embodiments, R1is fluoro. In some embodiments, R1is chloro. In some embodiments, R1is bromo. In some embodiments, R1is iodo.

[0156] In some embodiments, R1is substituted or unsubstituted carbocyclyl. In some embodiments, R1is. In some embodiments, R1is substituted or unsubstituted heterocyclyl. In some embodiments, R1is substituted or unsubstituted aryl. In some embodiments, R1is substituted or unsubstituted heteroaryl. In some embodiments, R1is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazolyl, substituted or unsubstituted imidazopyridazinyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted pyrrolidinyl.

[0157] In some embodiments, R1is -ORO. In some embodiments, R1is -OH. In some embodiments, R1is -OMe.

[0158] In some embodiments, R1is -SRS. In some embodiments, R1is -SH. In some embodiments, R1is -SMe.

[0159] In some embodiments, R1is -N(RN)2. In some embodiments, R1is -NH2. In some embodiments, R1is -NMe2. In some embodiments, R1is -NHMe.

[0160] In some embodiments, R1is -C(=O)RC. In some embodiments, R1is -C(=O)H. In some embodiments, R1is -C(=O)Me. In some embodiments, R1is -C(=O)Et. In some embodiments, R1is -C(=O)Pr. In some embodiments, R1is -C(=O)tBu.

[0161] In some embodiments, R1is -C(=O)ORO. In some embodiments, R1is -C(=O)OH. In some embodiments, R1is -C(=O)OMe. In some embodiments, R1is -C(=O)OtBu.

[0162] In some embodiments, R1is -C(=O)N(RN)2. In some embodiments, R1is -C(=O)N(H)2. In some embodiments, R1is -C(=O)N(Me)2. In some embodiments, R1is -C(=O)NHMe.

[0163] In some embodiments, R1is substituted or unsubstituted -NRNC(=O)RC. In some embodiments, R1is substituted or unsubstituted -NHC(=O)H. In some embodiments, R1is substituted or unsubstituted -NHC(=O)Me.

[0164] In some embodiments, R1is substituted or unsubstituted -SO2RS. In some embodiments, R1is substituted or unsubstituted -SO2Me.

[0165] In some embodiments, R1is substituted or unsubstituted -NRNSO2RS. In some embodiments, R1is substituted or unsubstituted -NHSO2Me.

[0166] In some embodiments, R1is substituted or unsubstituted -CN.

[0167] In some embodiments, R1is substituted or unsubstituted -NO3. In some embodiments, R1is substituted or unsubstituted -NO2.

[0168] In some embodiments, two instances of R1attached to the same carbon atom are taken together to form =O.

[0169] In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted carbocyclic ring. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted 3- to 7-membered carbocyclic ring. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted heterocyclic ring. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted heterocyclic ring comprising at least one heteroatom. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted heterocyclic ring comprising a nitrogen atom. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted heterocyclic ring comprising at least one oxygen atom. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted 3- to 7-membered heterocyclic ring. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted 4- to 6-membered heterocyclic ring. In some embodiments, two instances of R1attached to the same carbon atom are taken together with their intervening atom to form optionally substituted 1,3- dioxolanyl, optionally substituted azetidinyl, or optionally substituted piperidinyl.

[0170] As provided herein, each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen. In some embodiments, each instance of X is independently hydrogen, -ORO, -N(RN)2, or halogen. In some embodiments, each instance of X is independently hydrogen, -OH, -NH(RN), -NH2, or -F. In some embodiments, each instance of X is independently hydrogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHC(O)CH3, -NHC(O)NH2, -NHCO2Me, -NHCH2CF3, -NHSO2CH3, -NHSO2CF3, or -F.

[0171] In some embodiments, both instances of X are -OH. In some embodiments, one instance of X is -OH, and one instance of X is H. In some embodiments, one instance of X is -OH, and one instance of X is F. In some embodiments, one instance of X is -OH, and one instance of X is -N(RN)2. In some embodiments, one instance of X is -OH, and one instance of X is -NHRN. In some embodiments, one instance of X is -OH, and one instance of X is -NH2. In some embodiments, one instance of X is -OH, and one instance of X is -NH(CH3). In some embodiments, one instance of X is -OH, and one instance of X is -N(CH3)2. In some embodiments, one instance of X is -OH, and one instance of X is -NHC(O)CH3. In some embodiments, one instance of X is -OH, and one instance of X is -NHC(O)NH2. In some embodiments, one instance of X is -OH, and one instance of X is -NHCO2Me. In some embodiments, one instance of X is -OH, and one instance of X is -NHCH2CF3. In some embodiments, one instance of X is -OH, and one instance of X is -NHSO2CH3. In some embodiments, one instance of X is -OH, and one instance of X is -NHSO2CF3. In some embodiments, both instances of X are -NH2. In some embodiments, both instances of X are -NH(CH3).

[0172] In some embodiments, at least one instance of X is -OH. In some embodiments, at least one instance of X is -F. In some embodiments, at least one instance of X is -H. In some embodiments, at least one instance of X is -NHRN. R2and R3

[0173] As provided herein, R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN, or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O. In some embodiments, R2is hydrogen methyl, fluoro, -CN, -CH2F, -CHF2, or -CF3. In some embodiments, R2is methyl, fluoro, -CN, -CH2F, -CHF2, or -CF3. In some embodiments, R2is hydrogen, methyl, or fluoro. In some embodiments, R2is methyl.

[0174] As provided herein, R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O. In some embodiments, R3is hydrogen, methyl, fluoro, -CN, -CH2F, -CHF2, or -CF3. In some embodiments, R3is methyl, fluoro, -CN, -CH2F, -CHF2, or -CF3. In some embodiments, R3is hydrogen, methyl, fluoro, -OH, or -OMe. In some embodiments, R3is hydrogen, methyl, or fluoro. In some embodiments, R3is -OH or -OMe. In some embodiments, R3is methyl.

[0175] In some embodiments, R2and R3are the same. In some embodiments, R2and R3are different. In some embodiments, R3is hydrogen, and R2is hydrogen. In some embodiments, R3is methyl, and R2is hydrogen. In some embodiments, R3is fluoro, and R2is fluoro. In some embodiments, R3is fluoro, and R2is hydrogen. In some embodiments, R3is -CF3, and R2is hydrogen. In some embodiments, R3is methyl, and R2is methyl. In some embodiments, R3is -OH, and R2is hydrogen. In some embodiments, R3is -OMe, and R2is hydrogen. R4

[0176] As provided herein, R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -SRS, -SO2RS, -N(RN)2, or -CN. In some embodiments, R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN. In some embodiments, R4is hydrogen. In some embodiments, R4is substituted or unsubstituted C1-6 alkyl. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is -CF3. In some embodiments, R4is -OH. In some embodiments, R4is -N(RN)2. In some embodiments, R4is -N(RN)CH3. In some embodiments, R4is -NH2, -NH(CH3), or -N(CH3)2. In some embodiments, R4is -OH. In some embodiments, R4is -OH, -SCH3, or -N(RN)CH3. In some embodiments, R4is -SCH3or -SO2CH3.

[0177] In some embodiments, R4is substituted or unsubstituted heterocyclyl. In some embodiments, R4is substituted or unsubstituted piperidinyl. In some embodiments, R4is substituted or unsubstituted morpholinyl. In some embodiments, R4is substituted or unsubstituted piperazinyl. In some embodiments, R4is N-methylpiperidinyl. In some embodiments, R4is substituted or unsubstituted pyrrolidinyl. In some embodiments, R4is substituted or unsubstituted 2-oxa-5-azabicyclo[2.2.1]heptanyl. In some embodiments, R4is substituted or unsubstituted azetidinyl. In some embodiments, R4is substituted or unsubstituted thiomorpholinyl. R5

[0178] As provided herein, R5is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2Rs, -CN, or -NO3.

[0179] In some embodiments, R5is hydrogen.

[0180] In some embodiments, R5is substituted or unsubstituted C1-6alkyl. In some embodiments, R5is -CH2CF3. In some embodiments, R5is -CH2CH2OMe. In some embodiments, R5is. In some embodiments, R5is.

[0181] In some embodiments, R5is halogen. In some embodiments, R5is fluoro. In some embodiments, R5is chloro. In some embodiments, R5is bromo. In some embodiments, R5is iodo.

[0182] In some embodiments, R5is -ORO. In some embodiments, R5is -OH.

[0183] In some embodiments, R5is -N(RN)2.

[0184] In some embodiments, R5is -C(=O)RC. In some embodiments, R5is -C(=O)H. In some embodiments, R5is -C(=O)Me.

[0185] In some embodiments, R5is -C(=O)ORO. In some embodiments, R5is -C(=O)OMe. In some embodiments,

[0186] In some embodiments, R5is some embodiments, R5is -C(=O)NH2. In some embodiments,5. In some embodiments, R is -C(=O)NHMe.

[0187] In some embodiments, R5is -NRNC(=O)RC.

[0188] In some embodiments, R5is -SO2RS. In some embodiments, R5is -SO2Me. In some embodiments, R5is -SO2CF3.

[0189] In some embodiments, R5is -NRNSO2Rs.

[0190] In some embodiments, R5is -CN.

[0191] In some embodiments, R5is -NO3. RC, RO, RS, and RN

[0192] As provided herein, each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN. In some embodiments, RCis hydrogen. In some embodiments, RCis substituted or unsubstituted C1-6alkyl. In some embodiments, RCis substituted or unsubstituted carbocyclyl. In some embodiments, RCis halogen. In some embodiments, RCis -ORO. In some embodiments, RCis -N(RN)2. In some embodiments, RCis -CN.

[0193] As provided herein, each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted4-8 membered heterocyclic ring. In some embodiments, RNis RNis -CH3, -CH2CH3, -C(=O)CH3, -C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3. In some embodiments, RNis hydrogen. In some embodiments, RNis substituted or unsubstituted C1-6alkyl. In some embodiments, RNis -C(=O)RC. In some embodiments, RNis -C(=O)ORO. In some embodiments, RNis -C(=O)N(RN)2. In some embodiments, RNis -SO2RS. In some embodiments, RNis a nitrogen protecting group. In some embodiments, RNis substituted or unsubstituted C1-6 alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS. In some embodiments, two instances of RNare joined to form a substituted or unsubstituted 4-8 membered heterocyclic ring. In some embodiments, two instances of RNare joined to form a substituted or unsubstituted piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, or 2-oxa-5- azabicyclo[2.2.1]heptane.

[0194] As provided herein, each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group. In some embodiments, ROis hydrogen. In some embodiments, ROis substituted or unsubstituted C1-6 alkyl. In some embodiments, ROis substituted or unsubstituted carbocyclyl. In some embodiments, ROis an oxygen protecting group.

[0195] As provided herein, each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group. In some embodiments, RSis hydrogen. In some embodiments, RSis substituted or unsubstituted C1-6 alkyl. In some embodiments, RSis a sulfur protecting group. Ring A

[0196] As provided herein, Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl.

[0197] In some embodiments, Ring A is 3- to 7-membered monocyclic heterocyclyl. In some embodiments, Ring A is 5- to 6-membered monocyclic heterocyclyl. In some embodiments, Ring A is tetrahydropyranyl, tetrahydropyridinyl, or pyrrolidinyl. In some embodiments, Ring A is 9- to 10-membered bicyclic heterocyclyl. In some embodiments, Ring A is indolinyl or 2,3-dihydro-1H-benzo[d]imidazolyl.

[0198] In some embodiments, Ring A is 5- or 6-membered monocyclic heteroaryl. In some embodiments, Ring A is 9- or 10-membered bicyclic heteroaryl. In some embodiments, Ring A is thiopheneyl, pyridinyl, indazolyl, benzothiopheneyl, naphthaleneyl, or imidazolpyridinyl. In some embodiments, Ring A is thiopheneyl. In some embodiments, RingA is pyridinyl. In some embodiments, Ring A is indazolyl. In some embodiments, Ring A is benzothiopheneyl. In some embodiments, Ring A is imidazolpyridinyl.

[0199] In some embodiments, Ring A is naphthaleneyl.

[0200] In some embodiments, Ring A is substituted or unsubstituted, monocyclic or bicyclic heterocyclyl ring, or substituted or unsubstituted, monocyclic or bicyclic heteroaryl ring. In some embodiments, Ring A is substituted or unsubstituted, monocyclic or bicyclic heteroaryl ring or substituted or unsubstituted, bicyclic heteroaryl ring.

[0201] In some embodiments, Ring A contains one heteroatom. In some embodiments, Ring A contains at least one heteroatom. In some embodiments, Ring A contains a nitrogen heteroatom. In some embodiments, Ring A contains a sulfur heteroatom. In some embodiments, Ring A contains an oxygen heteroatom.

[0202] As provided herein, Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, substituted or unsubstituted heteroaryl ring. In some embodiments, Ring B is substituted or unsubstituted monocyclic or bicyclic carbocyclyl ring or substituted or unsubstituted monocyclic or bicyclic heterocyclyl ring. In some embodiments, Ring B is substituted or unsubstituted monocyclic or bicyclic aryl ring or substituted or unsubstituted monocyclic or bicyclic heteroaryl ring.

[0203] In some embodiments, Ring B is substituted or unsubstituted monocyclic or bicyclic carbocyclyl ring. In some embodiments, Ring B is substituted or unsubstituted 3- to 7- membered carbocyclyl ring. In some embodiments, Ring B is substituted or unsubstituted bicyclic carbocyclyl ring.

[0204] In some embodiments, Ring B is substituted or unsubstituted monocyclic or bicyclic heterocyclyl ring. In some embodiments, Ring B is substituted or unsubstituted 3- to 7- membered heterocyclyl ring. In some embodiments, Ring B is substituted or unsubstituted 5- to 6-membered heterocyclyl ring. In some embodiments, Ring B is substituted or unsubstituted heterocyclyl comprising one heteroatom. In some embodiments, Ring B is substituted or unsubstituted heterocyclyl comprising a nitrogen atom. In some embodiments, Ring B is substituted or unsubstituted heterocyclyl comprising an oxygen atom. In some embodiments, Ring B is pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl. In some embodiments, Ring B is piperidinyl. In some embodiments, Ring B is morpholinyl. In some embodiments, Ring B is piperazinyl. In some embodiments, Ring B is pyrrolidinyl.

[0205] In some embodiments, Ring B is substituted or unsubstituted monocyclic or bicyclic aryl ring. In some embodiments, Ring B is substituted or unsubstituted phenyl. In some embodiments, Ring B is substituted or unsubstituted naphthyl.

[0206] In some embodiments, Ring B is substituted or unsubstituted monocyclic or bicyclic heteroaryl ring. In some embodiments, Ring B is substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, Ring B is substituted or unsubstituted 9- or 10- membered heteroaryl. In some embodiments, Ring B is substituted or unsubstituted heteroaryl comprising one heteroatom. In some embodiments, Ring B is substituted or unsubstituted heteroaryl comprising a nitrogen atom. In some embodiments, Ring B is substituted or unsubstituted heteroaryl comprising an oxygen atom. In some embodiments, Ring B is substituted or unsubstituted heteroaryl comprising a sulfur atom. n, m, g, and q

[0207] As provided herein, n is an integer between 0 to 4, inclusive. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0208] As provided herein, m is 0, 1, or 2. In some embodiments, m is 0. In certain embodiments, m is 1. In some embodiments, m is 2.

[0209] As provided herein, g is an integer between 1 and 7, inclusive. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5. In some embodiments, g is 6. In some embodiments, g is 7.

[0210] As provided herein, q is 1 or 2. In some embodiments, q is 1. In certain embodiments, q is 2. Z

[0211] As provided herein, Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits. In some embodiments, Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-. In some embodiments, Z is -O-, -C(R2R3)-, -C(R2)-, -C(R3)-. In some embodiments, is a double bond and Z is -C(R2)- or -C(R3)-. In some embodiments, is a single bond and Z is -O-, -S-, or -C(R2R3)-. In some embodiments, is a single bond and Z is -O- or -C(R2R3)-.Other Embodiments

[0212] In some embodiments,within Formula (I), (I′), or (I′′), or sub genera thereof, is of the formula:.

[0213] In some embodiments,within Formula (II), (II′), or (II′′), or sub genera thereof, is of the formula:, , , , [, within Formula (IV), (IV′), or (IV′′), or sub genera thereof, is of the formula:, , ,.

[0215] In some embodiments,within Formula (VI), (VI′), or (VI′′), or sub genera thereof, is of the formula:, , , n some embodiments,within Formula (VI), (VI′), or (VI′′), or sub genera thereof, is optionally substituted. In some embodiments,within Formula (VI), (VI′), or (VI′′), or sub genera thereof, is optionally(VI), (VI′), or (VI′′), or sub genera thereof, is optionally substitutedor. , within Formula (VI), (VI′), or (VI′′), or sub genera thereof, is optionally substituted.

[0216] In some embodiments,within Formula (I′)-(VII′), (I′′)-(IV′′), (VI′′), or sub genera thereof, is of the formula:, , , ,, , , , ,. Species

[0218] In some embodiments, the compound is of the formula:,,,,,, ,,, , ,,,,.

[0219] In some embodiments, the compound of Formula (I)-(VII) or (I′)-(VII′) is of the

[0220] In some embodiments, the compound is of the formula: ,,, ,,,,,, ,,Pharmaceutical Compositions

[0222] The present disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0223] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0224] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0225] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0226] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary,depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0227] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0228] Exemplary diluents or fillers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, starches (such as dry starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, and mixtures thereof.

[0229] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0230] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0231] Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).

[0232] Exemplary binding agents include starch (e.g., glycolate starch, cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl- pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0233] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0234] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassiummetabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0235] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.

[0236] Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0237] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0238] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0239] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0240] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall®115, Germaben®II, Neolone®, Kathon®, and Euxyl®.

[0241] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate,sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0242] Exemplary lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0243] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0244] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0245] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0246] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready-to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0247] In some embodiments, the pharmaceutical compositions disclosed herein comprise a bulking agent. Bulking agents can be used, e.g., to improve the appearance of a solid composition, to provide visible “bulk” to demonstrate product quality or to facilitate preparation, e.g., of a solid composition prepared for reconstitution prior to administration. Bulking agents can be used for low dose (high potency) drugs that do not have the necessary bulk to support their own structure or provide a visible composition in a unit dosage form. Bulking agents are used in lyophilized formulations. Bulking agents provide a desirable structure for a lyophilized cake comprising pores that provide the means for vapor to escape from the product during lyophilization cycles, and facilitate dissolution on reconstitution. In some embodiments, the bulking agent is mannitol, lactose, sucrose, dextran, trehalose, povidone, dextran, glycine, isoleucine, methionine, or a cyclodextrin (e.g., (2- hydroxypropyl)-β-cyclodextrin).

[0248] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0249] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0250] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0251] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0252] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutics. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0253] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0254] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0255] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle deliverydevices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0256] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0257] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0258] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0259] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholicsolutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0260] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0261] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0262] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in aliposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0263] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0264] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0265] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound orpharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0266] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.

[0267] In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includesindependently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0268] In certain embodiments, the compounds of the present disclosure are administered at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0269] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0270] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in modulating voltage gated sodium or potassium channels), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0271] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0272] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti- inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from thegroup consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. Kits

[0273] Also provided herein are kits (e.g., pharmaceutical packs) comprising a comprising a compound of the disclosure (e.g., a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0274] The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0275] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kitsare useful for preventing a disease in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits are useful for modulating the activity of a voltage gated sodium or potassium channel in a subject or cell.

[0276] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for modulating the activity of a voltage gated sodium or potassium channel in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods and Uses

[0277] Also provided herein are methods and uses utilizing compounds of Formula (I)- (VII), (I′)-(VII′), (I′′)-(IV′′), and (VI′′).

[0278] In one aspect, provided herein is a method of modulating voltage gated potassium channels, the method comprising contacting a voltage gated potassium channel with a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′). Also provided herein are compounds of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), and (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′) for use in modulating voltage gated potassium channels.

[0279] In some embodiments, the voltage gated potassium channel is KV7.2 or KV7.3. In some embodiments, the voltage gated potassium channel comprises both KV7.2 and KV7.3. In some embodiments, the voltage gated potassium channel is hKv7.2 / 7.3. In some embodiments, the modulating is activating. In some embodiments, the modulating isinhibiting. In some embodiments, the modulating treats a disease. In some embodiments, the modulating treats a neurological disease. In some embodiments, the modulating treats a painful condition. In some embodiments, activating voltage gated potassium channels (e.g., in pain-sensing neurons or excitatory neurons in the central nervous system), treats pain or epilepsy (e.g., by reducing the activity of the neurons). In some embodiments, inhibiting voltage gated potassium channels (e.g., in inhibitory neurons in the central nervous system) treats a disease (e.g., by enhancing the activity of the neurons).

[0280] In one aspect, provided herein is a method of modulating voltage gated sodium channels, the method comprising contacting a voltage gated sodium channel with a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′). Also provided herein are compounds of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), and (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′) for use in modulating voltage gated sodium channels.

[0281] In some embodiments, the voltage gated sodium channel is Nav1.1, Nav1.3, Nav1.5, NaV1.6, NaV1.7, NaV1.8, and / or NaV1.9. In some embodiments, the voltage gated sodium channel is Nav1.1, Nav1.3, NaV1.6, NaV1.7, NaV1.8, and / or NaV1.9. In some embodiments, the voltage gated sodium channel is hNav1.7 and / or hNav1.8. In some embodiments, the voltage gated sodium channel is hNav1.7. In some embodiments, the voltage gated sodium channel is hNav1.8. In some embodiments, the modulating is activating. In some embodiments, the modulating is inhibiting. In some embodiments, the modulating treats a disease. In some embodiments, the modulating treats a neurological disease. In some embodiments, the modulating treats a painful condition.

[0282] In another aspect, provided herein is a method of modulating CB1 receptors, the method comprising contacting a CB1 receptor with a compound of Formula (I)-(VII), (I′)- (VII′), (I′′)-(IV′′), or (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising compound of Formula (I)-(VII), (I′)- (VII′), (I′′)-(IV′′), or (VI′′). Also provided herein are compounds of Formula (I)-(VII), (I′)- (VII′), (I′′)-(IV′′), and (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising compound of Formula (I)-(VII), (I′)- (VII′), (I′′)-(IV′′), or (VI′′) for use in modulating CB1 receptors. In some embodiments, the modulating is activating. In some embodiments, the modulating is inhibiting. In some embodiments, the modulating treats a disease. In some embodiments, the modulating treats a neurological disease. In some embodiments, the modulating treats a painful condition.

[0283] In some embodiments, the modulating is in a subject. In some embodiments, the modulating is in vivo. In some embodiments, the modulating is in vitro. In some embodiments, the modulating is ex vivo.

[0284] In another aspect, provided herein is a method of treating a disease or disorder comprising administering to a subject a therapeutically effective amount of a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof or a pharmaceutical composition comprising a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′). Also provided herein are compounds of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), and (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′) for use in treating a disease or disorder in a subject.

[0285] In another aspect, provided herein is a method of preventing a disease or disorder comprising administering to a subject a prophylactically effective amount of a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′). Also provided herein are compounds of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), and (VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a compound of Formula (I)-(VII), (I′)-(VII′), (I′′)-(IV′′), or (VI′′) for use in preventing a disease or disorder in a subject.

[0286] In some embodiments, the disease or disorder is a painful condition. In some embodiments, the painful condition is musculoskeletal pain, headache, transplant pain, neurogenic pain, cancer, or pain from fibromyalgia. In some embodiments, the painfulcondition is nociceptive pain, surgical or postoperative pain, post-traumatic pain, arthritis, visceral pain, low back pain, skin pain, neuropathic pain, or central neuropathic pain. In some embodiments, the arthritis is rheumatoid and osteoarthritis. In some embodiments, the skin pain is burn, trauma, or inflammation. In certain embodiments, the neuropathic pain is diabetic neuropathic pain, trigeminal neuralgia, post herpetic neuralgia, nerve injury induced pain, neuritis, chemotherapy induced neuropathy pain, or disc herniation pain. In some embodiments, the central neuropathic pain is spinal cord injury or post-stroke pain.

[0287] In some embodiments, the disease or disorder is a neurological disease. In some embodiments, the disease or disorder is a neuropsychiatric disease. In some embodiments, the disease or disorder is a neurodegenerative disease. In some embodiments, the neurological disease is epilepsy, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease, or bipolar disorder. In some embodiments, the neurological disease is epilepsy. In some embodiments, the neurological disease is seizure. In certain embodiments, the epilepsy is from Dravet Syndrome or Lennox Gastaut syndrome. In some embodiments, the disease or disorder is a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder is autism, fragile X syndrome, tuberous sclerosis, Turner Syndrome, 22q Deletion Syndrome, Prader-Willi and Angelman Syndrome, Williams syndrome, lysosomal storage diseases, dyslexia, specific language impairment, or fetal alcohol syndrome.

[0288] In some embodiments, the disease is associated with pathological hyperexcitability in neurons. In certain embodiments, the disease is a neurological disease associated with pathological hyperexcitability in neurons.

[0289] In some embodiments, the disease is associated with SCN1A, KCNQ2, CDKL5, SCN2A, PRRT2, PCDH19, STXBP1, SLC2A1, GABRG2, SCN8A, UBE3A, MECP2, GRIN2A, TSC2, FOXG1, GABRA1, TPP1, ZEB2, CHRNA4, ARX, TSCL, and / or ALDH7A1. In some embodiments, the disease is associated with SCN1A, SCN2A, TSC2, CHD2, CDKL5, KCNQ2, FOXG1, MECP2, SCN1A, SCN8A, STXBP1, PCDH19, and / or SLC2A1. In some embodiments, the disease is associated with SCN1A, KNCQ2, TSC2, CHD2, FOXG1, SCN8A, and / or STXBP1. In some embodiments, the disease is associated with SCN1A, KNCQ2, and / or TSC2. In some embodiments, the disease is associated with SCN1A and / or KNCQ2.

[0290] In some embodiments, the disease is associated with copy number variation or mutation in a gene. In some embodiments, the disease is associated with mutation in a gene. In some embodiments, the disease is associated with a missense mutation in a gene. In someembodiments, the disease is associated with an insertion or deletion in a gene. In some embodiments, the disease is associated with frameshift mutation in a gene. In some embodiments, the disease is associated with nonsense mutation in a gene. In some embodiments, the disease is associated with copy number variation or mutation in SCN1A, KCNQ2, CDKL5, SCN2A, PRRT2, PCDH19, STXBP1, SLC2A1, GABRG2, SCN8A, UBE3A, MECP2, GRIN2A, TSC2, FOXG1, GABRA1, TPP1, ZEB2, CHRNA4, ARX, TSCL, and / or ALDH7A1. In some embodiments, the disease is associated with copy number variation or mutation in SCN1A, SCN2A, TSC2, CHD2, CDKL5, KCNQ2, FOXG1, MECP2, SCN1A, SCN8A, STXBP1, PCDH19, and / or SLC2A1. In some embodiments, the disease is associated with copy number variation or mutation in SCN1A, KNCQ2, TSC2, CHD2, FOXG1, SCN8A, and / or STXBP1. In some embodiments, the disease is associated with copy number variation or mutation in SCN1A, KNCQ2, and / or TSC2. In some embodiments, the disease is associated with copy number variation or mutation in SCN1A and / or KNCQ2.

[0291] The compounds and compositions disclosed herein may be administered by any suitable route. In some embodiments, the compound or composition is administered systemically. In certain embodiments, the compound or composition is administered orally or by injection. In some embodiments, the compound or composition is administered locally. In certain embodiments, the compound or composition is administered topically. EXAMPLES

[0292] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0293] In the Examples and Figures, “HARV” and “KNA” are used interchangeably. For example, “HARV-001” corresponds to “KNA-001.”Synthesis of KNA-001

[0294] The synthesis steps of KNA-001 and KNA-002 are similar.

[0295] To a solution of silver; hexafluoroantimony (1 -) (16.5 mg, 48.0 μmol, 0.10 eq) in DCE (1 mL) was added compound 8 (110 mg, 720 μmol, 1.50 eq), then the mixture was added compound 9 (100 mg, 480 μmol, 1.00 eq), the mixture was stirred at 20 °C for 12 hr under dark. LCMS (EW32982-52-P1A) and TLC (PE:EA = 10 : 1) showed the reactant 1 was consumed and a new spot (Rf = 0.55) was detected. The mixture poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mLx3). The combined organic phase was washed with brine (5 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by perp_TLC (PE:EA = 10 : 1) and perp_HPLC (column: Phenomenex luna C18150x25 mmx 10um;mobile phase: [water (FA) -ACN];B%: 70%- 100%, 2 min). KNA-001 (40.8 mg, 119 μmol, 24.8 % yield, 99.8% purity) was obtained as off-white solid, checked by LCMS (EW32982-52-P1A2), HPLC (EW32982-52-P1A3), SFC (EW32982-52-P1A) and NMR (EW32982-52-P1A). LCMS: MS (ESI) Retention time: 1.105 min (M+H)+= 343.2, EW32982 - 52-P1A.1H NMR (400 MHz, CDCl3) δ = 6.53 - 6.19 (m, 2H), 5.98 (br d, J = 1.3 Hz, 1H), 5.60 (br s, 1H), 4.74 - 4.53 (m, 3H), 3.83 (br d, J = 8.6 Hz, 1H), 2.39 (dt, J = 3.6, 10.8 Hz, 1H), 2.31 - 2.17 (m, 1H), 2.16 - 2.06 (m, 1H), 1.90 - 1.74 (m, 5H), 1.65 (s, 3H), 1.55 - 1.46 (m, 2H), 1.28 - 1.13 (m, 8H), 1.08 - 0.92 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H)General procedure for preparation of compound 2 for KNA-002

[0296] To a solution of compound 1 (5.00 g, 39.00 mmol, 1.00 eq) in THF (100 mL) was added MeMgBr (3.0 M, 15.6 mL, 1.20 eq) at 0 °C, the mixture was stirred at 35 °C for 2 hr. TLC (PE : EA = 20:1) showed the reactant 1 was consumed and a new spot (Rf = 0.5) was detected. The mixture was cooled to 0 °C and water (100 mL) was added slowly, followed by aqueous saturated NH4Cl (200 mL) to dissolve the precipitate. The organic layer was separated. The aqueous layer was extracted with diethyl ether (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 - 200 mesh silica gel, Petroleum ether / Ethyl acetate = 50 / 1, 10 / 1). Compound 2 (2.2 g, 15.3 mmol, 39.1% yield) was obtained as Colorless oil, checked1.52 - 1.42 (m, 2H), 1.36 - 1.26 (m, 8H), 1.21 (s, 6H), 0.95 - 0.82 (m, 3H)

[0297] To a solution of compound 2 and compound 3 was warmed to 50 °C with stirring to effect solution, then the mixture was cooled to 0 °C and was added methanesulfonic acid (2.40 g, 25.0 mmol, 1.78 mL, 3.60 eq), The mixture was stirred at 0 °C for 3 h, allowed to warm to 25 °C and stirred for 12 h. LCMS (EW32982-81-P1A) and TLC (PE:EA = 3:1) showed the reactant 1 was consumed and a new spot (Rf = 0.48) was detected. The reaction mixture was poured onto ice, extracted with DCM (50 x 3), and the extracts were washed with water, saturated aqueous NaHCO3 (30 x 3 mL) and dried (NaSO4). The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 15 / 1, 5 / 1). compound 4 (1.3 g, 4.64 mmol, 66.88% yield) was obtained as yellow oil, checked by NMR (EW32982-81-P1A). LCMS: MS (ESI) Retention time: 1.011 min (M+H)+= 281.2, EW32982-81-P1A.1H NMR (400 MHz, CDCl3) δ = 6.54 (s, 2H), 5.50 - 5.28 (m, 1H), 3.90 (s, 6H), 1.62 - 1.46 (m, 3H), 1.27 (s, 6H), 1.25 - 1.15 (m, 5H), 1.11 - 0.99 (m, 2H), 0.85 (t, J = 6.9 Hz, 3H)

[0298] To a solution of compound 4 (1 g, 3.57 mmol, 1 eq) in DCM (10 mL) was added Py (705.24 mg, 8.92 mmol, 719.63 μL, 2.5 eq), the mixture was added Tf2O (1.21 g, 4.28 mmol, 706 μL, 1.20 eq) at 0 °C, then mixture was stirred at 25 °C for 12 hr. LCMS (EW32982-85- P1A) and TLC (PE:EA = 5 :1) showed the reactant 1 was consumed and a new spot (Rf = 0.65) was detected. The residue was poured into water (10 mL). The aqueous phase wasextracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100- 200 mesh silica gel, Petroleum ether / Ethyl acetate = 30 / 1, 5 / 1). compound 5 (1.20 g, 2.91 mmol, 81.6 % yield) was obtained as Colorless oil, checked by NMR (EW32982-85-P1A). LCMS: MS (ESI) Retention time: 1.142 min (M+H)+= 413.1, EW32982-85-P1A.1H NMR (400 MHz, CDCl3) δ = 6.56 (s, 2H), 3.89 (s, 6H), 1.61 - 1.55 (m, 2H), 1.29 (s, 6H), 1.27 - 1.17 (m, 6H), 1.12 - 1.01 (m, 2H), 0.86 (t, J = 6.8 Hz, 3H) General procedure for preparation of compound 5 for KNA-002

[0299] To a solution of compound 5 (600 mg, 1.45 mmol, 1.00 eq), Et3N (368 mg, 3.64 mmol, 506 μL, 2.50 eq) in MeOH (6 mL) was added Pd(OH)2 (44.9 mg, 160 μmol, 50% purity, 0.11 eq), the mixture was stirred at 25 °C for 12 hr. LCMS (EW32982- 89-P1A) showed the reactant 1 was consumed and desired mass was detected. The mixture was filtered with celatom and concentrated in vacuum. The residue was taken the next step and without other purification. Compound 6 (384 mg, 1.45 mmol, 99.84% yield) was obtained as Colorless oil. LCMS: MS (ESI) Retention time: 1.104 min (M+H)+= 265.2, EW32982-89- P1A

[0300] To a solution of compound 6 (384 mg, 1.45 mmol, 1.00 eq) in DCM (4 mL) was added BBr3 (1.09 g, 4.36 mmol, 420 μL, 3.00 eq) in DCM (4 mL) at -78 °C, and the mixture was stirred at 25 °C for 12 hr. LCMS (EW32982-92-P1A) and TLC (PE:EA = 3 : 1) showedthe reactant 1 was consumed and a new spot (Rf = 0.45) was detected. The mixture was poured into ice aq. NaHCO3 (10 mL). The aqueous phase was extracted with ethyl acetate (20 mLx3). The combined organic phase was washed with brine (15 mLx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 15 / 1, 2 / 1). compound 7 (200 mg, 846 μmol, 58.3 % yield) was obtained as white solid, checked by NMR (EW32982-92-P1A). LCMS: MS (ESI) Retention time: 0.916 min (M+H)+= 237.2, EW32982-92-P1A.1H NMR (400 MHz, CDCl3) δ = 6.39 (d, J = 2.3 Hz, 2H), 6.18 (t, J = 2.2 Hz, 1H), 4.63 (s, 2H), 1.57 - 1.49 (m, 2H), 1.31 - 1.16 (m, 12H), 1.12 - 1.00 (m, 2H), 0.86 (t, J = 6.9 Hz, 3H). General procedure for preparation of KNA-002

[0301] To a solution of silver;hexafluoroantimony (1 -) (29.08 mg, 84.62 μmol, 0.1 eq) in DCE (2 mL) was added compound 8 (193.23 mg, 1.27 mmol, 1.5 eq), then the mixture was added compound 7 (200 mg, 846.21 μmol, 1 eq), the mixture was stirred at 20 °C for 12 hr under dark. LCMS (EW32982-94-P1A) and TLC (PE:EA = 5 : 1, Rf = 0.65) showed the reactant 1 was consumed and a new spot was detected. The mixture poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mLx3). The combined organic phase was washed with brine (5 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by perp_TLC (PE:EA = 10 : 1) and perp_HPLC (column: Phenomenex Synergi C18150x25 mmx 10um;mobile phase: [water (FA) -ACN];B%: 80%-100%, 10min). KNA-002 (198.41 mg, 533.82 μmol, 63.08% yield, 99.7% purity) was obtained as Colorless gum, checked by LCMS (EW32982-94-P1A2), HPLC (EW32982-94-P1A3), SFC (EW32982-94-P1A) and NMR (EW32982-94-P1A). LCMS: MS (ESI) Retention time: 1.115 min (M+H)+= 371.3, EW32982-94-P1A.1H NMR (400 MHz, CDCl3) δ = 6.55 - 6.20 (m, 2H), 6.12 - 5.84 (m, 1H), 5.60 (br s, 1H), 4.75 - 4.50 (m, 3H), 3.83 (br d, J = 10.0 Hz, 1H), 2.39 (dt, J = 3.5, 10.8 Hz, 1H), 2.32 - 2.18 (m, 1H), 2.16 - 2.05 (m, 1H), 1.91 - 1.75 (m, 5H), 1.65 (s, 3H), 1.53 - 1.45 (m, 2H), 1.29 - 1.14 (m, 12H), 1.08 - 0.95 (m, 2H), 0.85 (br t, J = 6.8 Hz, 3H)Synthesis of KNA-003

[0302] To a solution of Compound 1 (3 g, 23.79 mmol, 1 eq) in DMF (15 mL) was added K2CO3(3.62 g, 26.17 mmol, 1.1 eq) and Compound 2 (3.26 g, 23.79 mmol, 2.57 mL, 1 eq). The mixture was stirred at 50 °C for 12 h. TLC (PE:EA = 1:1) indicated Reactant 1 was consumed and completely one new spot (Rf = 0.5) formed. The residue was poured into water (50 mL) and 1N HCl (40mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (100 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1). Compound 3 (1.42 g, 7.79 mmol, 32.76% yield) was obtained as a brown oil, checked by1H NMR (EW33026-10- P1A).1H NMR (400 MHz, CHLOROFORM-d) δ = 6.05 - 5.96 (m, 3H), 3.89 (t, J = 6.5 Hz, 2H), 1.79 - 1.68 (m, 2H), 1.53 - 1.42 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). General procedure for preparation of compound KNA-003

[0303] To a solution of silver;hexafluoroantimony (1 -) (87.55 mg, 254.79 μmol, 0.1 eq) in DCE (3 mL) was added Compound 4 (581.80 mg, 3.82 mmol, 1.5 eq), then the mixture was added Compound 3 (464.26 mg, 2.55 mmol, 1 eq), the mixture was stirred at 20 °C for 12 hr under dark. LC-MS (EW33026-14-P1A) showed Reactant 1 was consumed completely and desired was detected. Filter and remove the ether on a rotary evaporator. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (NH4HCO3) -ACN];B%: 50%-80%, 9min). Compound KNA-003 (32.51 mg, 102.74 μmol, 4.03% yield, 100% purity) was obtained as an off-white solid, checked by 1HNMR (EW33026-14-P1B2), LCMS (EW33026-14-P1B5), HPLC (EW33026-14-P1B4), SFC (EW33026-14-P1B2). LCMS: MS (ESI) Retention time: 0.961 min (M+1) = 317.2, EW33026-14-P1B5.

[0304] 1H NMR (400 MHz, CDCl3) δ = 6.17 - 5.87 (m, 3H), 5.56 (br s, 1H), 4.94 (br s, 1H), 4.68 (s, 1H), 4.58 (s, 1H), 3.93 - 3.74 (m, 3H), 2.37 (dt, J = 3.5, 10.8 Hz, 1H), 2.30 - 2.17 (m, 1H), 2.14 - 2.04 (m, 1H), 1.89 - 1.63 (m, 10H), 1.46 (sxt, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H)

[0305] The synthesis steps of KNA-004 are similar to KNA-003.

[0306] To a solution of silver;hexafluoroantimony (1 -) (81.71 mg, 237.79 μmol, 0.1 eq) in DCE (3 mL) was added Compound 4 (542.99 mg, 3.57 mmol, 1.5 eq), then the mixture was added Compound 3A (500 mg, 2.38 mmol, 1 eq), the mixture was stirred at 20 °C for 12 hr under dark. LC-MS (EW33026- 15-P1A) showed Reactant 3 was consumed completely and desired was detected. Filter and remove the ether on a rotary evaporator. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 70%-100%, 10min). Compound KNA-004 (74.14 mg, 206.61 μmol, 8.69% yield, 96% purity) was obtained as an off-white solid, checked by1H NMR (EW33026-15-P1A1), LCMS (EW33026-15-P1B2), HPLC (EW33026-15-P1B1), SFC (EW33026-15-P1A1). LCMS: MS (ESI) Retention time: 1.020min (M+1) = 345.3,EW33026-15-P1B2.1H NMR (400 MHz, CDCl3) δ = 6.18 - 5.88 (m, 3H), 5.57 (br s, 1H), 4.94 (br s, 1H), 4.69 (d, J = 1.3 Hz, 1H), 4.60 (s, 1H), 3.93 - 3.76 (m, 3H), 2.39 (dt, J = 3.6, 10.9 Hz, 1H), 2.31 - 2.19 (m, 1H), 2.17 - 2.05 (m, 1H), 1.87 - 1.64 (m, 10H), 1.51 - 1.26 (m, 6H), 0.92 (br t, J = 6.8 Hz, 3H) Synthesis of KNA-005

[0307] The synthesis steps of KNA-005 are similar to KNA-007 and KNA-008.

[0308] To a solution of silver;hexafluoroantimony (1 -) (28.30 mg, 82.36 μmol, 0.1 eq) in DCE (1 mL) was added Compound 8, then the mixture was added Compound 7, the mixture was stirred at 20 °C for 12 hr under dark. LC-MS (EW33026- 28-P1A) showed Reactant 1 was consumed completely and 36% of desired mass was detected. The aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with brine (100mL*N), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um;mobile phase: [water (FA) -ACN];B%: 68%-98%, 10min). Compound KNA- 005 was obtained as a white solid, checked by HPLC (EW33026 -28-P1A3), LCMS (EW33026-28- P1A2), SFC (EW33026-28-P1A1) and HNMR (EW33026-28-P1A). LCMS: MS (ESI) Retention time: 1.094 min (M+1) = 329.2, EW33026-28-P1A2.1H NMR (400 MHz, CDCl3) δ = 6.39 - 6.11 (m, 2H), 6.08 - 5.81 (m, 1H), 5.60 (br s, 1H), 4.68 (s, 1H), 4.57 (s, 2H), 3.92 - 3.74 (m, 1H), 2.56 - 2.45 (m, 1H), 2.39 (dt, J = 3.6, 10.7 Hz, 1H), 2.31 - 2.18 (m, 1H), 2.15 - 2.06 (m, 1H), 1.88 - 1.76 (m, 5H), 1.65 (s, 3H), 1.53 - 1.45 (m, 2H), 1.32 - 1.10 (m, 7H), 0.85 (t, J = 7.1 Hz, 3H).

[0309] To a solution of KOH (11.51 g, 205.15 mmol, 1.5 eq) was added hexan- 2 -one (13.70 g, 136.77 mmol, 16.91 mL, 1 eq) in H2O (50 mL) and MeOH (500 mL) at 0 °C over 30 min, and Compound 1 (25 g, 150.45 mmol, 1.1 eq) was added slowly to the mixture, and the mixture was stirred at 25 °C for 12 h. LC-MS (EW33026-27-P1A) showed 45% of desired compound was detected. TLC (PE:EA = 10:1) indicated Reactant 1 was one new spots (Rf = 0.3) formed. The mixture was extracted with EtOAc (300 mL). The recombined organic phases were washed with water (200mL), brine (100mL),. Dried (Na2SO4) and evaporated at reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% FA condition). Compound 2 (20 g, 76.52 mmol, 55.95% yield, 95% purity) was obtained as a white solid, checked by LCMS (EW33026-27-P1A1) and HNMR (EW33026-27-P1A1). LCMS: MS (ESI) Retention time: 0.974 min (M+1) + = 249.2, EW33026-27-P1A1.NMR (400 MHz, DMSO-d6) δ = 7.53 (d, J = 16.3 Hz, 1H), 7.08 - 6.71 (m, 3H), 6.56 (br s, 1H), 3.78 (s, 6H), 2.68 (t, J = 7.3 Hz, 2H), 1.62 - 1.46 (m, 2H), 1.40 - 1.22 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H)

[0310] To a mixture of chloro (trimethyl) silane (7.88 g, 72.49 mmol, 9.20 mL, 1.2 eq) inAlMe3(2 M, 33.22 mL, 1.1 eq) were added bromocopper (866.53 mg, 6.04 mmol, 183.98 μL, 0.1 eq) was stirred for 5 mins at 0 °C. And then Compound 2 (15 g, 60.41 mmol, 1 eq) in THF (4 mL) was added dropwise at 0°C.. The mixture was stirred for 30 mins at 20°C. LC- MS (EW33026-31-P1A) showed 51% of desired compound was detected. TLC (PE:EA = 5:1) indicated Reactant 1 was consumed completely and three new spots (Rf1= 0.35, Rf2= 0.5, Rf3 = 0.65) formed. The aqueous phase was extracted with ethyl acetate (200 mL*N). The combined organic phase was washed with brine (200 mL*N), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1). The crude product was purified by reversed-phase HPLC (0.1% FA condition). Compound 3 (400 mg, 1.50 mmol, 11.62% yield, 99% purity) was obtained as a yellow oil. Which was confirmed by HNMR (EW33026-30-P1A3) and LCMS (EW33026-30-P1A3). LCMS: MS (ESI) Retention time: δ ,

[0311] To a mixture of Compound 3 (4 g, 15.13 mmol, 1 eq) and KOH (4.24 g, 75.65 mmol, 5 eq) in DIETHYLENE GLYCOL (45 mL) was added hydrazine;hydrate (4.97 g, 99.32 mmol, 4.83 mL, 6.56 eq) at 0 °C under N2. The mixture was stirred at 145 °C for 4 hours. TLC (PE:EA = 10:1) showed the reactant 1 (Rf = 0.3) remained and two new point (Rf = 0.6,0.3) was formed. To the mixture was poured 100 mL H2O, The aqueous phase was extracted with MTBE (80 mL*3). The combined organic phase was washed with brine (100 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. And the aqueous phase was adjust pH = 7 and discarded. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1). Compound 4 (1.2 g, 4.79 mmol, 31.68% yield) -

[0312] To a solution of Compound 4 (500 mg, 2.00 mmol, 1 eq) in DCM (5 mL) was added a solution of BBr3 (1.50 g, 5.99 mmol, 577.26 μL, 3 eq) in DCM (5 mL) at - 68 °C, the mixture was stirred at 25 °C for 12 hr. LCMS (EW33026 -32-P1A) and TLC (PE:EA = 3:1) showed the reactant 1 was consumed and a new spot (Rf = 0.35) was detected. The residue was poured into water (10 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (10 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 1 / 1). Compound 5 (400 mg, 1.78 mmol, 89.19% yield, 99% purity) was obtained as Colorless oil, checked by LCMS (EW33026-32-P1A1) and HNMR (EW33026-32-P1A1). LCMS: MS (ESI) Retention time: 0.952 min (M+1) + = 223.2, EW33026-32-P1A1.1H NMR (400 MHz, CDCl3) δ = 6.47 - 5.93 (m, 3H), 5.10 (s, 2H), 2.55 (sxt, J = 7.0 Hz, 1H), 1.61 - 1.40 (m, 2H), 1.27 - 1.12 (m, 11H), 0.87 (t, J = 6.8 Hz, 3H).

[0313] To a solution of silver;hexafluoroantimony (1 -) (61.82 mg, 179.92 μmol, 0.1 eq) in DCE (8 mL) was added Compound 6 (342.37 mg, 2.25 mmol, 1.25 eq), then the mixture was added Compound 5 (400.00 mg, 1.80 mmol, 1 eq), the mixture was stirred at 20 °C for 12 hr under dark. LCMS (EW33026-33-P1A1) and TLC (PE:EA = 20:1) showed the reactant 1 was consumed and a new spot (Rf = 0.35) was detected. The aqueous phase was extracted with DCM (50 mL). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 50 / 1, 10 / 1). The residue was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm*30mm, 10um) ;mobile phase: [0.1%NH3H2O MEOH];B%: 15%-15%, 2.5min).

[0314] KNA-007 (45.45 mg, 119.83 μmol, 28.48% yield, 94% purity) was obtained as yellow oil, checked by LCMS (EW33026-34-P1A1), HPLC (EW33026-34-P1A5), HNMR (EW33026-34-P1A5) and SFC (EW33026-34-P1A1). LCMS: MS (ESI) Retention time: 1.095 min (M+1) + = 357.2, EW33042-34-P1A1.1H NMR (400 MHz, CDCl3) δ = 6.47 - 5.87 (m, 3H), 5.60 (br s, 1H), 5.08 - 4.48 (m, 3H), 3.86 (br d, J = 8.8 Hz, 1H), 2.65 - 2.34 (m, 2H), 2.32 - 2.18 (m, 1H), 2.16 - 2.03 (m, 1H), 1.89 - 1.74 (m, 5H), 1.66 (s, 3H), 1.53 - 1.44 (m, 2H), 1.32 - 1.14 (m, 11H), 0.87 (br t, J = 6.7 Hz, 3H).

[0315] KNA-008 (82.3 mg, 228.52 μmol, 54.32% yield, 99% purity) was obtained as yellow oil, checked by LCMS (EW33026-34-P1A2), HPLC (EW33026-34-P1A4), HNMR (EW33026-34-P1A4) and SFC (EW33026-34-P1A2). LCMS: MS (ESI) Retention time: 1.098 min (M+1)+ = 357.2, EW33042-34-P1A2.1H NMR (400 MHz, CDCl3) δ = 6.42 - 5.88 (m, 3H), 5.60 (br s, 1H), 5.11 - 4.41 (m, 3H), 3.97 - 3.77 (m, 1H), 2.62 - 2.34 (m, 2H), 2.33 - 2.17 (m, 1H), 2.16 - 2.05 (m, 1H), 1.93 - 1.75 (m, 5H), 1.67 (s, 3H), 1.57 - 1.41 (m, 2H), 1.34 - 1.05 (m, 11H), 0.87 (t, J = 6.8 Hz, 3H)

[0316] To a solution of compound 1 (9.37 g, 23.8 mmol, 1.30 eq) in THF (30 mL) was added tBuOK (2.63 g, 23.5 mmol, 1.30 eq) at 0 °C, then the mixture was stirred at 30 min, the mixture was added a solution of compound 5 (3 g, 18.1 mmol, 1.00 eq) in THF (10 mL) at 0 °C, the mixture was stirred at 30 °C for 12 hr under N2. LCMS (EW32982- 62-P1A) and TLC (PE:EA = 5 : 1, Rf = 0.65) showed the reactant 1 was consumed and desired mass was detected. The mixture was filtered and concentrated in vacuum, then the residue was poured into water (300 mL). The aqueous phase was extracted with ethyl acetate (300 mLx3). Thecombined organic phase was washed with brine (100 mLx3), dried with anhydrous Na2SO4,filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0, 10 / 1). Compound 2 (3.5 g, 17.0 mmol, 94.0 % yield) was obtained as Colorless oil, checked by NMR (EW32982-62-P1A). LCMS: MS (ESI) Retention time:0.958 min (M+H)+= 207.1, EW32982-62-P1A.1H NMR (400 MHz, CDCl3) δ = 6.57 - 6.20 (m, 4H), 5.67 (td, J = 7.2, 11.7 Hz, 1H), 3.81 (s, 6H), 2.33 (dq, J = 1.7, 7.4 Hz, 2H), 1.62 - 1.40 (m, 2H), 1.06 - 0.87 (m, 3H)

[0317] To a solution of silver;hexafluoroantimony (1 -) (333.16 mg, 969.56 μmol, 0.1 eq) in DCE (20 mL) was added compound 3 (2.21 g, 14.54 mmol, 1.5 eq), then the mixture was added compound 2 (2.0 g, 9.70 mmol, 1.0 eq), the mixture was stirred at 20 °C for 12 hr under dark. LCMS (EW32982-65-P1A) and TLC (PE:EA = 5 : 1) showed the reactant 1 was consumed and a new spot (Rf = 0.68) was detected. The mixture poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mLx3). The combined organic phase was washed with brine (15 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = X / 1, N / 1) and The crude product was purified by reversed-phase HPLC (0.1% FA condition). compound 4 was obtained as colorless oil, checked by LCMS (EW32982-65-P1A3). LCMS: MS (ESI) Retention time: 1.179 min (M+H)+= 341.2, EW32982-65-P1A. LCMS: MS (ESI) Retention time: 1.126 min (M+H)+= 341.2, EW32982-65-P1A3. General procedure for preparation of KNA-009

[0318] To a solution of compound 4 (739.11 mg, 2.17 mmol, 1 eq) in anhydrous THF (6 mL) under argon at 0 °C was added iodo (methyl) magnesium (3 M, 3.62 mL, 5 eq) dropwise and the solution was heated to 160 °C for 1.5 h under reduced pressure (house vacuum). LCMS (EW32982-76-P1A) and TLC (PE:EA = 5 : 1) showed the reactant 1 was consumed and a new spot (Rf = 0.65) was detected. The residue was poured into aq. NH4Cl (20 mL). The aqueous phase was extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by perp_TLC (PE:EA = 10 : 1, Rf = 0.4), then the residue was purified by perp_HPLC (column: Phenomenex Synergi C18150x25 mmx 10um;mobile phase: [water (FA) -ACN];B%: 62%-92%, 10min). KNA-009 (121.39 mg, 384.63 μmol, 17.72% yield, 99.0% purity) was obtained as yellow oil, checked by LCMS (EW32982-76-P1A5), HPLC (EW32982-76-P1A6), SFC (EW32982-76-P1A), NMR (EW32982-76-P1A1) and speacial_NMR (EW32982-76-P1A2). LCMS: MS (ESI) Retention time: 0.937 min (M+H)+= 313.2, EW32982-76-P1A5.(400 MHz, CDCl3) δ = 6.55 - 6.17 (m, 3H), 6.05 (br s, 1H), 5.73 - 5.45 (m, 2H), 4.91 (br s, 1H), 4.67 (s, 1H), 4.58 (s, 1H), 4.02 - 3.83 (m, 1H), 2.44 (dt, J = 3.6, 10.8 Hz, 1H), 2.37 - 2.19 (m, 3H), 2.18 - 2.04 (m, 1H), 1.92 - 1.76 (m, 5H), 1.69 (s, 3H), 1.47 (sxt, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H) Synthesis of KNA-010

[0319] The synthesis steps of KNA-009 and KNA-010 are similar.

[0320] To a solution of compound 5 (800 mg, 2.17 mmol, 1 eq) in anhydrous THF (6 mL) under argon at 0 °C was added iodo (methyl) magnesium (3 M, 3.62 mL, 5 eq) dropwise and the solution was heated to 160 °C for 1.5 h under reduced pressure (house vacuum). LCMS (EW32982-75-P1A) and TLC (PE:EA = 5 : 1) showed the reactant 1 was consumed and a new spot (Rf = 0.65) was detected. The residue was poured into aq. NH4Cl (20 mL). The aqueous phase was extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by perp_TLC (PE:EA = 10 : 1), then the residue waspurified by perp_HPLC (column: Phenomenex Synergi C18150x25 mmx 10um;mobile phase: [water (FA) -ACN];B%: 72%-100%, 10min).

[0321] KNA-010 (40.8 mg, 120 μmol, 5.51% yield, 99.8% purity) was obtained as yellow oil, checked by LCMS (EW32982-75-P1A5), HPLC (EW32982-75-P1A6), SFC (EW32982- 75-P1A), NMR (EW32982-75-P1A1) and speacial_NMR (EW32982-75-P1A3). LCMS: MS (ESI) Retention time: 0.982 min (M+H)+= 341.2, EW32982 - 75-P1A.1H NMR (400 MHz, CDCl3) δ = 6.52 - 6.18 (m, 3H), 6.11 - 5.93 (m, 1H), 5.67 - 5.52 (m, 2H), 4.77 - 4.52 (m, 3H), 3.95 - 3.82 (m, 1H), 2.43 (dt, J = 3.6, 10.9 Hz, 1H), 2.36 - 2.20 (m, 2H), 2.18 - 2.07 (m, 2H), 1.92 - 1.74 (m, 5H), 1.68 (s, 3H), 1.47 (sxt, J = 7.4 Hz, 2H), 1.42 - 1.24 (m, 4H), 0.94 (t, J = 7.4 Hz, 3H)

[0322] To a solution of Compound 2 (60.51 g, 157.05 mmol, 1 eq) in THF (150 mL) was added t-BuOK (22.91 g, 204.17 mmol, 1.3 eq) at 0 °C under N2, the reaction mixture was stirred at 0 °C for 1 hr, then Compound 1 (50 g, 157.05 mmol, 1 eq) in THF (150 mL) was added. The reaction mixture was allowed to heat at 30 °C for 4 hr. TLC (PE:EA = 5:1) showed that the reactant 1 (Rf = 0.4) was consumed and a new point (Rf = 0.6) was formed. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with H2O 500 mL and extracted with EA 1500 mL (500 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ethergradient @ 150 mL / min). Compound 3 (50 g, 143.71 mmol, 91.50% yield, 99.0% purity) was obtained as colorless oil, which was confirmed by LCMS (EW32981-2-P1B). LCMS: MS (ESI) Retention time: 1.161 min, (M+H)+= 345.3.

[0323] To a solution of Compound 3 (50 g, 145.16 mmol, 1 eq) in MeOH (100 mL) and EA (500 mL) was added Pd / C (5 g, 10% purity). The reaction mixture was stirred at 25 °C for 12 hours under H2(15 psi). TLC (PE:EA = 5:1) showed that the reactant (Rf = 0.6) and a new point (Rf = 0.4) formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 3 / 1). Compound 4 (19 g, 112.82 mmol, 77.72% yield, 98.7% purity) was obtained as brown oil, which was confirmed by LCMS (EW32981- 3-P1A1). LCMS: MS (ESI) Retention time: 0.754 min, (M+H)+= 167.1.General procedure for preparation of compound KNA-011

[0324] To a solution of silver;hexafluoroantimony (1 -) (103.36 mg, 300.81 umol, 0.1 eq)in DCE (3 mL) was added Compound 5 (572.42 mg, 3.76 mmol, 1.25 eq) and Compound 4 (500 mg, 3.01 mmol, 1 eq). The reaction mixture was stirred at 20 °C for 12 hr. LCMS (EW32981-7-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was diluted with H2O 15 mL and extracted with EA 60 mL (20 mL *3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40 mm* 15um;mobile phase: [water (FA) -ACN];B%: 62%-92%, 10min). KNA-011 (100 mg, 330.52 umol, 10.99% yield, 99.3% purity) was obtained as yellow oil. LCMS: MS (ESI) Retention time: 0.911 min (M+H)+= 301.2.(400 MHz, CDCl3) δ = 6.39 - 5.89 (m, 3H), 5.58 (br s, 1H), 4.98 - 4.60 (m, 2H), 4.57 (s, 1H), 3.85 (br s, 1H), 2.50 - 2.36 (m, 3H), 2.30 - 2.16 (m, 1H), 2.15 - 2.05 (m, 1H), 1.88 - 1.76 (m, 5H), 1.67 (s, 3H), 1.59 - 1.49 (m, 2H), 1.33 (qd, J = 7.4, 14.8 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H) Synthesis of KNA-012

[0325] To a solution of KNA-011 (70 mg, 233.00 μmol, 1 eq) in MeOH (1 mL) was added Pd / C (50 mg, 10% purity). The reaction mixture was stirred at 25 °C for 12 hr under H2 (50 psi). LCMS (EW32981-12-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenexluna C18150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 62%-92%, 2min). KNA-012 (65 mg, 212.21 μmol, 91.08% yield, 99.4% purity) was obtained as yellow oil. LCMS: MS (ESI) Retention time: 0.977 min (M+H)+= 305.2.1H NMR (400 MHz, CDCl3) δ = 6.22 - 6.09 (m, 2H), 4.68 - 4.59 (m, 2H), 3.01 - 3.00 (m, 1H), 3.33 - 2.92 (m, 1H), 2.50 - 2.40 (m, 2H), 2.26 - 1.95 (m, 2H), 1.83 - 1.48 (m, 8H), 1.39 - 1.32 (m, 2H), 1.15 - 1.03 (m, 2H), 0.96 - 0.89 (m, 5H), 0.85 (d, J = 6.9 Hz, 3H), 0.79 - 0.66 (m, 3H).General procedure for preparation of compound 2 for KNA-016

[0326] To a solution of Compound 1 (4 g, 26.28 mmol, 1 eq) in THF (40 mL) and H2O (10 mL) was added Hg(OAc)2(8.39 g, 26.33 mmol, 1 eq) along with AcOH (0.1 mL) at 25 °C and stirred at 25 °C for 1 h. The mixture was quenched with NaBH4 (1.39 g, 36.75 mmol, 1.40 eq) in NaOH (40 mL) was added to the mixture at 0 °C and the mixture was stirred at 10 min at 25 °C. TLC (PE:EA = 1:1) showed the reactant 1 (Rf = 0.7) remained and a new point (Rf = 0.4) was formed. The reaction mixture was extracted with EA (100 mL x3), and the combined organic phase was washed with brine (200 mL x 1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. And All the aqueous phase was added Na2S (5 g) and stirred at 25 °C for 24 h then poured. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1), Compound 2 (350 mg, 2.06 mmol, 7.82% yield) was obtained as colorless oil which was confirmed by HNMR (EW33042-22- P1A2).1H NMR (400 MHz, CDCl3) δ = 5.94 - 5.85 (m, 1H), 5.83 - 5.73 (m, 1H), 2.12 - 2.05(m, 1H), 1.94 - 1.86 (m, 1H), 1.79 - 1.72 (m, 1H), 1.59 (br d, J = 4.5 Hz, 2H), 1.56 - 1.49 (m, 2H), 1.31 - 1.28 (m, 3H), 1.26 (s, 3H), 1.20 (s, 3H). General procedure for preparation of compound KNA-016

[0327] The mixture of Compound 2 (200 mg, 1.17 mmol, 1 eq) , Compound 3 (292.90 mg, 1.76 mmol, 1.5 eq) ,[(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (27.29 mg, 117.48 umol, 0.1 eq) ,4A MOLECULAR SIEVE (500 mg) in DCM (4 mL) was stirred at 30 °C for 1.5 h. LCMS(EW33042-24-P1A) showed the desired compound in 220 nm. The mixture was filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (NH4HCO3) - ACN];B%: 55%- 75%, 9min) and the residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50*10um;mobile phase: [Hexane-EtOH (0.1% NH3. H2O) ];B%: 1%- 15%, 15min). LCMS: MS (ESI) Retention time: 0.998 min (M-18) = 315.2, EW33042-24- P1A. KNA- 016 (69.92 mg, 208.68 μmol, 33.23% yield, 99.23% purity) was obtained as yellow gum, which was confirmed by LCMS (EW32981 -85-P1B3), HPLC (EW32981-85- P1C), SFC (EW32981-85-P1D) and HNMR (EW32981-86-P1E). LCMS: MS (ESI) Retention time: 1.107 min (M-H)- = 331.2.1H NMR (400 MHz, CDCl3) δ = 7.81 (br s, 1H), 6.47 (br s, 1H), 6.28 (br s, 2H), 5.66 (br d, J = 1.6 Hz, 1H), 3.88 (br d, J = 1.3 Hz, 1H), 2.75 (br s, 1H), 2.48 - 2.38 (m, 2H), 2.20 - 2.06 (m, 2H), 2.02 - 1.89 (m, 2H), 1.81 (s, 3H), 1.70 (qd, J = 6.3, 12.9 Hz, 1H), 1.56 (quin, J = 7.5 Hz, 2H), 1.36 - 1.28 (m, 4H), 1.24 (s, 6H), 0.89 (t, J = 6.8 Hz, 3H).Synthesis of KNA-019General procedure for preparation of compound 2 for KNA-019

[0328] The Compound 1 (5 g, 27.74 mmol, 1 eq) and NaHCO3 (6.99 g, 83.22 mmol, 3.24 mL, 3 eq) was dissolved in MTBE (15 mL) and H2O (40 mL), the mixture was cooled to 0 °C and I2 (14.08 g, 55.48 mmol, 11.18 mL, 2 eq) in MTBE (25 mL) was added dropwise. The reaction was stirred at 0 °C for 1 h. Then, Na2SO3(6.99 g, 55.48 mmol, 2 eq) was added to the mixture slowly. The mixture was stirred at 30 °C for 30 min. TLC (PE:EA = 3:1) showed the reactant 1 (Rf = 0.3) was consumed and a new point (Rf = 0.5) was formed. The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (100 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. Filtered and concentrated in vacuum, and without any purification. Compound 2(11 g, crude) was obtained as brown oil which was confirmed by LCMS (EW33042-6-P1A1). LCMS: MS (ESI) Retention time: 0.878 min (M+2)+ = 307.1, EW33042-6-P1A1.General procedure for preparation of compound 3 for KNA-019

[0329] The mixture of 2 -iodo- 5-pentyl-benzene-1, 3-diol (8.49 g, 27.73 mmol, 1 eq), K2CO3(11.50 g, 83.20 mmol, 3 eq), MeI (11.81 g, 83.20 mmol, 5.18 mL, 3 eq) in DMF (20 mL) was stirred at 25 °C for 3 h. LCMS (EW33042-9-P1A1) showed the desired compound in 220 nm. The residue was poured into water (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (300 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by reversed-phase HPLC (0.1% FA condition). Compound 3 (5.1 g, 15.26 mmol, 55.03% yield) was obtained as yellow oil which was confirmed by H NMR (EW33042-9-P1B). LCMS: MS (ESI) Retention time: 1.012 min (M+2)+ = 335.0, EW33042-9-P1B.1H NMR (400 MHz, CDCl3) δ = 6.35 (s, 2H), 3.89 (s, 6H), 2.71 - 2.47 (m, 2H), 1.70 - 1.53 (m, 2H), 1.41 - 1.26 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0330] To a solution of Compound 3 (5 g, 14.96 mmol, 1 eq) in THF (50 mL) cooled to - 78 °C was added dropwise n-BuLi (2.5 M, 6.58 mL, 1.1 eq), after the precipitation of a white solid, 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.06 g, 16.46 mmol, 3.36 mL, 1.1 eq) was added at once. The reaction mixture was allowed to warm up slowly to 25 °C for 2 hr. LCMS (EW32981-20-P1A) that the reactant was remained and desired compound observed. TLC (PE:EA = 4:1) showed that the reactant (Rf = 0.5) was remained and a new point (Rf = 0.45) formed. The reaction mixture was quenched with 1 N HCl to pH = 5. The residue was diluted with H20100 mL and extracted with EA 600 mL (200 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated underreduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ethergradient @ 60 mL / min). Compound 4 (3.1 g, 9.27 mmol, 61.99% yield) was obtained as colorless oil, which was confirmed by HNMR (EW32981-20-P1C). LCMS MS ESI R t ti ti 0966 i M+1 + = 3353 EW3298120 P1A1H NMR .

[0331] To a solution of Compound 5 (10 g, 66.57 mmol, 1 eq) in DCM (60 mL) was added Py (13.16 g, 166.43 mmol, 13.43 mL, 2.5 eq), then the Tf2O (22.54 g, 79.88 mmol, 13.18 mL, 1.2 eq) was added dropwise at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 hours. TLC (PE:EA = 5:1) showed that the reactant (Rf = 0.3) was consumed and a new point (Rf = 0.6) formed. LCMS (EW25981-1-P1A) showed a main peak and need to go further with NMR was confirmed. The reaction mixture was partitioned between H2O 100 mL and DCM 100 mL. The organic phase was separated, washed with aq.1 M HCl, water, brine, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ethergradient @ 80 mL / min). Compound 6 (17 g, 60.22 mmol, 90.47% yield) was obtained as colorless oil, which was confirmed by HNMR (EW32981-1-P1A).NMR (400 MHz, CDCl3) δ = 7.25 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 3.23 (spt, J = 6.9 Hz, 1H), 2.34 (s, 3H), 1.23 (d, J = 6.9 Hz, 6H).

[0332] To a solution of Compound 6 (200 mg, 708.52 μmol, 1 eq) in dioxane (1 mL) was added Cs2CO3 (692.55 mg, 2.13 mmol, 3 eq), Pd(dppf) Cl2 (51.84 mg, 70.85 μmol, 0.1 eq) and Compound 4 (260.51 mg, 779.37 μmol, 1.1 eq). The reaction mixture was stirred at 100 °C for 12 hr. LCMS (EW32981-30-P1A) showed that the reactant 1 was consumed and desired compound observed. The reaction mixture was diluted with H2020 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25 mm* 10um;mobile phase: [water (FA) - ACN];B%: 90%-100%, 2min). LCMS: MS (ESI) Retention time: 1.100 min (M+1)+ = 341.3, EW32981-30-P1A. Compound 7 (60 mg, 173.92 μmol, 24.55% yield, 98.7% purity) was obtained as yellow oil, which was confirmed by LCMS (EW32981-30-P1B). LCMS: MS (ESI) Retention time: 1.132 min (M+1)+ = 341.2, EW32981-30-P1B. General procedure for preparation of compound KNA-019

[0333] To a solution of 2 -(2-isopropyl- 5-methyl-phenyl) -1, 3-dimethoxy-5-pentyl-benzene (60 mg, 176.21 μmol, 1 eq) in DCM (1 mL) was added BBr3(1 M, 881.06 μL, 5 eq) at - 10 °C, the reaction mixture was stirred at 25 °C for 12 hr. LCMS (EW32981-38-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was dilutedwith H2O 10 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 51%-81%, 7min). LCMS: MS (ESI) Retention time: 1.037 min (M+1)+ = 313.2, EW32981-38-P1A. KNA-019 (45 mg, 143.16 μmol, 81.24% yield, 99.4% purity) was obtained as yellow gum, which was confirmed by LCMS (EW32981-38-P1B), HPLC (EW32981-38-P1C), SFC (EW32981-38-P1D) and HNMR (EW32981-38-P1E). LCMS: MS (ESI) Retention time: 0.941 min (M+1)+ = 313.2, EW32981-38-P1B.1H NMR (400 MHz, CDCl3) δ = 7.62 (d, J = 8.1 Hz, 1H), 7.49 (br d, J = 8.9 Hz, 1H), 7.27 (s, 1H), 6.65 (s, 2H), 4.78 (s, 2H), 2.98 (spt, J = 6.8 Hz, 1H), 2.78 (t, J = 7.8 Hz, 2H), 2.57 (s, 3H), 1.87 (quin, J = 7.3 Hz, 2H), 1.64 - 1.53 (m, 4H), 1.34 (d, J = 6.9 Hz, 6H), 1.14 (br t, J = 6.6 Hz, 3H).

[0334] To a solution of Compound 1 (5 g, 31.65 mmol, 3.05 mL, 1 eq) in THF (100 mL) cooled to 0 °C, BF3. Et2O (4.94 g, 34.81 mmol, 4.30 mL, 1.1 eq) was added dropwise and stirred at 0 °C for 15 min. The reaction mixture was cooled to - 50 °C followed by dropwise addition of a THF solution of lithium;chloro (isopropyl) magnesium;chloride (1.3 M, 29.21 mL, 1.2 eq) and stirred at -50 °C for 30 min. Then 2, 3, 5, 6-tetrachloro-1, 4-benzoquinone (15.56 g, 63.29 mmol, 2 eq) was added and the mixture was warmed up to 25 °C and stirred for 2 hr. TLC (PE:EA = 4:1) showed that the reactant (Rf = 0.5) and a new point (Rf = 0.55) formed. The reaction mixture was quenched by addition aq. NaHCO3 to pH = 8 and extracted with EA 600 mL (200 mL * 3). The combined organic layers were dried over[Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ethergradient @ 50 mL / min). Compound 2 (3 g, 14.99 mmol, 47.38% yield, 100% purity) was obtained as brown oil, which was confirmed by LCMS (EW32981-10-P1A) and HNMR (EW32981-10-P1A). LCMS: MS (ESI) Retention time: 0.618 min (M+3)+ = 202.0, EW32981-10-P1A.1H NMR (400 MHz, CDCl3) δ = 8.65 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H), 7.21 (d, J = 5.0 Hz, 1H), 3.48 - 3.16 (m, 1H), 1.27 (d, J = 7.0 Hz, 6H)

[0335] To a solution of Compound 2 (200 mg, 999.62 μmol, 1 eq) in DME (1 mL) was added Cs2CO3 (977.09 mg, 3.00 mmol, 3 eq), Compound 3 (367.54 mg, 1.10 mmol, 1.1 eq) and Pd(PPh3)4(115.51 mg, 99.96 μmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 12 hr. LCMS (EW32981-37-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was diluted with H2020 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex C1875*30 mm*3um;mobile phase: [water (FA) -ACN];B%: 30%-60%, 7min). Compound 4 (130 mg, 397.00 μmol, 39.71% yield, 100% purity) was obtained as yellow oil, which was confirmed by LCMS (EW32981-37-P1B2). LCMS: MS (ESI) Retention time: 0.884 min (M+1)+ = 328.2, EW32981-37-P1A. LCMS: MS (ESI) Retention time: 0.777 min (M+1)+ = 328.2, EW32981-37-P1B2.General procedure for preparation of compound KNA-020

[0336] To a solution of Compound 4 (130 mg, 397.00 μmol, 1 eq) in DCM (5 mL) was added BBr3(1 M, 1.98 mL, 5 eq) at -10 °C, the reaction mixture was stirred at 25 °C for 12 hr. LCMS (EW32981-49-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was diluted with H2015 mL and extracted with DCM 60 mL (20 mL * 3). The combined organic layers were washed dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (NH4HCO3) -ACN];B%: 40%-70%, 8min). KNA-020 (58.84 mg, 195.80 μmol, 49.32% yield, 99.63% purity) was obtained as white solid, which was confirmed by LCMS (EW32981-49-P1B), HPLC (EW32981-49-P1C) and HNMR (EW32981-49-P1E). LCMS: MS (ESI) Retention time: 0.802 min (M+1)+ = 300.2.1H NMR (400 MHz, CDCl3) δ = 8.36 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 7.31 (d, J = 5.3 Hz, 1H), 6.43 (s, 2H), 5.93 - 5.08 (m, 2H), 2.86 (quin, J = 6.8 Hz, 1H), 2.60 - 2.52 (m, 2H), 1.69 - 1.62 (m, 2H), 1.40 - 1.34 (m, 4H), 1.18 (d, J = 6.8 Hz, 6H), 0.96 - 0.88 (m, 3H).

[0337] To a solution of Compound 2 (200 mg, 714.02 μmol, 125.79 μL, 1 eq) in DME (1 mL) was added Cs2CO3(697.93 mg, 2.14 mmol, 3 eq), Compound 1 (286.40 mg, 856.83 μmol, 1.2 eq) and Pd(PPh3)4 (82.51 mg, 71.40 μmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 12 hr. LCMS (EW32981-31-P1A) showed that the reactant 1 was consumed and desired compound observed. The reaction mixture was diluted with H2020 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 80%-100%, 2min). Compound 3 (60 mg, 161.78 μmol, 22.66% yield, 97.2% purity) was obtained as yellow oil, which was confirmed by LCMS (EW32981- 31-P1B). LCMS: MS (ESI) Retention time: 1.070 min (M+1)+ = 361.2.EW32981-31-P1A. L

[0338] To a solution of 1, 3 -dimethoxy- 5 -pentyl- 2-(2-phenylphenyl) benzene (60 mg, 166.44 μmol, 1 eq) in DCM (1 mL) was added BBr3(1 M, 832.21 μL, 5 eq) at -10 °C, the reaction mixture was stirred at 25 °C for 12 hr. LCMS (EW32981-39-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with H2O 10 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were dried over[Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 46%-76%, 7min). Compound KNA-025(37.96 mg, 113.96 μmol, 68.47% yield, 99.8% purity) was obtained as yellow gum, which was confirmed by LCMS (EW32981-39-P1B), HPLC (EW32981-39-P1C), SFC (EW32981-39-P1D) and HNMR (EW32981-39-P1E). LCMS: MS (ESI) Retention time: 0.902 min (M+1)+ = 333.2

[0339] 1H NMR (400 MHz, CDCl3) δ = 7.64 - 7.48 (m, 3H), 7.46 - 7.39 (m, 1H), 7.27 - 7.16 (m, 5H), 6.27 (s, 2H), 4.62 (s, 2H), 2.48 (t, J = 7.6 Hz, 2H), 1.58 (quin, J = 7.4 Hz, 2H), 1.38 - 1.22 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).

[0340] To a solution of Compound 1 (2 g, 11.10 mmol, 1 eq) and NaHCO3 (2.80 g, 33.29 mmol, 1.29 mL, 3 eq) in MTBE (20 mL) and H2O (20 mL), then the reaction mixture was cooled to 0 °C and I2(5.63 g, 22.19 mmol, 4.47 mL, 2 eq) was added, the reaction mixturewas stirred at 0 °C for 1 hr. Then Na2SO3(2.80 g, 22.19 mmol, 2 eq) was added and stirred at 25 °C for 30 min. LCMS (EW32981-54-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was partitioned between H2O 50 mL and MTBE 100 mL. The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition). Compound 2 (1.7 g, 5.54 mmol, 49.91% yield, 99.74% purity) was obtained as yellow oil, which was confirmed by LCMS (EW32981-54- P1B). LCMS: MS (ESI) Retention time: 0.898 min, (M+H)+= 307.1, EW32981-54-P1A. LCMS: MS (ESI) Retention time: 0.881 min, (M+H)+= 307.0, EW32981-54-P1B. General procedure for preparation of compound 3 for KNA-026

[0341] To a solution of Compound 2 (1.6 g, 5.23 mmol, 1 eq) in Py (8 mL) was added Ac2O (8.72 g, 85.42 mmol, 8 mL, 16.34 eq), the reaction mixture was stirred at 25 °C for 12 hr. TLC (PE:EA = 5:1) showed that the reactant (Rf = 0.2) and a new point (Rf = 0.5) formed. The reaction mixture was quenched by addition 1 M HCl 20 mL, and then diluted with H2O 50 mL and extracted with EA 150 mL (50 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ethergradient @ 50 mL / min). Compound 3 (1.7 g, 4.36 mmol, 83.36% yield) was obtained as colorless oil, which was confirmed by HNMR (EW32981-94-P1A).1H NMR (400 MHz, CDCl3) δ = 6.84 (s, 2H), 2.64 - 2.55 (m, 2H), 2.37 (s, 6H), 1.62 (quin, J = 7.5 Hz, 2H), 1.36 - 1.27 (m, 4H), 0.90 (br t, J = 6.7 Hz, 3H). General procedure for preparation of compound 5 for KNA-026

[0342] To the mixture of Compound 4 (1 g, 5.07 mmol, 1 eq) in THF (10 mL) was added n- BuLi (2.5 M, 2.23 mL, 1.1 eq) at - 78 °C and stirred for 1.5 h. Then TRIISOPROPYL BORATE (4.77 g, 25.37 mmol, 5.83 mL, 5 eq) in THF (5 mL) was added to the mixture and the mixture was stirred at 25 °C for 12 h. TLC (PE:EA = 3:1) showed the reactant 1 (Rf = 0.8) was consumed and a new point (Rf = 0.3) was formed. The residue was poured into HCl (3M, 20 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (100 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 2 / 1). Compound 5 (570 mg, 3.49 mmol, 68.79% yield, 99.2% purity) was obtained as yellow oil which was confirmed by LCMS (EW33042- 30-P1A). LCMS: MS (ESI) Retention time: 0.566 min, (M+H)+= 163.2.

[0343] To a solution of Compound 3 (1.25 g, 3.21 mmol, 1 eq) and Pd(PPh3)4(370.94 mg, 321.00 μmol, 0.1 eq) in DME (20 mL) stirred at 25 °C for 10 min under N2, then Compound 5 (520 mg, 3.21 mmol, 1 eq) and Na2CO3(2 M, 3.21 mL, 2 eq) was added, the reaction mixture was stirred at 110 °C for 3 hr. LCMS (EW32981-99-P1A) showed that the reactant was consumed and desired compound observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (ammonia hydroxide v / v) -ACN];B%: 53%-83%, 9min). Compound 7 (200 mg, crude) was obtained as yellow oil. LCMS: MS (ESI) Retention time: 1.001 min, (M+H)+= 381.3, EW32981-99- P1A.

[0344] To a solution of [3 -acetoxy- 2-(2-isopropenylphenyl) -5-pentyl-phenyl] acetate (80 mg, 210.26 μmol, 1 eq) in MeOH (4 mL) was added a solution of Na2CO3 (66.86 mg, 630.79 μmol, 3 eq) in H2O (2 mL), the reaction mixture was stirred at 25 °C for 1.5 hr. LCMS (EW32981-111-P1A1) showed that the reactant was consumed and desired compound observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 49%-69%, 10min). KNA-026 (1.14 mg, 3.81 μmol, 1.81% yield, 99.14% purity) was obtained as yellow gum, which was confirmed by LCMS (EW32981-111-P1B), HPLC (EW32981-111-P1C) and HNMR (EW32981-111-P1F). LCMS: MS (ESI) Retention time: 0.933 min (M+Na)+= 319.2.1H NMR (400 MHz, CDCl3) δ = 7.80 (br d, J = 7.5 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.40 - 7.31 (m, 2H), 6.40 (s, 2H), 6.22 - 5.78 (m, 4H), 2.59 - 2.47 (m, 2H), 2.11 - 2.03 (m, 3H), 1.68 - 1.59 (m, 4H), 1.52 - 1.42 (m, 2H), 1.35 (br d, J = 4.8 Hz, 3H)

[0345] To a solution of compound 2 (62.48 g, 156.46 mmol, 1.3 eq) in THF (200 mL) was added t-BuOK (13.51 g, 120.36 mmol, 1 eq) at 0 °C, then the mixture was stirred at 30 min, the mixture was added a solution of compound 1 (20 g, 120.36 mmol, 1 eq) in THF (80 mL) at 0 °C, the mixture was stirred at 30 °C for 12 hr under N2. LCMS (EW32982- 26-P1A) and TLC (PE:EA = 5 : 1, Rf = 0.65) showed the reactant 1 was consumed and desired mass was detected. The mixture was filtered and concentrated in vacuum, then the residue was poured into water (300 mL). The aqueous phase was extracted with ethyl acetate (300 mLx3). The combined organic phase was washed with brine (100 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0, 10 / 1). compound 3 (22 g, 106.65 mmol, 88.61% yield) was obtained as Colorless oil, checked by NMR (EW32982-26-P1A). LCMS: MS (ESI) Retention time: 1.010 min (M+H)+= 207.2 , EW32982-26-P1A.1H NMR (400 MHz, CDCl3) δ = 7.21 - 7.12 (m, 1H), 6.52 - 6.41 (m, 3H), 5.66 (td, J = 7.2, 11.6 Hz, 1H), 3.98 - 3.64 (m, 6H), 2.30 - 2.15 (m, 2H), 1.53 - 1.38 (m, 2H), 0.97 - 0.90 (m, 3H).

[0346] To a solution of compound 3 (20 g, 97.0 mmol, 1.00 eq) in EA (200 mL) and MeOH (40 mL) (v / v = 5 / 1) was added Pd / C (8 g, 10% purity) under H2 , the mixture was stirred at 25 °C for 12 hr . LCMS (EW32982-30-P1A) showed the reactant 1 was consumed and desired mass was detected . The mixture was filtered with celatom and concentrated invacuum. The residue was taken the next step and without other purification . Compound 4 (20 g, 96.0 mmol, 99.0% yield) was obtained as Colorless oil. LCMS: MS (ESI) Retention time: 1.004 min (M+H)+= 209.1 , EW32982-30-P1A.

[0347] To a solution of compound 4 (3 g, 14.4 mmol, 1.00 eq) in DCM (30 mL) was added BBr3(10.8 g, 43.2 mmol, 4.16 mL, 3.00 eq) in DCM (30 mL) at -78 °C, and the mixture was stirred at 25 °C for 12 hr. LCMS (EW32982-53-P1A) and TLC (PE : EA = 3: 1) showed the reactant 1 was consumed and a new spot (Rf = 0.35) was detected. The residue was poured into water (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 101, 1 / 1). Compound 5 (2.30 g, 12.8 mmol, 88.6 % yield) was obtained as white solid, checked by NMR (EW32982-53-P1A). LCMS: MS (ESI) Retention time: 0.819 min (M+H)+= 181.2 , EW32982-53-P1A.1H NMR (400 MHz, CDCl3) δ = 6.96 (d, J = 8.1 Hz, 1H), 6.49 - 6.22 (m, 2H), 4.86 - 4.57 (m, 2H), 2.66 - 2.41 (m, 2H), 1.68 - 1.51 (m, 2H), 1.41 - 1.30 (m, 4H), 0.98 - 0.80 (m, 3H). General procedure for preparation of compound 5 for KNA-027

[0348] To a solution of silver;hexafluoroantimony (1 -) (286 mg, 832 μmol, 0.10 eq) in DCE (5 mL) was added compound 6 (1.90 g, 12.5 mmol, 1.50 eq), then the mixture was addedcompound 5 (1.50 g, 8.32 mmol, 1.00 eq), the mixture was stirred at 20 °C for 12 hr under dark. LCMS (EW32982-57-P1A) and TLC (PE:EA = 10 : 1) showed the reactant 1 was consumed and a new spot (Rf = 0.55) was detected. The mixture poured into water (15 mL). The aqueous phase was extracted with ethyl acetate (15 mLx3). The combined organic phase was washed with brine (15 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by perp_TLC (PE:EA = 10 : 1) and perp_HPLC (column: Phenomenex luna C18150x25 mmx 10um;mobile phase: [water (FA) -ACN];B%: 70%- 100%, 2min). KNA-027 (14.5 mg, 46.1 μmol, 5.54e-1% yield, 99.9% purity) was obtained as yellow oil, checked by LCMS (EW32982-57-P1A3), HPLC (EW32982-57-P1A5), SFC (EW32982-57-P1A), speacial_NMR (EW32982-57-P1A1) and NMR (EW32982-57-P1A). LCMS: MS (ESI) Retention time: 1.068 min (M+H)+= 315.2 , EW32982-57-P1A.1H NMR (400 MHz, CDCl3) δ = 6.82 (br d, J = 7.3 Hz, 1H), 6.47 - 6.19 (m, 1H), 6.16 - 5.85 (m, 1H), 5.59 (br s, 1H), 4.80 - 4.43 (m, 3H), 3.92 (br s, 1H), 2.64 - 2.37 (m, 3H), 2.25 (br d, J = 7.3 Hz, 1H), 2.17 - 2.06 (m, 1H), 1.90 - 1.75 (m, 5H), 1.65 (s, 3H), 1.62 - 1.48 (m, 2H), 1.42 - 1.22 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H).General procedure for preparation of compound 2 for KNA-028 and KNA-042

[0349] To the mixture of compound 1A (3 g, 19.71 mmol, 1 eq) in EA (20 mL) was added chlororhodium;triphenylphosphane (911.65 mg, 985.33 μmol, 0.05 eq), and the mixture was stirred at 65 °C for 8 h under H2balloon. TLC (PE:EA = 5:1) showed no new point was formed and there are a new point (Rf = 0.4) was alike with SM. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 2 / 1). This was successful, and compound 2 (1.5 g, 9.72 mmol, 49.35% yield) was obtained as colorless oil which was confirmed by HNMR5.74 - 5.62 (m, 2H), 1.92 - 1.80 (m, 2H), 1.71 - 1.58 (m, 4H), 1.57 - 1.32 (m, 7H), 1.32 - 1.23 (m, 6H), 1.20 (d, J = 1.6 Hz, 2H), 1.01 (br d, J = 6.8 Hz, 1H), 0.93 - 0.83 (m, 12H). General procedure for preparation of compound 3 for KNA-028 and KNA-042

[0350] To the mixture of compound 2 (1.49 g, 9.65 mmol, 3 eq), AgOTf (82.68 mg, 321.79 μmol, 0.1 eq) in DCE (10 mL) was added compound 1 (0.58 g, 3.22 mmol, 1 eq) slowly under N2and the mixture was stirred at 20 °C for 14 h in dark. LCMS (EW33348-2-P1A) showed the reaction was completed. The mixture was poured into ice-water (15 mL) and extracted with DCM (15 mL*2). The combined organic phase was washed with brine (10 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 63%-93%, 11min). compound 3 (260 mg, 821.55 μmol, 25.53% yield) was obtained as yellow oil, which was checked with HNMR (EW33348-2-P1A). LCMS: MS (ESI) Retention time: 1.113 min (M+H)+=317.3.NMR (400 MHz, CDCl3) δ = 6.35 - 5.83 (m, 3H), 5.53 (br s, 1H), 4.66 - 4.35 (m, 1H), 3.86 - 3.76 (m, 1H), 2.54 - 2.40 (m, 2H), 2.23 - 2.07 (m, 2H), 1.84 - 1.77 (m, 3H), 1.65 - 1.53 (m, 5H), 1.45 - 1.30 (m, 5H), 0.93 - 0.84 (m, 9H).

[0351] To a mixture of compound 3 (260 mg, 821.55 μmol, 1 eq) in Py (1.5 mL) was added Ac2O (1.64 g, 16.02 mmol, 1.5 mL, 19.49 eq). The mixture was stirred at 20 °C for 16 hours. LCMS (EW33348-5-P1A) showed the reaction was completed. The solution was poured onto ice water (15 mL) and extracted with EA (15×3). The combined organic extracts were washed successively with 1 M HCl, then washed successively with aqueous NaHCO3. The combined organic phase was washed with brine (10 mL×1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. compound 4 (300 mg, crude) was obtained as yellow oil, which was checked HNMR (EW33348-5-P1B). LCMS: MS (ESI) Retention time: 1.180 min (M+H)+= 401.3.1H NMR (400 MHz, CDCl3) δ = 6.66 (s, 2H), 5.07 (br s, 1H), 3.41 - 3.29 (m, 1H), 2.53 - 2.45 (m, 2H), 2.14 (s, 6H), 1.85 - 1.76 (m, 1H), 1.69 (td, J = 2.4, 12.8 Hz, 1H), 1.58 (s, 3H), 1.56 - 1.50 (m, 2H), 1.42 - 1.32 (m, 1H), 1.29 - 1.22 (m, 5H), 1.19 (t, J = 7.2 Hz, 2H), 0.82 (br t, J = 6.8 Hz, 3H), 0.76 (d, J = 7.2 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). General procedure for preparation of compound 5,5A for KNA-028 and KNA-042

[0352] To a mixture of compound 4 (300 mg, 748.97 μmol, 1 eq) in EtOH (2 mL) was added SeO2 (249.32 mg, 2.25 mmol, 244.43 μL, 3 eq) under N2. The mixture was stirred at 90 °C for 4 hours. LCMS (EW33348-13-P1A1) showed the reaction was completed. The mixture was cooled to 30 °C and concentrated in reduced pressure. The residue was poured into ice- water (5 mL) and extracted with ethyl acetate (5 mL ×3). The combined organic phase was washed with brine (5 mL ×1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE:EA = 7:1). Compound 5(100 mg, 241.24 μmol, 32.21% yield) was obtained as yellow oil, which was checked with HNMR (EW33348-13-P1A). compound 5A (100 mg, 241.24 μmol, 32.21% yield) was obtained as yellow oil, which was checked with HNMR (EW33348-13-P2A). LCMS: MS (ESI) Retention time: 0.970 min (M+H)+= 399.2.1H NMR (400 MHz, CDCl3) δ = 9.33 (s, 1H), 6.72 (s, 2H), 6.50 (s, 1H), 3.58 (br dd, J = 1.6, 10.0 Hz, 1H), 2.56 - 2.47 (m, 3H), 2.28 - 2.05 (m, 5H), 1.88 - 1.82 (m, 2H), 1.60 - 1.40 (m, 4H), 1.33 - 1.22 (m, 6H), 0.84 - 0.77 (m,

[0353] To a mixture of compound 5 (100 mg, 241.24 μmol, 1 eq) and compound 5A (100.00 mg, 241.24 μmol, 1 eq) in EtOH (5 mL) was added NaBH4 (86 mg, 2.27 mmol, 9.42 eq) at 0 °C under N2. The mixture was stirred at 90 °C for 1 hours. LCMS (EW33348-17- P1A) showed the reaction was completed. The mixture was concentrated in reduced pressure. The residue was poured into ice-water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by perp-HPLC (column: Waters Xbridge 150*25 mm* 5um;mobile phase: [water (NH4HCO3) -ACN];B%: 47%-77%, 9min) and lyophilization. KNA-028 (8.50 mg, 25.00 μmol, 10.36% yield, 97.790% purity) was obtained as yellow oil. KNA-042 (4.84 mg, 13.75 μmol, 5.70% yield, 94.440% purity) was obtained as yellow oil. LCMS: MS (ESI) Retention time: 0.879 min (M+H)+= 333.3.

[0354] KNA-028. LCMS: MS (ESI) Retention time: 0.892 min (M+H)+= 333.2.1H NMR (400 MHz, CDCl3) δ = 6.24 (br s, 2H), 5.82 (br s, 1H), 5.75 - 5.43 (m, 1H), 5.10 - 4.54 (m, 1H), 4.22 - 4.03 (m, 2H), 3.91 (br d, J = 10.4 Hz, 1H), 2.53 - 2.41 (m, 2H), 2.32 - 2.12 (m, 2H), 1.89 (td, J = 2.0, 12.8 Hz, 1H), 1.77 - 1.56 (m, 5H), 1.48 - 1.39 (m, 1H), 1.38 - 1.29 (m, 4H), 0.99 - 0.81 (m, 9H).

[0355] KNA-042. LCMS: MS (ESI) Retention time: 0.875 min (M+H)+= 333.3.1H NMR (400 MHz, CDCl3) δ = 6.29 - 5.97 (m, 2H), 5.51 (br s, 1H), 4.64 (br s, 1H), 4.30 (br d, J = 3.3 Hz, 1H), 3.81 (br dd, J = 2.3, 10.6 Hz, 1H), 2.44 - 2.26 (m, 2H), 2.11 - 2.03 (m, 1H), 1.80 (s, 4H), 1.51 (br d, J = 7.1 Hz, 4H), 1.37 - 1.16 (m, 6H), 0.89 - 0.76 (m, 9H).General procedure for preparation of compound 2 for KNA-029

[0356] To a mixture of compound 1A (5.48 g, 36.01 mmol, 1.5 eq) and AgOTf (616.76 mg, 2.40 mmol, 0.1 eq) in DCE (50 mL) was added compound 1 (5 g, 24.00 mmol, 1 eq) slowly under N2 and the mixture was stirred at 30 °C for 14 h in dark. LCMS (EW33348-30-P1B4) showed the reaction was completed. The mixture was poured into ice-water (80 mL) and extracted with DCM (50 mL*2). The combined organic phase was washed with brine (30 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 1 / 0, 25 / 1). compound 2 (2 g, 5.84 mmol, 24.33% yield) was obtained as yellow oil. LCMS: MS (ESI) Retentiontime: 1.257 min (M+H)+= 343.3.

[0357] To a mixture of m-CPBA (1.19 g, 5.84 mmol, 85% purity, 1 eq) in DCM (40 mL) was added a solution of compound 2 (2 g, 5.84 mmol, 1 eq) in DCM (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. LCMS (EW33348-36-P1A) showed most of reactant 2 was consumed, and desired mass was detected. The mixture was poured into aqueous NaHCO3 (35 mL) and extracted with DCM (20 mL*2). The combined organic phase was washed with brine (20 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 18 / 1). compound 3 (1.1 g, 3.07 mmol, 52.55% yield) was obtained as yellow oil, which was checked with HNMR (EW33348-36-P1A). LCMS: MS (ESI) Retention time: 1.173 min (M+H)+= 359.3.1H NMR (400 MHz, CDCl3) δ = 6.29 - 6.22 (m, 2H), 4.31 (s, 1H), 4.10 (d, J = 2.4 Hz, 1H), 3.75 - 3.72 (m, 3H), 3.64 (s, 3H), 3.52 (d, J = 10.8 Hz, 1H), 2.53 - 2.43 (m, 2H), 2.24 - 2.13 (m, 1H), 2.01 - 1.91 (m, 1H), 1.76 (dt, J = 4.4, 13.2 Hz, 1H), 1.60 - 1.49 (m, 6H), 1.36 - 1.12 (m, 9H), 0.83 (t, J = 6.8 Hz, 3H).

[0358] To a mixture of N-isopropylcyclohexanamine (1.73 g, 12.27 mmol, 2.02 mL, 4 eq) in toluene (20 mL) was added n-BuLi (2.5 M, 6.14 mL, 5 eq) i at 0 °C under N2. The mixture was stirred at 0 °C for 15 min, then MeMgBr (3 M, 4.09 mL, 4 eq) was added at 0 °C and the mixture was stirred at 0 °C for 1 hours. compound 3 (1.10 g, 3.07 mmol, 1 eq) in toluene (10 mL) was added and the mixture was stirred at 40 °C for 2 hours. LCMS (EW33348-37-P1A) showed the reaction was completed. Then the reaction was cooled to 0 °C and quenched bythe slow addition of 5M HCl, then extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 10 / 1). compound 4 (1.1 g, 3.07 mmol, 100.00% yield) was obtained as yellow oil, which was checked with HNMR (EW33348-37-P1A). LCMS: MS (ESI) Retention time: 1.044 min (M+H)+= 359.3.1H NMR (400 MHz, CDCl3) δ = 6.34 (s, 2H), 5.09 (s, 1H), 4.83 (d, J = 1.6 Hz, 1H), 4.63 (br d, J = 10.0 Hz, 1H), 4.50 (d, J = 2.0 Hz, 1H), 4.39 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.36 - 3.27 (m, 1H), 3.25 - 3.16 (m, 1H), 2.59 - 2.52 (m, 2H), 2.49 (td, J = 3.2, 13.3 Hz, 1H), 2.23 (dt, J = 4.0, 13.6 Hz, 1H), 1.74 (qd, J = 3.6, 12.4 Hz, 1H), 1.62 (td, J = 7.6, 15.2 Hz, 2H), 1.54 - 1.43 (m, 5H), 1.41 - 1.29 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H). General procedure for preparation of compound 5 for KNA-029

[0359] To a mixture of compound 4 (1.10 g, 3.07 mmol, 1 eq) in Py (5.5 mL) was added Ac2O (6.00 g, 58.72 mmol, 5.50 mL, 19.14 eq). The mixture was stirred at 30 °C for 15 hours. TLC (PE:EA = 10:1) showed the reaction was completed, a new spot was detected. The solution was poured onto iced water (60 mL) and extracted with ether. The combined organic extracts were washed successively with 1N HCl, aqueous sodium bicarbonate and brine, dried on MgSO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 10 / 1). compound 5 (1 g, 2.50 mmol, 81.37% yield) was obtained as yellow oil, which was checked with HNMR6.29 (d, J = 5.6 Hz, 2H), 5.96 (br d, J = 11.2 Hz, 1H), 4.82 - 4.70 (m, 2H), 4.59 - 4.40 (m, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.47 (t, J = 11.2 Hz, 1H), 3.25 (dt, J = 3.6, 12.0 Hz, 1H), 2.52 (t, J = 7.6 Hz, 2H), 2.30 (dt, J = 4.0, 13.6 Hz, 1H), 1.76 - 1.70 (m, 3H), 1.67 - 1.51 (m, 6H), 1.50 - 1.20 (m, 6H), 0.90 (t, J = 7.2 Hz, 3H).General procedure for preparation of compound 6 for KNA-029

[0360] To a mixture of compound 5 (0.5 g, 1.25 mmol, 1 eq) in DCM (20 mL) was added TMSBr (955.50 mg, 6.24 mmol, 809.75 μL, 5 eq). The mixture was stirred at 25 °C for 4 hours. TLC (PE:EA = 10:1) showed the reaction was completed, and new spot was detected. The mixture was poured into aqueous NaHCO3(50 mL) and extracted with DCM (50 mL*3). The combined organic phase was washed with brine (50 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 20 / 1, 10 / 1). compound 6 (150 mg, 355.95 μmol, 28.51% yield) was obtained as yellow oil. General procedure for preparation of compound 7 for KNA-029

[0361] To a mixture of compound 6 (150 mg, 355.95 μmol, 1 eq) in ACETONE (3 mL) was added tetrabutylammonium;acetate (118.05 mg, 391.54 μmol, 119.25 μL, 1.1 eq) under N2. The mixture was stirred at 60 °C for 2 hours. TLC (PE:EA = 10:1) showed the reaction was completed, and new spot was detected. The mixture was concentrated in reduced pressure. The residue was poured into ice-water (10 mL) and extracted with ethyl acetate (8 mL*2). The combined organic phase was washed with brine (2 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1). compound 7 (50 mg, crude) was obtained as yellow oil, which was checked with HNMR (EW33348-54-P1A).1H NMR (400 MHz, CDCl3) δ = 6.24 (s, 2H), 5.51 (s, 1H), 4.44 - 4.27 (m, 4H), 3.95 (br d, J = 10. Hz, 1H), 3.63 (s, 5H), 2.82 - 2.72 (m, 1H), 2.50 -2.42 (m, 2H), 2.18 - 2.03 (m, 2H), 1.97 (s, 3H), 1.73 - 1.63 (m, 2H), 1.57 - 1.49 (m, 5H), 1.25 (br d, J = 3.6 Hz, 4H), 0.83 - 0.80 (m, 3H). General procedure for preparation of compound 8 for KNA-029

[0362] To a mixture of compound 7 (50 mg, 124.83 μmol, 1 eq) in EtOH (2 mL) was added NaOH (1 M, 0.2 mL, 1.60 eq). The mixture was stirred at 90 °C for 1 hours. TLC (PE:EA = 5:1) showed the reactant 1 was consumed and a new spot (Rf = 0.3) was detected. The mixture was concentrated in reduced pressure. The residue was poured into ice-water (5 mL) and 2N HCl was added to acid pH, extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The reaction was succeeded, compound 8 (50 mg, crude) was obtained as Colorless oil, checked by HNMR (EW33026-35-P1A).1H NMR (400 MHz, CDCl3) δ = 6.33 (s, 2H), 5.56 - 5.47 (m, 1H), 5.52 (s, 1H), 5.31 (s, 2H), 4.52 - 4.35 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 3.78 - 3.67 (m, 6H), 2.98 - 2.80 (m, 1H), 2.59 - 2.49 (m, 2H), 2.31 - 2.13 (m, 2H), 1.88 - 1.71 (m, 2H), 1.66 - 1.54 (m, 5H), 1.40 - 1.30 (m, 5H), 0.92 - 0.86 (m, 3H). General procedure for preparation of KNA-029

[0363] To a mixture of compound 8 (50 mg, 139.46 μmol, 1 eq) in THF (1 mL) was added iodo (methyl) magnesium (3 M, 232.44 μL, 5 eq) at 0 °C under N2. The mixture was stirred at 145 °C for 2 hours. LCMS (EW33348-55-P1A) showed the reactant was consumed, anddesired mass was detected. The mixture was cooled to 30 °C and poured into ice-water (8 mL) and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (3 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum The residue was purified by prep-HPLC (column: Shim-pack C18150*25*10um;mobile phase: [water (FA) -ACN];B%: 35%-65%, 10 min) and lyophilization. KNA-029 (6.7 mg, 19.36 μmol, 13.88% yield, 95.494% purity) was obtained as yellow gum, which was checked with HNMR (EW33348-55-P1A), LCMS (EW33348-55-P1B), LCMS (EW33348-55-P1B1), HPLC (EW33348-55-P1B2), HSQC (EW33348-55-P1B), SFC (EW33348-55-P1C). LCMS: MS (ESI) Retention time: 0.940 min (M+H)+= 331.3. KNA-029. LCMS: MS (ESI) ), ,

[0364] To the compound 1 (50 g, 277.40 mmol, 1 eq) and K2CO3(115.02 g, 832.21 mmol, 3 eq) in ACETONE (450 mL) was added Me2SO4 (108.57 g, 860.76 mmol, 81.63 mL, 3.10 eq) dropwise. And the mixture was stirred at 80 °C under N2for 12 h. TLC (PE:EA = 5:1) showed that the reactant 1 (Rf = 0.5) was consumed and a new point (Rf = 0.7) was formed. The reaction mixture was vacuum filtered and rinsed with EA (800 mL). The filtrate was washed with 1N HCl (300 mL), brine (1000 mL x 2), dried over MgSO4, filtered and concentrated to give an orange oil. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1). Compound 2 (53 g, 254.45 mmol, 91.72% yield) was obtained as colorless oil which was confirmed by HNMR (EW33042-11- P1A.).1H NMR (400 MHz, CDCl3) δ = 6.37 (d, J = 2.0 Hz, 2H), 6.32 (d, J = 2.1 Hz, 1H), 3.80 (s, 6H), 2.56 (t, J = 7.8 Hz, 2H), 1.68 - 1.57 (m, 2H), 1.41 - 1.28 (m, 4H), 0.91 (br t, J = 6.9 Hz, 3H)

[0365] To a solution of compound 2 (20 g, 96.02 mmol, 1 eq) and sulfurochloridic acid (55.94 g, 480.09 mmol, 31.97 mL, 5 eq) in CYCLOHEXANE (60 mL) at 60 °C was added dimethyl carbonate (44.98 g, 499.29 mmol, 42.03 mL, 5.2 eq) dropwise, and the mixture was stirred at 70 °C at 2 hr. TLC (PE:EA = 3:1) showed the reactant 1 was consumed and two spot (Rf = 0.4, 0.30) was detected. The residue was poured into ice-water (w / w = 1 / 1) (150 mL) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (150 mLx3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 15 / 1, 3 / 1) Compound 3 (2 g, 6.52 mmol, 6.79% yield) was obtained as yellow oil, checked by NMR (EW32982-77-P1A).1H NMR (400 MHz, ACETONITRILE-d3) δ = 6.60 (d, J = 2.4 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H), 3.88 (s, 3H), 3.05 - 2.91 (m, 2H), 1.67 - 1.54 (m, 2H), 1.38 - 1.32 (m, 4H), 0.93 - 0.88 (m, 3H).

[0366] To a solution of SODIUM SULFITE (3.29 g, 26.08 mmol, 4 eq) and NaHCO3 (2.19 g, 26.08 mmol, 1.01 mL, 4 eq) in H2O (32 mL) was added compound 3 (2 g, 6.52 mmol, 1 eq) at 25 °C, the mixture was stirred at 70 °C for 12 hr. LCMS (EW32982-82-P1A) showed the reactant 1 was consumed. The mixture was filtered and the filtrate was concentrated. The residue was taken the next step and without other purification. compound 4 (1.45 g, 4.93 mmol, 75.57% yield) was obtained as yellow oil, checked by NMR (EW32982-82-P1A).1H NMR (400 MHz, CDCl3) δ = 6.18 - 6.01 (m, 2H), 3.72 (br d, J = 2.0 Hz, 3H), 3.62 - 3.43 (m, 3H), 2.82 - 2.66 (m, 2H), 2.01 (br s, 3H), 1.62 - 1.55 (m, 2H), 1.37 - 1.29 (m, 4H), 0.90 (br t, J = 6.9 Hz, 3H).

[0367] To a solution of compound 4 (1.4 g, 4.76 mmol, 1 eq) in DMF (21 mL) was added CH3I (1.35 g, 9.51 mmol, 592.20 μL, 2 eq) at 25 °C, the mixture was stirred at 80 °C for 12 hr. TLC (PE:EA = 3:1) showed the reactant 1 was consumed and A new spot (Rf = 0.55) was detected. The mixture poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mLx3). The combined organic phase was washed with brine (5 mLx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 3 / 1). compound 5 (700 mg, 2.44 mmol, 51.39% yield)13

[0368] To a solution of compound 5 (700 mg, 2.44 mmol, 1 eq) in DCM (7 mL) was added BBr3 (1 M, 12.22 mL, 5 eq) at - 78 °C, the mixture was stirred at 25 °C for 12 hr. TLC (PE:EA = 3 : 1) showed the reactant 1 was consumed and a new spot (Rf = 0.45) was detected. The mixture was poured into 1 N HCl (10 mL). The aqueous phase was extracted with DCM (20 mLx3). The combined organic phase was washed with brine (15 mLx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 15 / 1, 2 / 1). compound 6 (550 mg, 2.13 mmol, 87.10% yield) was obtained as white solid, che...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I′′):(I′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of R1is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN;each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

2. The compound of claim 1, wherein the compound is of Formula (I′):(I′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive;R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

3. The compound of claim 1 or 2, wherein the compound is of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or - CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

4. The compound of any one of claims 1-3, wherein R2is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

5. The compound of any one of claims 1-4, wherein R3is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

6. The compound of any one of claims 1-5, wherein R3is methyl, and R2is hydrogen.

7. The compound of any one of claims 1-5, wherein R3is fluoro, and R2is fluoro.

8. The compound of any one of claims 1-5, wherein R3is -CF3, and R2is hydrogen.

9. The compound of any one of claims 1-5, wherein R3is methyl, and R2is methyl.

10. The compound of claim 1, wherein the compound is of Formula (I-A):(I-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

11. The compound of any one of claims 1-10, wherein R1is substituted C1-6 alkyl.

12. The compound of any one of claims 1-11, wherein R1is C1-6 alkyl substituted with halogen, carbocyclyl, -OH, -NH2, -CN, or -SO2CH3.

13. The compound of any one of claims 1-12, wherein R1is -CF3, -C(CH3)2(CH2OH),.

14. The compound of any one of claims 1-10, wherein R1is halogen.

15. The compound of any one of claims 1-10 and 14, wherein R1is fluoro.

16. The compound of any one of claims 1-10, wherein R1is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

17. The compound of any one of claims 1-10 or 16, wherein R1is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazolyl, substituted or unsubstituted imidazopyridazinyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted pyrrolidinyl.

18. The compound of any one of claims 1-17, wherein R4is hydrogen.

19. The compound of any one of claims 1-17, wherein R4is substituted or unsubstituted C1-6alkyl.

20. The compound of any one of claims 1-17, wherein R4is -CF3.

21. The compound of any one of claims 1-17, wherein R4is -OH.

22. The compound of any one of claims 1-17, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

23. The compound of claim 1, wherein RNis substituted or unsubstituted C1-6 alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

24. The compound of claim 1 or 23, wherein RNis -CH3, -CH2CH3, -C(=O)CH3, - C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

25. The compound of any one of claims 1-24, wherein both instances of X are -OH.

26. The compound of any one of claims 1-24, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

27. The compound of any one of claims 1-24, wherein one instance of X is -OH, and one instance of X is -NH2.

28. The compound of any one of claims 1-24, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

29. The compound of any one of claims 1-24, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

30. The compound of any one of claims 1-24, wherein both instances of X are -NH2.

31. The compound of any one of claims 1-24, wherein both instances of X are -NH(CH3).

32. A compound of Formula ′′(II′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of R1is independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ,n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN;R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

33. The compound of claim 32, wherein the compound is of Formula (II′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2,,n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

34. The compound of claim 32 or 33, wherein the compound is of Formula (II):(II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, - C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, - NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

35. The compound of any one of claims 32-34, wherein R2is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

36. The compound of any one of claims 32-35, wherein R3is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

37. The compound of any one of claims 32-36, wherein R3is methyl, and R2is hydrogen.

38. The compound of any one of claims 32-36, wherein R3is fluoro, and R2is fluoro.

39. The compound of any one of claims 32-36, wherein R3is -CF3, and R2is hydrogen.

40. The compound of any one of claims 32-36, wherein R3is methyl, and R2is methyl.

41. The compound of claim 34, wherein the compound is of Formula (II-A):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

42. The compound of any one of claims 31-41, wherein R1is substituted C1-6alkyl.

43. The compound of any one of claims 32-42, wherein R1is C1-6 alkyl substituted with halogen, carbocyclyl, -OH, -NH2, -CN, or -SO2CH3.

44. The compound of any one of claims 32-43, wherein R1is -CF3, -C(CH3)2(CH2OH),.

45. The compound of any one of claims 32-41, wherein R1is halogen.

46. The compound of any one of claims 32-41 and 45, wherein R1is fluoro.

47. The compound of any one of claims 32-41, wherein R1is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

48. The compound of any one of claims 32-41 or 47, wherein R1is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazolyl, substituted or unsubstituted imidazopyridazinyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted pyrrolidinyl.

49. The compound of any one of claims 32-48, wherein R4is hydrogen.

50. The compound of any one of claims 32-48, wherein R4is substituted or unsubstituted C1-6 alkyl.

51. The compound of any one of claims 32-48 or 50, wherein R4is -CF3.

52. The compound of any one of claims 32-48, wherein R4is -OH.

53. The compound of any one of claims 32-48, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

54. The compound of claim 32, wherein RNis substituted or unsubstituted C1-6alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

55. The compound of claim 32 or 54, wherein RNis -CH3, -CH2CH3, -C(=O)CH3, -C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

56. The compound of any one of claims 32-55, wherein both instances of X are -OH.

57. The compound of any one of claims 32-55, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

58. The compound of any one of claims 32-55, wherein one instance of X is -OH, and one instance of X is -NH2.

59. The compound of any one of claims 32-55, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

60. The compound of any one of claims 32-55, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

61. The compound of any one of claims 32-55, wherein both instances of X are -NH2.

62. The compound of any one of claims 32-55, wherein both instances of X are -NH(CH3).

63. A compound of Formula (III′′):(III′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl; each instance of R1is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, -NO2, or two instances of R1attached to the same carbon atom are taken together to form =O; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:,.

64. The compound of claim 63, wherein the compound is of Formula (III′):(III′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl; R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O;R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl,, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:, , .

65. The compound of claim 63 or 64, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:Ring A is monocyclic or bicyclic heterocyclyl ring, monocyclic or bicyclic heteroaryl ring, or bicyclic aryl ring, provided Ring A is not pyrazolyl; R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group; provided that the compound is not of the formula:,66. The compound of any one of claims 63-65, wherein R2is methyl, fluoro, -CN, -CH2F, -67. The compound of any one of claims 63-66, wherein R3is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

68. The compound of any one of claims 63-67, wherein R3is methyl, and R2is hydrogen.

69. The compound of any one of claims 63-67, wherein R3is fluoro, and R2is fluoro.

70. The compound of any one of claims 63-65 or 67, wherein R3is -CF3, and R2is hydrogen.

71. The compound of any one of claims 63-67, wherein R3is methyl, and R2is methyl.

72. The compound of claim 65, wherein the compound is of Formula (III-A):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

73. The compound of any one of claims 63-72, wherein Ring A is thiopheneyl, pyridinyl, indazolyl, benzothiopheneyl, naphthaleneyl, or imidazolpyridinyl.

74. The compound of any one of claims 63-72, wherein Ring A is substituted or unsubstituted, monocyclic or bicyclic heterocyclyl ring, or substituted or unsubstituted, monocyclic or bicyclic heteroaryl ring.

75. The compound of claim 74, wherein Ring A contains one heteroatom.

76. The compound of any one of claims 63-75, wherein R1is substituted C1-6 alkyl.

77. The compound of any one of claims 63-76, wherein R1is C1-6 alkyl substituted with halogen, carbocyclyl, -OH, -NH2, -CN, or -SO2CH3.

78. The compound of any one of claims 63-77, wherein R1is -CF3, -C(CH3)2(CH2OH),.

79. The compound of any one of claims 63-75, wherein R1is halogen.

80. The compound of any one of claims 63-75 and 79, wherein R1is fluoro.

81. The compound of any one of claims 63-75, wherein R1is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

82. The compound of any one of claims 63-75 or 81, wherein R1is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazolyl, substituted or unsubstituted imidazopyridazinyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted pyrrolidinyl.

83. The compound of any one of claims 63-82, wherein R4is hydrogen.

84. The compound of any one of claims 63-82, wherein R4is substituted or unsubstituted C1-6alkyl.

85. The compound of any one of claims 63-82 and 84, wherein R4is -CF3.

86. The compound of any one of claims 63-82, wherein R4is -OH.

87. The compound of any one of claims 63-82, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

88. The compound of claim 63, wherein RNis substituted or unsubstituted C1-6alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

89. The compound of claim 63 or 88, wherein RNis -CH3, -CH2CH3, -C(=O)CH3, -C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

90. The compound of any one of claims 63-89, wherein both instances of X are -OH.

91. The compound of any one of claims 63-89, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

92. The compound of any one of claims 63-89, wherein one instance of X is -OH, and one instance of X is -NH2.

93. The compound of any one of claims 63-89, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

94. The compound of any one of claims 63-89, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

95. The compound of any one of claims 63-89, wherein both instances of X are -NH2.

96. The compound of any one of claims 63-89, wherein both instances of X are -NH(CH3).

97. A compound of Formula (IV′′):(IV′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, or substituted or unsubstituted heteroaryl ring; is a single or double bond, as valency permits; q is 1 or 2 each instance of R1is independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C26 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ,n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN;each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

98. The compound of claim 97, wherein the compound is of Formula (IV′):(IV′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, or substituted or unsubstituted heteroaryl ring; is a single or double bond, as valency permits; q is 1 or 2 R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond;Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

99. The compound of claim 97 or 98, wherein the compound is of Formula (IV):(IV), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring B is substituted or unsubstituted carbocyclyl ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclyl ring, or substituted or unsubstituted heteroaryl ring; is a single or double bond, as valency permits; q is 1 or 2R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or - CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

100. The compound of any one of claims 97-99, wherein R2is methyl, fluoro, -CN, -CH2F, -CHF2, or -CF3.

101. The compound of any one of claims 97-100, wherein R3is methyl, fluoro, -CN, - CH2F, -CHF2, or -CF3.

102. The compound of any one of claims 97-99, wherein R3is methyl, and R2is hydrogen.

103. The compound of any one of claims 97-101, wherein R3is fluoro, and R2is fluoro.

104. The compound of any one of claims 97-101, wherein R3is -CF3, and R2is hydrogen.

105. The compound of any one of claims 97-101, wherein R3is methyl, and R2is methyl.

106. The compound of claim 99, wherein the compound is of Formula (IV-A):(IV-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

107. The compound of any one of claims 97-106, wherein Ring B is pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl.

108. The compound of any one of claims 97-107, wherein R1is substituted C1-6 alkyl.

109. The compound of any one of claims 97-108, wherein R1is C1-6 alkyl substituted with halogen, carbocyclyl, -OH, -NH2, -CN, or -SO2CH3.

110. The compound of any one of claims 97-109, wherein R1is -CF3, -C(CH3)2(CH2OH),.

111. The compound of any one of claims 97-107, wherein R1is halogen.

112. The compound of any one of claims 97-107 and 111, wherein R1is fluoro.

113. The compound of any one of claims 97-107, wherein R1is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

114. The compound of any one of claims 97-107 or 113, wherein R1is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazolyl, substituted or unsubstituted imidazopyridazinyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted pyrrolidinyl.

115. The compound of any one of claims 97-114, wherein R4is hydrogen.

116. The compound of any one of claims 97-114, wherein R4is substituted or unsubstituted C1-6alkyl.

117. The compound of any one of claims 97-114 and 116, wherein R4is -CF3.

118. The compound of any one of claims 97-114, wherein R4is -OH.

119. The compound of any one of claims 97-114, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

120. The compound of claim 97, wherein RNis substituted or unsubstituted C1-6 alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

121. The compound of claim 97 or 120, wherein RNis -CH3, -CH2CH3, -C(=O)CH3, -C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

122. The compound of any one of claims 97-121, wherein both instances of X are -OH.

123. The compound of any one of claims 97-122, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

124. The compound of any one of claims 97-123, wherein one instance of X is -OH, and one instance of X is -NH2.

125. The compound of any one of claims 97-124, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

126. The compound of any one of claims 97-125, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

127. The compound of any one of claims 97-126, wherein both instances of X are -NH2.

128. The compound of any one of claims 97-127, wherein both instances of X are - NH(CH3).

129. A compound of Formula (V′):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R5is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2Rs, -CN, or -NO3; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN;each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

130. The compound of claim 129, wherein the compound is of Formula (V):(V), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R5is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, -N(RN)2,r -NO3; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; ortwo instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

131. The compound of claim 129 or 130, wherein R2is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

132. The compound of any one of claims 129-131, wherein R3is methyl, fluoro, -CN, - CH2F, -CHF2, or -CF3.

133. The compound of any one of claims 129, 130, or 132, wherein R3is methyl, and R2is hydrogen.

134. The compound of any one of claims 129-132, wherein R3is fluoro, and R2is fluoro.

135. The compound of any one of claims 129, 130, or 132, wherein R3is -CF3, and R2is hydrogen.

136. The compound of any one of claims 129-132, wherein R3is methyl, and R2is methyl.

137. The compound of claim 130, wherein the compound is of Formula (V-A):(V-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

138. The compound of any one of claims 129-137, wherein R5is hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

139. The compound of any one of claims 129-137, wherein R5is hydrogen, - CH2CH2OCH3, -CH2CH2OH, -CH2CF3, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)N(CH3)2, -C(=O)NH(CH3), -SO2CH3, or -SO2CF3.

140. The compound of any one of claims 129-139, wherein R4is hydrogen.

141. The compound of any one of claims 129-139, wherein R4is substituted or unsubstituted C1-6alkyl.

142. The compound of any one of claims 129-139 and 141, wherein R4is -CF3.

143. The compound of any one of claims 129-139, wherein R4is -OH.

144. The compound of any one of claims 129-139, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

145. The compound of claim 129, wherein RNis substituted or unsubstituted C1-6 alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

146. The compound of claim 129 or 145, wherein RNis -CH3, -CH2CH3, -C(=O)CH3, - C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

147. The compound of any one of claims 129-146, wherein both instances of X are -OH.

148. The compound of any one of claims 129-146, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

149. The compound of any one of claims 129-146, wherein one instance of X is -OH, and one instance of X is -NH2.

150. The compound of any one of claims 129-146, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

151. The compound of any one of claims 129-146, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

152. The compound of any one of claims 129-146, wherein both instances of X are -NH2.

153. The compound of any one of claims 129-146, wherein both instances of X are -NH(CH3).

154. A compound of Formula (VI′′):(VI′′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: m is 0, 1, or 2; is a single or double bond; each instance of R1is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, - SO2RS, -NRNSO2RS, -CN, -NO3, -NO2, or two instances of R1attached to the same carbon atom are taken together to form =O; or two instances of R1attached to the same carbon atom are taken together with their intervening atom to form a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive;R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group; provided that the compound is not of the formula:.

155. The compound of claim 154, wherein the compound is of Formula (VI′):(VI′), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:m is 0, 1, or 2; is a single or double bond; R1is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl,-SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

156. The compound of claim 154 or 155, wherein the compound is of Formula (VI):(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: m is 0, 1, or 2; is a single or double bond; R1is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, halogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORO, -SRS, -N(RN)2, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, -NRNC(=O)RC, -SO2RS, -NRNSO2RS, -CN, -NO3, or -NO2; n is an integer between 0 to 4, inclusive; each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6 carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl,, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; andeach instance of RSis independently hydrogen, substituted or unsubstituted C1-6alkyl, or a sulfur protecting group.

157. The compound of any one of claims 154-156, wherein R2is methyl, fluoro, -CN, - CH2F, -CHF2, or -CF3.

158. The compound of any one of claims 154-157, wherein R3is methyl, fluoro, -CN, - CH2F, -CHF2, or -CF3.

159. The compound of any one of claims 154-156 or 158, wherein R3is methyl, and R2is hydrogen.

160. The compound of any one of claims 154-158, wherein R3is fluoro, and R2is fluoro.

161. The compound of any one of claims 154-156 ot 158, wherein R3is -CF3, and R2is hydrogen.

162. The compound of any one of claims 154-158, wherein R3is methyl, and R2is methyl.

163. The compound of claim 156, wherein the compound is of Formula (VI-A):(VI-A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

164. The compound of any one of claims 154-163, wherein m is 1.

165. The compound of any one of claims 154-163, wherein m is 2.

166. The compound of any one of claims 154-165, wherein R1is substituted C1-6 alkyl.

167. The compound of any one of claims 154-166, wherein R1is C1-6alkyl substituted with halogen, carbocyclyl, -OH, -NH2, -CN, or -SO2CH3.

168. The compound of any one of claims 154-167, wherein R1is -CF3, -C(CH3)2(CH2OH),.

169. The compound of any one of claims 154-165, wherein R1is halogen.

170. The compound of any one of claims 154-165 and 169, wherein R1is fluoro.

171. The compound of any one of claims 154-165, wherein R1is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

172. The compound of any one of claims 154-165 or 171, wherein R1is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazolyl, substituted or unsubstituted imidazopyridazinyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted pyrrolidinyl.

173. The compound of any one of claims 154-172, wherein R4is hydrogen.

174. The compound of any one of claims 154-172, wherein R4is substituted or unsubstituted C1-6 alkyl.

175. The compound of any one of claims 154-172 and 174, wherein R4is -CF3.

176. The compound of any one of claims 154-172, wherein R4is -OH.

177. The compound of any one of claims 154-172, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

178. The compound of claim 154, wherein RNis substituted or unsubstituted C1-6alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

179. The compound of claim 154 or 178, whereinNis -CH3, -CH2CH3, -C(=O)CH3, - C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

180. The compound of any one of claims 154-179, wherein both instances of X are -OH.

181. The compound of any one of claims 154-179, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

182. The compound of any one of claims 154-179, wherein one instance of X is -OH, and one instance of X is -NH2.

183. The compound of any one of claims 154-179, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

184. The compound of any one of claims 154-179, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

185. The compound of any one of claims 154-179, wherein both instances of X are -NH2.

186. The compound of any one of claims 154-179, wherein both instances of X are -NH(CH3).

187. A compound of Formula, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond; Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -SRS, -SO2RS, - N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

188. The compound of claim 187, wherein the compound is of Formula (VII):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: each instance of X is independently hydrogen, -ORO, -SRS, -N(RN)2, or halogen; is a single or double bond;Z is -O-, -S-, -C(R2R3)-, -C(R2)-, -C(R3)-, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, as valency permits; g is an integer between 1 and 7, inclusive; R2is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; R3is hydrogen, substituted or unsubstituted C1-6 alkyl, halogen, -ORO, or -CN; or R2and R3are combined to form a substituted or unsubstituted C3-6carbocyclic ring or =O; R4is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RCis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, halogen, -ORO, -N(RN)2, or -CN; each instance of RNis independently hydrogen, substituted or unsubstituted C1-6 alkyl, -C(=O)Rc, -C(=O)ORO, -C(=O)N(RN)2, -SO2RS, or a nitrogen protecting group; or two instances of RNare combined to form a substituted or unsubstituted 4-8 membered heterocyclic ring; each instance of ROis independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted carbocyclyl, or an oxygen protecting group; and each instance of RSis independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a sulfur protecting group.

189. The compound of claim 187 or 188, wherein R2is methyl, fluoro, -CN, -CH2F, - CHF2, or -CF3.

190. The compound of any one of claims 187-189, wherein R3is methyl, fluoro, -CN, - CH2F, -CHF2, or -CF3.

191. The compound of any one of claims 187, 188, or 190, wherein R3is methyl, and R2is hydrogen.

192. The compound of any one of claims 187-190, wherein R3is fluoro, and R2is fluoro.

193. The compound of any one of claims 187, 188, or 190, wherein R3is -CF3, and R2is hydrogen.

194. The compound of any one of claims 187-190, wherein R3is methyl, and R2is methyl.

195. The compound of any one of claims 187-194, wherein R4is hydrogen.

196. The compound of any one of claims 187-194, wherein R4is substituted or unsubstituted C1-6 alkyl.

197. The compound of any one of claims 187-194 and 196, wherein R4is -CF3.

198. The compound of any one of claims 187-194, wherein R4is -OH.

199. The compound of any one of claims 187-194, wherein R4is -NH2, -NH(CH3), or -N(CH3)2.

200. The compound of claim 188, wherein the compound is of Formula (VII-A):or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

201. The compound of claim 187, wherein two instances of RNare joined to form a substituted or unsubstituted 4-8 membered heterocyclic ring.

202. The compound of claim 201, wherein two instances of RNare joined to form a substituted or unsubstituted piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, or 2-oxa-5- azabicyclo[2.2.1]heptane.

203. The compound of any one of claims 187-202, wherein is a double bond and Z is - C(R2)- or -C(R3)-.

204. The compound of any one of claims 187-202, wherein is a single bond and Z is - O-, -S-, or -C(R2R3)-.

205. The compound of any one of claims 187-204, wherein g is 1.

206. The compound of any one of claims 187-204, wherein g is 2.

207. The compound of any one of claims 187-204, wherein g is 3.

208. The compound of any one of claims 187-204, wherein g is 4.

209. The compound of any one of claims 187-204, wherein g is 5.

210. The compound of claim 187, wherein RNis substituted or unsubstituted C1-6 alkyl, -C(=O)RC, -C(=O)ORO, -C(=O)N(RN)2, or -SO2RS.

211. The compound of claim 187 or 210, whereinNis -CH3, -CH2CH3, -C(=O)CH3, -C(=O)OCH3, -C(=O)NH2, -SO2CF3, or -SO2CH3.

212. The compound of any one of claims 187-211, wherein both instances of X are -OH.

213. The compound of any one of claims 187-211, wherein one instance of X is -OH, and one instance of X is -N(RN)2.

214. The compound of any one of claims 187-211, wherein one instance of X is -OH, and one instance of X is -NH2. The compound of any one of claims 187-211, wherein one instance of X is -OH, and one instance of X is -NH(CH3).

216. The compound of any one of claims 187-211, wherein one instance of X is -OH, and one instance of X is -N(CH3)2.

217. The compound of any one of claims 187-211, wherein both instances of X are -NH2.

218. The compound of any one of claims 187-211, wherein both instances of X are -NH(CH3).

219. A pharmaceutical composition comprising the compound of any one of claims 1-218, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and optionally a pharmaceutically acceptable excipient.

220. The pharmaceutical composition of claim 219 further comprising an additional pharmaceutical agent.

221. A method of modulating voltage gated potassium channels, the method comprising contacting a voltage gated potassium channel with the compound of any one of claims 1-218, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or the pharmaceutical composition of claim 219 or 220.

222. The method of claim 221, wherein the voltage gated potassium channel is KV7.2 or KV7.

3. . A method of modulating voltage gated sodium channels, the method comprising contacting a voltage gated sodium channel with the compound of any one of claims 1- 218, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or the pharmaceutical composition of claim 219 or 220.

224. The method of claim 223, wherein the voltage gated sodium channel is Nav1.1, Nav1.3, NaV1.6, NaV1.7, NaV1.8, and / or NaV1.

9.

225. A method of modulating CB1 receptors, the method comprising contacting a CB1 receptor with the compound of any one of claims 1-218, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or the pharmaceutical composition of claim 219 or 220.

226. The method of any one of claims 221-225, wherein the modulating treats a disease or disorder.

227. A method of treating a disease or disorder comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-218, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or the pharmaceutical composition of claim 219 or 220.

228. The method of claim 227, wherein the disease or disorder is a painful condition.

229. The method of claim 228, wherein the painful condition is musculoskeletal pain, headache, transplant pain, neurogenic pain, cancer, or pain from fibromyalgia.

230. The method of claim 228, wherein the painful condition is nociceptive pain, surgical or postoperative pain, post-traumatic pain, arthritis, visceral pain, low back pain, skin pain, neuropathic pain, or central neuropathic pain.

231. The method of claim 230, wherein the arthritis is rheumatoid and osteoarthritis.

232. The method of claim 230, wherein the skin pain is due to a burn, trauma, or inflammation.

233. The method of claim 230, wherein the neuropathic pain is diabetic neuropathic pain, trigeminal neuralgia, post herpetic neuralgia, nerve injury induced pain, neuritis, chemotherapy induced neuropathy pain, or disc herniation pain.

234. The method of claim 230, wherein the central neuropathic pain is spinal cord injury or post-stroke pain.

235. The method of claim 227, wherein the disease or disorder is a neurological disease.

236. The method of claim 235, wherein the neurological disease is epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease, or bipolar disorder.

237. The method of any one of claims 227-236, wherein the disease is associated with pathological hyperexcitability in neurons.

238. The method of any one of claims 227-237, wherein the disease is a neurological disease associated with pathological hyperexcitability in neurons.

239. The method of any one of claims 221-238, wherein the compound or composition is administered systemically.

240. The method of claim 239, wherein the compound or composition is administered orally or by injection.

241. The method of any one of claims 221-238, wherein the compound or composition is administered locally.

242. The method of any one of claims 221-238, wherein the compound or composition is administered topically.

Images