Azepane and pyrrolidine compounds and uses thereof

Abstract

Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can act as potentiators of voltage-gates potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3) and are therefore useful in the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction).

Description

[0001] AZEPANE AND PYRROLIDINE COMPOUNDS AND USES THEREOF RELATEDAPPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Applications, U.S.S.N. 63 / 520,186, filed August 17, 2023, and U.S.S.N. 63 / 568,042, filed March 21, 2024, the entire contents of each of which is incorporated herein by reference. BACKGROUND

[0002] Voltage-gated potassium channels, including the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), are important in controlling neuronal excitability. Kv7.2 / Kv7.3 underlie the neuronal “M-current,” named according to its initial characterization as a neuronal current decreased in response to muscarinic / cholinergic agonists (see Brown, D.A. et al., Nature (1980), 283:673-676). The M-current is a non-inactivating, hyperpolarizing current known to act as a brake on neuronal hyperexcitability. Consequently, a decrease in the Kv7.2-mediated M-current, for example through genetic loss-of-function, can cause neuronal depolarization and an increase in membrane and neuronal excitability that can lead to action potential bursts that manifest as, e.g., epileptic seizures. In contrast, an increase in the Kv7.2-mediated M-current can hyperpolarize the cell membrane and thereby reduce neuronal excitability and prevent the initiation and propagation of action potential bursts and the resultant seizures. Enhancing the open state of Kv7.2 / Kv7.3 channels in neurons favors a hyperpolarized resting state, which reduces rapid action potential spiking (i.e., burst firing). Such enhancement can provide a stabilizing effect on excitable, particularly hyper-excitable, neurons and can therefore be useful in treating certain seizure disorders. This enhancement has been clinically proven to be effective for treatment of seizure disorders, such as partial onset seizures in adults with epilepsy, with retigabine (ezogabine), a known Kv7.2 / Kv7.3 potentiator.

[0003] While significant advances have been made in this field, there remains a substantial need for improved compounds and methods for potentiating voltage-gated potassium channels, including the voltage-gated potassium channels Kv7.2 / Kv7.3. Such compounds and methods can be used to treat diseases, disorders, and conditions in which potassium channel dysfunction is implicated. SUMMARY

[0004] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can act as potentiators of voltage-gated potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3) and are therefore useful in the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto. 1 / 167 12728106_1

[0005] In one aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein Z1, Z2, R1, R2, R3, R4, R5, R6, L, X, Y, RN1, m, n, and p are as defined herein.

[0006] In certain embodiments, for example, a compound of Formula (I) is selected from those recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.

[0007] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0008] As described, compounds and pharmaceutical compositions provided herein can potentiate voltage- gated potassium channels (e.g., Kv7.2 / Kv7.3 potassium channels) and are therefore useful for treating and / or preventing diseases, disorders, and conditions in a subject, including, e.g., indications in which Kv7 potassium channel dysfunction is implicated.

[0009] In other aspects, provided herein are methods and uses of the compounds and pharmaceutical compositions provided herein, including, but not limited to, the following: (a) Methods of potentiating a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. (b) Methods of treating a disease, disorder, or condition associated with Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) dysfunction in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. (c) Method of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled

[0002] 2 / 167 12728106_1 derivative, or prodrug thereof, or a pharmaceutical composition thereof. (d) Methods of potentiating a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) in a cell in vitro comprising contacting the cell with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0010] In another aspect, provided herein are compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In another aspect, provided herein are compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as medicaments and / or in the preparation of medicaments.

[0011] In another aspect, provided herein are kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g., instructions for using the compound or composition included in the kit).

[0012] Also provided herein are methods of preparing compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. Synthetic intermediates useful in the preparation of the compounds and compositions are also provided herein.

[0013] The details of certain embodiments of the disclosure are set forth in the Detailed Description, as described below. Other embodiments of the disclosure will be apparent from the Definitions, Examples, Abstract, and Claims. DEFINITIONS Chemical Definitions

[0014] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0015] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds

[0003] 3 / 167 12728106_1 described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0016] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0017] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0018] 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.

[0019] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0020] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). 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 (“C1–7 alkyl”). 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 (“C1–4 alkyl”). 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 (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In

[0004] 4 / 167 12728106_1 some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), 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 C1–12 alkyl (such as unsubstituted C1–6 alkyl, 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 or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).

[0021] 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. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all 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 20 carbon atoms (“C1–20haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0022] 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, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., 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 (“C1–20

[0005] 5 / 167 12728106_1 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–12 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–11 heteroalkyl”). 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 (“C1–10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–9 heteroalkyl”). 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 (“C1–8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–7 heteroalkyl”). 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 (“C1–6heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1–5heteroalkyl”). 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 (“C1–4heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1–3heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1–2heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6heteroalkyl”). 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.

[0023] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 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 20 carbon atoms (“C2-20alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2–12alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2–11alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). 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 (“C2–6 alkenyl”). 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 (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C2 alkenyl”). 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 C2–4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2-4 alkenyl groups as

[0006] 6 / 167 12728106_1 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 an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 or or (Z)- configuration.

[0024] 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, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., 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 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–20heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–12heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–11heteroalkenyl”). 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 (“C2–10heteroalkenyl”). 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 (“C2–9heteroalkenyl”). 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 (“C2–8heteroalkenyl”). 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 (“C2–7heteroalkenyl”). 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 (“C2–6 heteroalkenyl”). 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 (“C2–5heteroalkenyl”). 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 (“C2–4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2–3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2 heteroalkenyl”). 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 (“C2–6 heteroalkenyl”). 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.

[0025] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having

[0007] 7 / 167 12728106_1 from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). 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 (“C2-8 alkynyl”). 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 (“C2-5 alkynyl”). 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 (“C2-3 alkynyl”). 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 C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0026] 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, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., 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 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2–20heteroalkynyl”). 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 (“C2–10heteroalkynyl”). 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 (“C2–9heteroalkynyl”). 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 (“C2–8 heteroalkynyl”). 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 (“C2–7 heteroalkynyl”). 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 (“C2–6 heteroalkynyl”). 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 (“C2–5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“C2–4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2–3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2 heteroalkynyl”). In some

[0008] 8 / 167 12728106_1 embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C1–6 heteroalkynyl”). 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.

[0027] 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 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). 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 (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl 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 includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0009] 9 / 167 12728106_1

[0028] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). 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 7 ring carbon atoms (“C3-7 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). 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 (“C5-6 cycloalkyl”). 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 C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl 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.

[0029] 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, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is 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. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes 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 is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0030] 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

[0010] 10 / 167 12728106_1 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.

[0031] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzo- thienyl, 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-tetrahydro- pyrano[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.

[0032] 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 pi 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 6-10 ring carbon atoms (“C6-10aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; 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

[0011] 11 / 167 12728106_1 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 more substituents.

[0033] 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 pi 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, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is 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 pi 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. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, 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, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0034] 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

[0012] 12 / 167 12728106_1 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.

[0035] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include 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 naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0036] The term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, −C(=O)−O−C(=O)Raa, −C(=O)SRaa, −C(=O)N(Rbb)2, −C(=S)Raa, −C(=S)N(Rbb)2, −C(=S)S(Raa), −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)SRaa, and −C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0037] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0038] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0039] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted”

[0013] 13 / 167 12728106_1 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 disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur 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 embodiments described herein are not limited in any manner by the exemplary substituents described herein.

[0040] Exemplary substituents (e.g., carbon atom substituents) include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa, −SC(=O)SRaa, −OC(=O)SRaa, −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20 heteroalkenyl, C2–20 heteroalkynyl, C3-10 carbocyclyl, 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, and 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; wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C2–20 alkenyl, C2–20 alkynyl, C1–20 heteroalkyl, C2–20 heteroalkenyl, C2–20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa

[0014] 14 / 167 12728106_1 groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the 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, C1–20 alkyl, C1–20 perhaloalkyl, C2–20 alkenyl, C2–20 alkynyl, C1–20 heteroalkyl, C2–20 heteroalkenyl, C2–20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, 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; each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10 heteroalkenyl, C2–10 heteroalkynyl, C3-10 carbocyclyl, 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 are joined to form =O or =S, and wherein X−is a counterion; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C1–10 heteroalkyl, C2–10 heteroalkenyl, C2–10 heteroalkynyl, 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;

[0015] 15 / 167 12728106_1 each instance of Rffis, independently, selected from hydrogen, C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C1–10 heteroalkyl, C2–10 heteroalkenyl, C2–10 heteroalkynyl, 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; 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, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1–6alkyl), −OCO2(C1–6alkyl), −C(=O)NH2, −C(=O)N(C1–6alkyl)2, −OC(=O)NH(C1–6alkyl), −NHC(=O)( C1–6alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6alkyl)2, −NHC(=O)NH(C1–6alkyl), −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(C1–6alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6alkyl)2, −OC(NH)NH(C1–6alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6alkyl)2, −SO2NH(C1–6alkyl), −SO2NH2, −SO2C1–6alkyl, −SO2OC1–6alkyl, −OSO2C1–6alkyl, −SOC1–6alkyl, −Si(C1–6alkyl)3, −OSi(C1–6alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6alkyl, −SC(=S)SC1–6alkyl, −P(=O)(OC1–6alkyl)2, −P(=O)(C1–6alkyl)2, −OP(=O)(C1–6alkyl)2, −OP(=O)(OC1–6alkyl)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C1–10heteroalkyl, C2–10heteroalkenyl, C2–10heteroalkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; and each X−is a counterion.

[0041] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0042] In certain embodiments, exemplary substituents (e.g., carbon atom substituents) include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −N(Rbb)2, −N(Rbb)3+X−, −SH, −SRaa, −C(=O)Raa, −CO2H, −CHO, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa,

[0016] 16 / 167 12728106_1 −NRbbP(=O)(N(Rbb)2)2, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, 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, C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 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; 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, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C2-10heteroalkenyl, C2-10heteroalkynyl, C3-10carbocyclyl, 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; and each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C1-10heteroalkyl, C2-10heteroalkenyl, C2-10heteroalkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0043] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–6alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–6 alkyl, an oxygen protecting group (e.g., silyl,

[0017] 17 / 167 12728106_1 TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0044] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or a nitrogen protecting group.

[0045] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −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), C2–20alkenyl, C2–20alkynyl, C1–20heteroalkyl, C2–20heteroalkenyl, C2–20heteroalkynyl, 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, Rccand Rddare as defined herein. Nitrogen 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.

[0046] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, 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,

[0018] 18 / 167 12728106_1 N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0047] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of 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.

[0048] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a

[0019] 19 / 167 12728106_1 moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of 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.

[0049] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 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-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 derivatives, N-diphenylborinic acid derivatives, 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 some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.

[0050] In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC),

[0020] 20 / 167 12728106_1 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).

[0051] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0052] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or an oxygen protecting group.

[0053] 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 −Raa, 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.

[0054] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, 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 (PMB), 3,4-

[0021] 21 / 167 12728106_1 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, 4,4'-Dimethoxy-3"'-[N- (imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 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), ethyl carbonate, 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 carbonate (MTMEC-OR), 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).

[0055] 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),

[0022] 22 / 167 12728106_1 allyl, or pivaloyl (Piv).

[0056] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0057] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or a sulfur protecting group.

[0058] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected Raa, 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.

[0059] In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0060] 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 (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., 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.

[0061] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The embodiments provided herein are not limited in any manner by the above

[0023] 23 / 167 12728106_1 exemplary listing of substituents. Other Definitions

[0062] The following definitions are more general terms used throughout the present application.

[0063] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of 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 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, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0064] 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 the present disclosure 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,

[0024] 24 / 167 12728106_1 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+(C1-4 alkyl)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.

[0065] 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”.

[0066] “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.”

[0067] 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.

[0068] The term “solvate” refers to forms of a compound, including salts 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.

[0025] 25 / 167 12728106_1

[0069] The term “hydrate” refers to a solvate wherein the compound 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)).

[0070] 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. See, e.g., Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985. Prodrugs include acid derivatives 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. 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 subject.

[0071] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Isotopically labeled derivatives are also included.

[0072] The terms “composition” and “formulation” are used interchangeably.

[0073] 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 term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0074] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0075] 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

[0026] 26 / 167 12728106_1 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 and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0076] 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.

[0077] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0078] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, 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. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. 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 is an amount sufficient for potentiating a Kv7 potassium channel (e.g., in a subject or in a cell in vitro).

[0079] 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 treating a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with Kv7 potassium channel dysfunction) in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for potentiating a Kv7 potassium channel in a subject.

[0080] 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

[0027] 27 / 167 12728106_1 prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with Kv7 potassium channel dysfunction) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for potentiating a Kv7 potassium channel in a subject.

[0081] “Voltage-gated potassium channels” (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in a cell’s membrane potential. During action potentials, they play an important role in returning the depolarized cell to a resting state. In VGKCs, alpha subunits form the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane cores, the alpha subunits of voltage-gated potassium channels are grouped into 12 families (Kv1-12), of which Kv7 is one family. The Kv7 family of voltage-gated potassium channels consists of five members (Kv7.1-7.5) which are encoded for by the KCNQ1-5 genes, respectively. Of the five, Kv7.2 / Kv7.3 is the active heterotetramer that is the main active Kv7 current in neurons (M-current). A Kv7 potassium channel can be a member selected from Kv7.1, Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5.

[0082] “Potassium channel potentiator” and “potassium channel opener” are used interchangeably and refer to an agent that restores, enhances, or increases the activity of a potassium channel (e.g., voltage- gated potassium channel, e.g., Kv7 potassium channel), for example, by facilitating ion transmission through the potassium channel. “Potentiating,” “potentiation,” and the like, for the purposes of this disclosure, refer to restoring, enhancing, or increasing the activity or effect of a potassium channel. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0083] Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein can act as potentiators of voltage-gated potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3) and can therefore be used in the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same. Additionally, the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.

[0028] 28 / 167 12728106_1 Compounds

[0084] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1and R2are each independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8alkyl, C3-10cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6 alkyl, C3-7 cycloalkyl, or a nitrogen protecting group, or RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted; L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10 aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6 acyl, or two R5are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same

[0029] 29 / 167 12728106_1 carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6 alkyl, C1-6 haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor -N(RN)2; or R4and R6are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted; m and n are both 1; each instance of R’ is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6 alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O; each instance of RN1, RL, and RNis independently H, C1-6alkyl, C3-7cycloalkyl, C1-6acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C1-6acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C1-6acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

[0085] Also provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1and R2are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7

[0030] 30 / 167 12728106_1 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8 alkyl, C3-10 cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6alkyl, C3-7cycloalkyl, or a nitrogen protecting group, or RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted; L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C6-10aryl, 5-10 membered heteroaryl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C1-6acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6acyl, or two R5attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6 alkyl, C1-6 haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor - N(RN)2; m and n are both 0, or m and n are both 1; each instance of R’ is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6 alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O;

[0031] 31 / 167 12728106_1 each instance of RN1, RL, and RNis independently H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

[0086] In certain embodiments of Formula (I), m and n are both 1.

[0087] Also provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein: R1and R2are each independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8alkyl, C3-10cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6 alkyl, C3-7 cycloalkyl, or a nitrogen protecting group, or RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted;

[0032] 32 / 167 12728106_1 L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10 aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6 acyl, or two R5attached to the same carbon atom are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6alkyl, C1-6haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor - N(RN)2; m and n are both 0, or m and n are both 1; each instance of R’ is independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O; each instance of RN1, RL, and RNis independently H, C1-6alkyl, C3-7cycloalkyl, C1-6acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

[0088] In certain embodiments of Formula (I), m and n are both 1.

[0033] 33 / 167 12728106_1

[0089] In certain embodiments, the compound of Formula (I) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0090] In certain embodiments of Formula (I), when m and n are both 1, the compound is of Formula (Iʹ): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0091] In certain embodiments, the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0092] In certain embodiments, the compound of Formula (I-a) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0034] 34 / 167 12728106_1

[0093] In certain embodiments, the compound of Formula (I) is of Formula (I-a-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0094] In certain embodiments, the compound of Formula (I-a-1) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0095] In certain embodiments, the compound of Formula (I) is of Formula (I-a-2): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0096] In certain embodiments, the compound of Formula (I-a-2) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0035] 35 / 167 12728106_1

[0097] In certain embodiments, the compound of Formula (I) is of Formula (I-a-3): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0098] In certain embodiments, the compound of Formula (I-a-3) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0099] In certain embodiments, the compound of Formula (I) is of Formula (I-a-4): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0100] In certain embodiments, the compound of Formula (I-a-4) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0036] 36 / 167 12728106_1

[0101] In certain embodiments, the compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0102] In certain embodiments, the compound of Formula (I) is of the formula: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0103] In certain embodiments, the compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0104] In certain embodiments, the compound of Formula (I) is of Formula (I-a-5): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0105] In certain embodiments, the compound of Formula (I-a-5) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or

[0037] 37 / 167 12728106_1 prodrug thereof.

[0106] In certain embodiments, the compound of Formula (I) is of Formula (I-a-6): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0107] In certain embodiments, the compound of Formula (I) is of Formula (I-a-7): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0108] In certain embodiments, the compound of Formula (I) is of Formula (I-a-8): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0109] In certain embodiments, the compound of Formula (I) is of Formula (I-a-9): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0038] 38 / 167 12728106_1

[0110] In certain embodiments, the compound of Formula (I-a-9) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0111] In certain embodiments, the compound of Formula (I) is of Formula (I-a-10): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0112] In certain embodiments, the compound of Formula (I-a-10) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0113] In certain embodiments, the compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0039] 39 / 167 12728106_1

[0114] In certain embodiments, the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0115] In certain embodiments, the compound of Formula (I-b) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0116] In certain embodiments, the compound of Formula (I) is of Formula (I-b-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0117] In certain embodiments, the compound of Formula (I-b-1) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0040] 40 / 167 12728106_1

[0118] In certain embodiments, the compound of Formula (I) is of Formula (I-b-2): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0119] In certain embodiments, the compound of Formula (I-b-2) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0120] In certain embodiments, the compound of Formula (I) is of Formula (I-b-3): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0121] In certain embodiments, the compound of Formula (I-b-3) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0122] In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In

[0041] 41 / 167 12728106_1 certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, as a free base.

[0123] In the various aspects and embodiments disclosed herein, express reference to a compound of Formula (I) is understood to alternatively refer to a compound of any disclosed subgenus or species thereof, for example, to a compound of Table 1.

[0124] In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts thereof. In certain embodiments, a compound disclosed herein is selected from the compounds recited in Table 1 (in free base form). Table 1

[0042] 42 / 167 12728106_1

[0043] 43 / 167 12728106_1

[0044] 44 / 167 12728106_1

[0045] 45 / 167 12728106_1

[0046] 46 / 167 12728106_1

[0047] 47 / 167 12728106_1

[0048] 48 / 167 12728106_1

[0049] 49 / 167 12728106_1

[0050] 50 / 167 12728106_1

[0051] 51 / 167 12728106_1

[0052] 52 / 167 12728106_1

[0053] 53 / 167 12728106_1 Ex. 127l129 131m133n135 137o

[0054] 54 / 167 12728106_1 a The absolute stereochemistry of Examples 2 and 3 have been arbitrarily defined. b The absolute stereochemistry of Examples 4 and 5 have been arbitrarily defined. c The absolute stereochemistry of Examples 6 and 7 have been arbitrarily defined. d The absolute stereochemistry of Examples 8 and 9 have been arbitrarily defined. e The absolute stereochemistry of Examples 10 and 11 have been arbitrarily defined. f The absolute stereochemistry of Examples 18 and 19 have been arbitrarily defined. g The absolute stereochemistry of Examples 20 and 21 have been arbitrarily defined. h The absolute stereochemistry of Examples 22 and 23 have been arbitrarily defined. i The absolute stereochemistry of Examples 25 and 26 have been arbitrarily defined. j The absolute stereochemistry of Examples 28 and 29 have been arbitrarily defined. k The absolute stereochemistry of Examples 31 and 32 have been arbitrarily defined.lThe absolute stereochemistry of Examples 33 and 34 have been arbitrarily defined.mThe absolute stereochemistry of Example 35 has been arbitrarily defined. n The absolute stereochemistry of Example 36 has been arbitrarily defined.oThe absolute stereochemistry of Examples 37 and 38 have been arbitrarily defined.pThe absolute stereochemistry of Examples 39 and 40 have been arbitrarily defined.qThe absolute stereochemistry of Examples 41 and 42 have been arbitrarily defined.rThe absolute stereochemistry of Examples 43 and 44 have been arbitrarily defined.sThe absolute stereochemistry of Examples 45 and 46 have been arbitrarily defined. t The absolute stereochemistry of Examples 47 and 48 have been arbitrarily defined.uThe absolute stereochemistry of Example 49 has been arbitrarily defined.vThe absolute stereochemistry of Example 50 has been arbitrarily defined.wThe absolute stereochemistry of Example 51 has been arbitrarily defined. x The absolute stereochemistry of Examples 52 and 53 have been arbitrarily defined. y The absolute stereochemistry of Examples 54 and 55 have been arbitrarily defined. z The absolute stereochemistry of Examples 56 and 57 have been arbitrarily defined. aa The absolute stereochemistry of Examples 62 and 63 have been arbitrarily defined. bb The absolute stereochemistry of Examples 65 and 66 have been arbitrarily defined.

[0055] 55 / 167 12728106_1 cc The absolute stereochemistry of Examples 67 and 68 have been arbitrarily defined. dd The absolute stereochemistry of Examples 70 and 71 have been arbitrarily defined. ee The absolute stereochemistry of Examples 72 and 73 have been arbitrarily defined. ff The absolute stereochemistry of Examples 74 and 75 have been arbitrarily defined. gg The absolute stereochemistry of Examples 76 and 77 have been arbitrarily defined. hh The absolute stereochemistry of Examples 78 and 79 have been arbitrarily defined. ii The absolute stereochemistry of Examples 80 and 81 have been arbitrarily defined. jj The absolute stereochemistry of Examples 82 and 83 have been arbitrarily defined. kk The absolute stereochemistry of Examples 85 and 86 have been arbitrarily defined. ll The absolute stereochemistry of Examples 88 and 89 have been arbitrarily defined. mm The absolute stereochemistry of Examples 90 and 93 have been arbitrarily defined. nn The absolute stereochemistry of Examples 91 and 92 have been arbitrarily defined. oo The absolute stereochemistry of Examples 94 and 95 have been arbitrarily defined. pp The absolute stereochemistry of Examples 96 and 97 have been arbitrarily defined. qq The absolute stereochemistry of Example 98 has been arbitrarily defined. rr The absolute stereochemistry of Example 99 has been arbitrarily defined. ss The absolute stereochemistry of Example 100 has been arbitrarily defined. tt The absolute stereochemistry of Examples 101 and 102 have been arbitrarily defined. uu The absolute stereochemistry of Example 103 has been arbitrarily defined. vv The absolute stereochemistry of Example 104 has been arbitrarily defined. ww The absolute stereochemistry of Example 105 has been arbitrarily defined. xx The absolute stereochemistry of Example 106 has been arbitrarily defined. yy The absolute stereochemistry of Example 107 has been arbitrarily defined. zz The absolute stereochemistry of Example 108 has been arbitrarily defined. a1 The absolute stereochemistry of Example 109 has been arbitrarily defined. b1 The absolute stereochemistry of Example 110 has been arbitrarily defined. c1 The absolute stereochemistry of Examples 111 and 112 have been arbitrarily defined. d1 The absolute stereochemistry of Example 113 has been arbitrarily defined. e1 The absolute stereochemistry of Example 114 has been arbitrarily defined. f1 The absolute stereochemistry of Examples 115 and 116 have been arbitrarily defined. g1 The absolute stereochemistry of Examples 117 and 118 have been arbitrarily defined. h1 The absolute stereochemistry of Examples 119 and 120 have been arbitrarily defined. i1 The absolute stereochemistry of Example 121 has been arbitrarily defined. j1 The absolute stereochemistry of Examples 122 and 123 have been arbitrarily defined. k1 The absolute stereochemistry of Example 125 has been arbitrarily defined. l1 The absolute stereochemistry of Examples 126 and 127 have been arbitrarily defined. m1 The absolute stereochemistry of Examples 131 and 132 have been arbitrarily defined. n1 The absolute stereochemistry of Examples 133 and 134 have been arbitrarily defined. o1 The absolute stereochemistry of Examples 137 and 138 have been arbitrarily defined. p1 The absolute stereochemistry of Examples 139 and 140 have been arbitrarily defined.

[0125] The following definitions and embodiments apply to all generic formulae comprising the relevant groups (e.g., Formula (I) or any subgeneric formula thereof) provided herein. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0126] As defined herein, R1is H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6acyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0127] In certain embodiments, R1is H.

[0128] In certain embodiments, R1is halogen. In certain embodiments, R1is F. In certain embodiments, R1

[0056] 56 / 167 12728106_1 is Cl.

[0129] In certain embodiments, R1is optionally substituted C1-6 alkyl. In certain embodiments, R1is unsubstituted C1-6 alkyl. In certain embodiments, R1is optionally substituted C1-3 alkyl. In certain embodiments, R1is unsubstituted C1-3 alkyl. In certain embodiments, R1is methyl.

[0130] In certain embodiments, R1is C1-6 haloalkyl. In certain embodiments, R1is C1-3 haloalkyl. In certain embodiments, R1is C1 haloalkyl. In certain embodiments, R1is -CF3.

[0131] In certain embodiments, R1is optionally substituted C3-7 cycloalkyl. In certain embodiments, R1is unsubstituted C3-7 cycloalkyl. In certain embodiments, R1is C3-7 cycloalkyl substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. In certain embodiments, R1is C3-7 cycloalkyl substituted with one or more instances of halogen. In certain embodiments, R1is C3-7 cycloalkyl substituted with one or more instances of F.

[0132] In certain embodiments, R1is optionally substituted C3-5cycloalkyl. In certain embodiments, R1is C3-5cycloalkyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. In certain embodiments, R1is C4cycloalkyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. In certain embodiments, R1is C4cycloalkyl optionally substituted with one or more instances of halogen. In certain embodiments, R1is C4cycloalkyl optionally substituted with one or more instances of F.

[0133] In certain embodiments, R1is unsubstituted C3cycloalkyl (cyclopropyl). In certain embodiments, R1is cyclopropyl substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. In certain embodiments, R1is cyclopropyl substituted with one or more instances of halogen. In certain embodiments, R1is cyclopropyl substituted with one or more instances of F.

[0134] In certain embodiments, R1is unsubstituted C4cycloalkyl (cyclobutyl). In certain embodiments, R1is cyclobutyl substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. In certain embodiments, R1is cyclobutyl substituted with one or more instances of halogen. In certain embodiments, R1is cyclobutyl substituted with one or more instances of F.

[0135] In certain embodiments, R1is unsubstituted C5cycloalkyl (e.g., cyclopentyl). In certain embodiments, R1is cyclopentyl substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. In certain embodiments, R1is cyclopentyl substituted with one or more instances of halogen. In certain embodiments, R1is cyclopentyl substituted with one or more instances of F.

[0136] In certain embodiments, R1is unsubstituted C6 cycloalkyl (e.g., cyclohexyl). In certain embodiments, R1is cyclohexyl substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. In certain embodiments, R1is cyclohexyl substituted with one or more instances of halogen. In certain embodiments, R1is cyclohexyl substituted with one or more instances of F.

[0137] In certain embodiments, R1is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1is optionally substituted 3-7 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R1is optionally substituted 3-6 membered heterocyclyl. In certain embodiments, R1is optionally substituted 3-6 membered heterocyclyl with 1 or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R1is

[0057] 57 / 167 12728106_1 optionally substituted 3-5 membered heterocyclyl. In certain embodiments, R1is optionally substituted 3- 5 membered heterocyclyl having 1 ring heteroatom selected from O, N, and S. In certain embodiments, R1is optionally substituted 4-membered heterocyclyl having 1 ring heteroatom selected from O, N, and S. In certain embodiments, R1is optionally substituted 4-membered heterocyclyl with 1 ring heteroatoms independently selected from O and N. In certain embodiments, R1is optionally substituted oxetanyl. In certain embodiments, R1is unsubstituted oxetanyl.

[0138] In certain embodiments, R1is optionally substituted C6-10 aryl. In certain embodiments, R1is optionally substituted C6 aryl (phenyl). In certain embodiments, R1is phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl.

[0139] In certain embodiments, R1is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is optionally substituted 5-10 membered heteroaryl with 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R1is optionally substituted 5-6 membered heteroaryl. In certain embodiments, R1is optionally substituted 5-6 membered heteroaryl with 1, 2, or 3 ring heteroatoms independently selected from O, N, and S.

[0140] In certain embodiments, R1is selected from:

[0141] In certain embodiments, R1is -CN.

[0142] In certain embodiments, R1is -ORO. In certain embodiments, R1is -ORO, wherein ROis optionally substituted C1-6alkyl. In certain embodiments, R1is -ORO, wherein ROis optionally substituted C1-3alkyl. In certain embodiments, R1is -ORO, wherein ROis unsubstituted C1-3 alkyl. In certain embodiments, R1is -OMe.

[0143] In certain embodiments, R1is -ORO, wherein ROis C1-6 haloalkyl. In certain embodiments, R1is -ORO, wherein ROis C1-3 haloalkyl. In certain embodiments, R1is -ORO, wherein ROis C1 haloalkyl. In certain embodiments, R1is -OCF3.

[0144] In certain embodiments, R1is -N(RN)2. In certain embodiments, R1is optionally substituted C1-6 acyl.

[0145] In certain embodiments, R1is -SRS. In certain embodiments, R1is -SMe.

[0146] In certain embodiments, R1is -S(=O)2RS1. In certain embodiments, R1is -S(=O)2Me.

[0147] As defined herein, R2is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6 acyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0148] In certain embodiments, R2is H.

[0149] In certain embodiments, R2is halogen. In certain embodiments, R2is F. In certain embodiments, R2

[0058] 58 / 167 12728106_1 is Cl.

[0150] In certain embodiments, R2is optionally substituted C1-6 alkyl. In certain embodiments, R2is unsubstituted C1-6 alkyl. In certain embodiments, R2is optionally substituted C1-3 alkyl. In certain embodiments, R2is unsubstituted C1-3 alkyl. In certain embodiments, R2is methyl.

[0151] In certain embodiments, R2is C1-6 haloalkyl. In certain embodiments, R2is optionally substituted C3-7 cycloalkyl. In certain embodiments, R2is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R2is optionally substituted C6-10 aryl. In certain embodiments, R2is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R2is -CN.

[0152] In certain embodiments, R2is -ORO.

[0153] In certain embodiments, R2is -ORO, wherein ROis optionally substituted C1-6 alkyl. In certain embodiments, R2is -ORO, wherein ROis optionally substituted C1-3 alkyl. In certain embodiments, R2is -ORO, wherein ROis unsubstituted C1-3alkyl. In certain embodiments, R2is -OMe.

[0154] In certain embodiments, R2is -ORO, wherein ROis C1-6haloalkyl. In certain embodiments, R2is -ORO, wherein ROis C1-3haloalkyl. In certain embodiments, R2is -ORO, wherein ROis C1haloalkyl. In certain embodiments, R2is -OCF3.

[0155] In certain embodiments, R2is -N(RN)2. In certain embodiments, R2is optionally substituted C1-6acyl.

[0156] In certain embodiments, R2is -SRS. In certain embodiments, R2is -SMe.

[0157] In certain embodiments, R2is -S(=O)2RS1. In certain embodiments, R2is -S(=O)2Me.

[0158] As defined herein, R3is C1-8alkyl, C3-10cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; and Ar1is C6-10aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted.

[0159] In certain embodiments, R3is optionally substituted C1-8alkyl. In certain embodiments, R3is unsubstituted C1-8alkyl. In certain embodiments, R3is optionally substituted C1-4alkyl. In certain embodiments, R3is unsubstituted C1-4alkyl. In certain embodiments, R3is tert-butyl.

[0160] In certain embodiments, R3is C1-6alkyl substituted with one or more halogen. In certain embodiments, R3is C1-6alkyl substituted with one or more F. In certain embodiments, R3is C1-3alkyl substituted with one or more F. In certain embodiments, R3is -CF3, -CH2CF3, or .

[0161] In certain embodiments, R3is optionally substituted C3-10cycloalkyl.

[0162] In certain embodiments, R3is optionally substituted C3-8 cycloalkyl. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-3 alkyl. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of F and / or methyl. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of F. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of halogen, C1-6 haloalkyl, and / or unsubstituted C1-6 alkyl. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of

[0059] 59 / 167 12728106_1 halogen, C1-3 haloalkyl, and / or unsubstituted C1-3 alkyl. In certain embodiments, R3is C3-8 cycloalkyl optionally substituted with one or more instances of F, -CF3, and / or methyl.

[0163] In certain embodiments, R3is optionally substituted C3-6 cycloalkyl. In certain embodiments, R3is C3-6 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl. In certain embodiments, R3is C3-6 cycloalkyl optionally substituted with one or more instances of F, Me, and / or -CF3. In certain embodiments, R3is C3-6 cycloalkyl optionally substituted with one or more halogen. In certain embodiments, R3is C3-6 cycloalkyl optionally substituted with one or more F. In certain embodiments, R3is C3-6 cycloalkyl substituted with one or more F.

[0164] In certain embodiments, R3is optionally substituted C3-5 cycloalkyl. In certain embodiments, R3is C3-5 cycloalkyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. In certain embodiments, R3is C3-5 cycloalkyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-3alkyl. In certain embodiments, R3is C3-5cycloalkyl optionally substituted with one or more instances of F and / or methyl. In certain embodiments, R3is C3-5cycloalkyl optionally substituted with one or more instances of halogen, C1-6haloalkyl, and / or unsubstituted C1-6alkyl. In certain embodiments, R3is C3-5cycloalkyl optionally substituted with one or more instances of halogen, C1-3haloalkyl, and / or unsubstituted C1-3alkyl. In certain embodiments, R3is C3-5cycloalkyl optionally substituted with one or more instances of F, -CF3, and / or methyl.

[0165] In certain embodiments, R3is C3-5cycloalkyl optionally substituted with one or more instances of F. In certain embodiments, R3is C3-5cycloalkyl substituted with one or more instances of F. In certain embodiments, R3is C4cycloalkyl (cyclobutyl) substituted with one or more instances of F.

[0166] In certain embodiments, R3is C4cycloalkyl substituted with one or more F. In certain embodiments, R3is: . In certain embodiments, R3is: . In certain embodiments, .

[0167] In certain embodiments, R3is selected from:

[0060] 60 / 167 12728106_1

[0168] In certain embodiments, R3is: . In certain embodiments, R3is selected from:

[0169] In certain embodiments, R3is optionally substituted C6-10aryl. In certain embodiments, R3is optionally substituted phenyl. In certain embodiments, R3is phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. In certain embodiments, R3is phenyl optionally substituted with one or more instances of halogen. In certain embodiments, R3is phenyl optionally substituted with one or more instances of F.

[0170] In certain embodiments, R3is selected from:

[0171] In certain embodiments, R3is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R3is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring N atoms. In certain embodiments, R3is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more halogen. In certain embodiments, R3is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more F. In certain embodiments, R3is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and substituted with one or more F. In certain embodiments, R3is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O. In certain embodiment, R3is 3-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O, wherein the heterocyclyl is optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl. In certain embodiment, R3is 3-6 membered heterocyclyl having 1 ring N atom, wherein the heterocyclyl is optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl. In certain embodiments, R3is 3-6 membered heterocyclyl having 1 ring heteroatom selected from N and O, wherein the heterocyclyl is optionally substituted with one or more instances of F, Me, and / or -CF3. In certain embodiments, R3is 3-6 membered heterocyclyl having 1 ring N atom, wherein the heterocyclyl is optionally substituted with one or more instances of F, Me, and / or -CF3.

[0172] In certain embodiments, R3is azetidinyl substituted with one or more F. In certain embodiments, R3is: .

[0061] 61 / 167 12728106_1

[0173] In certain embodiments, R3is selected from: ,

[0174] In certain embodiments, R3is or -(CR’R”)w-Ar1.

[0175] As defined herein, w is 0, 1, or 2. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is 2.

[0176] As defined herein, Ar1is C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted. In certain embodiments, Ar1is optionally substituted C6-10 aryl. In certain embodiments, Ar1is optionally substituted 5-10 membered heteroaryl.

[0177] As defined herein, Z1is CRZor N. In certain embodiments, Z1is CRZ. In certain embodiments, Z1is CH. In certain embodiments, Z1is CCl. In certain embodiments, Z1is CF. In certain embodiments, Z1is N.

[0178] As defined herein, Z2is CRZor N. In certain embodiments, Z2is CRZ. In certain embodiments, Z2is CH. In certain embodiments, Z2is CCl. In certain embodiments, Z2is CF. In certain embodiments, Z2is N.

[0179] In certain embodiments, Z1is CRZand Z2is CRZ. In certain embodiments, Z1is CH and Z2is CH. In certain embodiments, Z1is CRZand Z2is N. In certain embodiments, Z1is CH and Z2is N. In certain embodiments, Z1is N and Z2is CRZ. In certain embodiments, Z1is N and Z2is CH. In certain embodiments, Z1is N and Z2is N.

[0180] As defined herein, each instance of RZis independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted.

[0181] In certain embodiments, at least one instance of RZis H. In certain embodiments, each instance of RZis H.

[0182] In certain embodiments, at least one instance of RZis halogen. In certain embodiments, at least one instance of RZis F. In certain embodiments, at least one instance of RZis Cl.

[0183] In certain embodiments, at least one instance of RZis optionally substituted C1-6alkyl. In certain embodiments, at least one instance of RZis C1-6haloalkyl. In certain embodiments, at least one instance of RZis optionally substituted C3-7cycloalkyl. In certain embodiments, at least one instance of RZis optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of RZis optionally substituted C6-10aryl. In certain embodiments, at least one instance of RZis optionally

[0062] 62 / 167 12728106_1 substituted 5-10 membered heteroaryl. In certain embodiments, at least one instance of RZis -CN. In certain embodiments, at least one instance of RZis -ORO. In certain embodiments, at least one instance of RZis -N(RN)2. In certain embodiments, at least one instance of RZis optionally substituted C1-6 acyl.

[0184] As defined herein, Y is a bond, -CR’R”-, -O-, or -NRY-.

[0185] In certain embodiments, Y is a bond.

[0186] In certain embodiments, Y is -CR’R”-. In certain embodiments, Y is -CH2-.

[0187] In certain embodiments, Y is -O-.

[0188] In certain embodiments, Y is -NRY-. In certain embodiments, Y is -NH-.

[0189] As defined herein, RYis H, C1-6 alkyl, C3-7 cycloalkyl, or a nitrogen protecting group, wherein the alkyl, or cycloalkyl is optionally substituted.

[0190] In certain embodiments, RYis H.

[0191] In certain embodiments, RYis optionally substituted C1-6alkyl. In certain embodiments, RYis optionally substituted C3-7cycloalkyl. In certain embodiments, RYis a nitrogen protecting group.

[0192] In other embodiments, RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the heterocyclyl is optionally substituted. In some embodiments, RYand R3are joined together with the intervening atoms to form optionally substituted 4-6 membered heterocyclyl.

[0193] In certain embodiments, Y is -CR’R”- and R3is optionally substituted C1-8alkyl. In certain embodiments, Y is -CR’R”- and R3is optionally substituted C1-4alkyl. In certain embodiments, Y is -CH2- and R3is unsubstituted C1-4alkyl. In certain embodiments, Y is -CH2- and R3is tert-butyl.

[0194] In certain embodiments,

[0195] In certain embodiments, Y is -CH2- and R3is selected , .

[0196] In certain embodiments, Y is -CH2- and R3is selected , ,

[0197] As defined herein, L is a bond, -CR’R”-, -O-, or -NRL-.

[0198] In certain embodiments, L is a bond.

[0199] In certain embodiments, L is -CR’R”-. In certain embodiments, L is -CH2-.

[0063] 63 / 167 12728106_1

[0200] In certain embodiments, L is -O-.

[0201] In certain embodiments, L is -NRL-. In certain embodiments, L is -NH-.

[0202] As defined herein, RLis H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, or acyl is optionally substituted.

[0203] In certain embodiments, RLis H.

[0204] In certain embodiments, RLis optionally substituted C1-6 alkyl. In certain embodiments, RLis optionally substituted C3-7 cycloalkyl. In certain embodiments, RLis optionally substituted C1-6 acyl. In certain embodiments, RLis a nitrogen protecting group.

[0205] In certain embodiments, when X is -O-, -NRX-, or -S-, then L is not -O- or -NRL-. In certain embodiments, when R6is -OROor -N(RN)2, then L is not -O- or -NRL-.

[0206] As defined herein, R4is H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted.

[0207] In certain embodiments, R4is C1-6alkyl, C1-6haloalkyl, C6-10aryl, 5-10 membered heteroaryl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted.

[0208] In certain embodiments, R4is H, C6-10aryl, 5-10 membered heteroaryl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted.

[0209] In certain embodiments, R4is H, C6-10aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted.

[0210] In certain embodiments, R4is H.

[0211] In certain embodiments, R4is optionally substituted C6-10aryl. In certain embodiments, R4is optionally substituted phenyl. In certain embodiments, R4is unsubstituted phenyl. In certain embodiments, R4is phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl.

[0212] In certain embodiments, R4is phenyl substituted with one or more instances of halogen. In certain embodiments, R4is phenyl substituted with one or more instances of F. In certain embodiments, R4is phenyl substituted with one or more instances of Cl. In certain embodiments, R4is phenyl substituted with one or more instances of unsubstituted C1-6 alkyl.

[0213] In certain embodiments, R4is phenyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or -ORO. In certain embodiments, R4is phenyl optionally substituted with one or more instances of F, Cl, -OMe, and / or -OCF3.

[0214] In certain embodiments, R4is of the formula: , wherein: each instance of R4ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7

[0064] 64 / 167 12728106_1 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.

[0215] In certain embodiments, at least one instance of R4ais halogen. In certain embodiments, at least one instance of R4ais F. In certain embodiments, at least one instance of R4ais Cl.

[0216] In certain embodiments, at least one instance of R4ais -ORO. In certain embodiments, at least one instance of R4ais -OMe or -OCF3.

[0217] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5.

[0218] In certain embodiments,

[0219] In certain embodiments, R4is of the formula: .

[0220] In certain embodiments, R4is: .

[0221] In certain embodiments, R4is: certain embodiments, R4is: .

[0222] In certain embodiments, R4is of one of the following formulae:

[0065] 65 / 167 12728106_1

[0224] In certain embodiments, R4is selected from: ,

[0226] In certain embodiments, R4is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R4is optionally substituted 5-6 membered heteroaryl. In certain embodiments, R4is optionally substituted 5-6 membered heteroaryl having one or two ring heteroatoms independently selected from N, O, and S. In certain embodiments, R4is optionally substituted 5-6 membered heteroaryl having one or two ring heteroatoms independently selected from N and S. In certain embodiments, R4is optionally substituted 5-6 membered heteroaryl having one or two ring heteroatoms independently selected from N and O.

[0227] In certain embodiments, R4is optionally substituted pyridyl. In certain embodiments, R4is pyridyl optionally substituted with one or more instances of halogen, unsubstituted C1-6alkyl, and / or C1-6haloalkyl. In certain embodiments, R4is pyridyl optionally substituted with C1-6haloalkyl. In certain embodiments, R4is pyridyl optionally substituted with -CF3.

[0228] In certain embodiments, R4is optionally substituted thiazolyl. In certain embodiments, R4is thiazolyl optionally substituted with one or more instances of halogen, unsubstituted C1-6alkyl, and / or C1-6haloalkyl. In certain embodiments, R4is thiazolyl optionally substituted with C1-6haloalkyl. In certain embodiments, R4is thiazolyl optionally substituted with -CF3.

[0229] In certain embodiments, R4is optionally substituted imidazolyl. In certain embodiments, R4is imidazolyl optionally substituted with one or more instances of halogen, unsubstituted C1-6alkyl, and / or C1-6haloalkyl. In certain embodiments, R4is imidazolyl optionally substituted with one or more instances of unsubstituted C1-6alkyl and / or C1-6haloalkyl. In certain embodiments, R4is imidazolyl optionally substituted with methyl and / or -CF3.In certain embodiments, R4is optionally substituted isoxazolyl. In certain embodiments, R4is isoxazolyl optionally substituted with one or more instances of halogen, unsubstituted C1-6alkyl, and / or C1-6haloalkyl. In certain embodiments, R4is isoxazolyl optionally substituted with C1-6haloalkyl. In certain embodiments, R4is isoxazolyl optionally substituted with -CF3.

[0066] 66 / 167 12728106_1

[0230] In certain embodiments, R4is selected from:

[0232] In certain embodiments, R4is optionally substituted C3-7 cycloalkyl. In certain embodiments, R4is C3-7 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl. In certain embodiments, R4is C3-7 cycloalkyl optionally substituted with C1-6 haloalkyl. In certain embodiments, R4is C3-7 cycloalkyl optionally substituted with -CF3. In certain embodiments, R4is C3-7 cycloalkyl optionally substituted with one or more halogen. In certain embodiments, R4is C3-7 cycloalkyl optionally substituted with one or more F.

[0233] In certain embodiments, R4is optionally substituted C3-6 cycloalkyl. In certain embodiments, R4is C3-6 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl. In certain embodiments, R4is C3-6 cycloalkyl optionally substituted with C1-6 haloalkyl. In certain embodiments, R4is C3-6cycloalkyl optionally substituted with -CF3. In certain embodiments, R4is C3-6cycloalkyl optionally substituted with one or more halogen. In certain embodiments, R4is C3-6 cycloalkyl optionally substituted with one or more F.

[0234] In certain embodiments, R4is selected from:

[0235] In certain embodiments, R4is selected from:

[0236] In certain embodiments, R4is optionally substituted 3-7 membered heterocyclyl.

[0237] In certain embodiments, R4is optionally substituted 3-7 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O. In certain embodiments, R4is optionally substituted 3-6 membered heterocyclyl having 1 ring oxygen atom. In certain embodiments, R4is optionally substituted 4-membered heterocyclyl having 1 ring oxygen atom. In certain embodiments, R4is: .

[0238] In certain embodiments, R4is optionally substituted C1-6 alkyl. In certain embodiments, R4is unsubstituted C1-6alkyl. In certain embodiments, R4is optionally substituted C1-4alkyl. In certain embodiments, R4is unsubstituted C1-4alkyl. In certain embodiments, R4is tert-butyl. In certain

[0067] 67 / 167 12728106_1 embodiments, R4is methyl.

[0239] In certain embodiments, R4is C1-6 haloalkyl. In certain embodiments, R4is C1-3 haloalkyl. In certain embodiments, R4is C1 haloalkyl. In certain embodiments, R4is trihalomethyl. In certain embodiments, R4is -CF3. In certain embodiments, R4is dihalomethyl. In certain embodiments, R4is -CF2H.

[0240] In certain embodiments, R4and R6are joined together with the intervening atoms to form optionally substituted C3-7 cycloalkyl or optionally substituted 3-7 membered heterocyclyl.

[0241] In certain embodiments, R4and R6are joined together with the intervening atoms to form optionally substituted C3-7 cycloalkyl. In certain embodiments, R4and R6are joined together with the intervening atoms to form unsubstituted C3-7 cycloalkyl. In certain embodiments, R4and R6are joined together with the intervening atoms to form optionally substituted C3-5 cycloalkyl. In certain embodiments, R4and R6are joined together with the intervening atoms to form unsubstituted C3-5cycloalkyl. In certain embodiments, R4and R6are joined together with the intervening atoms to form optionally substituted C4cycloalkyl. In certain embodiments, R4and R6are joined together with the intervening atoms to form: .

[0242] As defined herein, X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-.

[0243] In certain embodiments, X is -CR’R”-. In certain embodiments, X is -CH2-.

[0244] In certain embodiments, X is -O-.

[0245] In certain embodiments, X is -NRX-. In certain embodiments, X is -NH-. In certain embodiments, X is -NMe-.

[0246] In certain embodiments, X is -S-. In certain embodiments, X is -S(=O)2-.

[0247] In certain embodiments, when L is -O- or -NRL-, then X is not -O-, -NRX-, or -S-. In certain embodiments, when R6is -OROor -N(RN)2, then X is not -O-, -NRX-, or -S-.

[0248] As defined herein, RXis H, C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted.

[0249] In certain embodiments, RXis H.

[0250] In certain embodiments, RXis optionally substituted C1-6 alkyl. In certain embodiments, RXis unsubstituted C1-6 alkyl. In certain embodiments, RXis optionally substituted C1-3 alkyl. In certain embodiments, RXis unsubstituted C1-3 alkyl. In certain embodiments, RXis methyl.

[0251] In certain embodiments, RXis optionally substituted C3-7 cycloalkyl. In certain embodiments, RXis optionally substituted C1-6 acyl. In certain embodiments, RXis a nitrogen protecting group.

[0252] In certain embodiments, RXis optionally substituted C6-10aryl. In certain embodiments, RXis optionally substituted phenyl. In certain embodiments, RXis unsubstituted phenyl. In certain embodiments, RXis phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl.

[0253] In certain embodiments, RXis phenyl substituted with one or more instances of halogen. In certain

[0068] 68 / 167 12728106_1 embodiments, RXis phenyl substituted with one or more instances of F. In certain embodiments, RXis phenyl substituted with one or more instances of unsubstituted C1-6 alkyl.

[0254] In certain embodiments, RXis of the formula: , wherein: each instance of RXais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and q is 0, 1, 2, 3, 4, or 5.

[0255] In certain embodiments, at least one instance of RXais halogen. In certain embodiments, at least one instance of RXais F.

[0256] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5.

[0260] In certain embodiments, RXis optionally substituted 5-10 membered heteroaryl.

[0261] In certain embodiments, exactly one of R4and RXis C6-10aryl or 5-10 membered heteroaryl (i.e., both R4and RXcannot be C6-10aryl or 5-10 membered heteroaryl at the same time). In certain embodiments, when RXis C6-10aryl or 5-10 membered heteroaryl, then R4is H. In certain embodiments, when RXis C6-10aryl or 5-10 membered heteroaryl, then R4is H and L is a bond.

[0262] As defined herein, each instance of R5is independently halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6acyl, or two R5are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted.

[0263] In certain embodiments, each instance of R5is independently halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6acyl, or two R5attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O,

[0069] 69 / 167 12728106_1 wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted.

[0264] In certain embodiments, at least one instance of R5is halogen. In certain embodiments, at least one instance of R5is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R5is C1-6 haloalkyl. In certain embodiments, at least one instance of R5is optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of R5is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R5is -CN. In certain embodiments, at least one instance of R5is -ORO. In certain embodiments, at least one instance of R5is -N(RN)2. In certain embodiments, at least one instance of R5is optionally substituted C1-6 acyl.

[0265] In certain embodiments, two R5are joined together with the intervening atoms to form optionally substituted C3-7 cycloalkyl. In certain embodiments, two R5are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl

[0266] In certain embodiments, two R5attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted C3-7cycloalkyl. In certain embodiments, two R5attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl.

[0267] In certain embodiments, two R5attached to the same carbon atom are taken together to form =O.

[0268] As defined herein, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits.

[0269] In certain embodiments, p is 0.

[0270] In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8.

[0271] As defined herein, R6is H, halogen, C1-6alkyl, C1-6haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted.

[0272] In certain embodiments, R6is H.

[0273] In certain embodiments, R6is halogen. In certain embodiments, R6is F.

[0274] In certain embodiments, R6is -ORO. In certain embodiments, R6is -OH.

[0275] In certain embodiments, R6is -N(RN)2.

[0276] In certain embodiments, R6is optionally substituted C1-6alkyl. In certain embodiments, R6is optionally substituted C1-3 alkyl. In certain embodiments, R6is unsubstituted C1-3 alkyl. In certain embodiments, R6is methyl.

[0277] In certain embodiments, R6is C1-6 haloalkyl.

[0278] In certain embodiments, R6is -OH or F. In certain embodiments, R6is -OH, F, or methyl.

[0279] In certain embodiments, when X is -O- or -NRX-, then R6is not -OROor -N(RN)2. In certain embodiments, when L is -O- or -NRL-, then R6is not -OROor -N(RN)2.

[0280] As defined herein, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.

[0281] As defined herein, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1.

[0282] In certain embodiments, m and n are both 0.

[0283] In certain embodiments, m and n are both 1.

[0070] 70 / 167 12728106_1

[0284] As defined herein, each instance of R’ is independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

[0285] In certain embodiments, at least one instance of R’ is H.

[0286] In certain embodiments, at least one instance of R’ is halogen. In certain embodiments, at least one instance of R’ is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R’ is C1-6 haloalkyl. In certain embodiments, at least one instance of R’ is optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of R’ is optionally substituted 3-7 membered heterocyclyl.

[0287] As defined herein, each instance of R” is independently H, halogen, C1-6 alkyl, -ORO, or -N(RN)2, wherein the each alkyl is independently optionally substituted.

[0288] In certain embodiments, at least one instance of R” is H.

[0289] In certain embodiments, at least one instance of R” is halogen. In certain embodiments, at least one instance of R” is optionally substituted C1-6alkyl. In certain embodiments, at least one instance of R” is -ORO. In certain embodiments, at least one instance of R” is -N(RN)2.

[0290] In certain embodiments, R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted. In certain embodiments, R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted C3-7cycloalkyl. In certain embodiments, R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl.

[0291] In certain embodiments, R’ and R” attached to the same carbon atom are taken together to form =O.

[0292] As defined herein, RN1is H, C1-6alkyl, C3-7cycloalkyl, C1-6acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, or acyl is optionally substituted.

[0293] In certain embodiments, RN1is H.

[0294] In certain embodiments, RN1is optionally substituted C1-6alkyl. In certain embodiments, RN1is optionally substituted C3-7cycloalkyl. In certain embodiments, RN1is optionally substituted C1-6acyl. In certain embodiments, RN1is a nitrogen protecting group.

[0295] As defined herein, each RNis independently H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted.

[0296] In certain embodiments, at least one instance of RNis H. In certain embodiments, each instance of RNis H.

[0297] In certain embodiments, at least one instance of RNis optionally substituted C1-6 alkyl.

[0298] In certain embodiments, at least one instance of RNis optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of RNis optionally substituted C1-6 acyl. In certain

[0071] 71 / 167 12728106_1 embodiments, at least one instance of RNis a nitrogen protecting group.

[0299] In certain embodiments, two RNattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, two RNattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 4-6 membered heterocyclyl.

[0300] As defined herein, each instance of ROis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.

[0301] In certain embodiments, at least one instance of ROis H. In certain embodiments, each instance of ROis H.

[0302] In certain embodiments, at least one instance of ROis optionally substituted C1-6 alkyl.

[0303] In certain embodiments, at least one instance of ROis C1-6haloalkyl. In certain embodiments, at least one instance of ROis C1-3haloalkyl. In certain embodiments, at least one instance of ROis C1haloalkyl. In certain embodiments, at least one instance of ROis -CF3.

[0304] In certain embodiments, at least one instance of ROis optionally substituted C3-7cycloalkyl. In certain embodiments, at least one instance of ROis optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of ROis optionally substituted C1-6acyl. In certain embodiments, at least one instance of ROis an oxygen protecting group.

[0305] As defined herein, each instance of RSis independently H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C1-6acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.

[0306] In certain embodiments, at least one instance of RSis H.

[0307] In certain embodiments, at least one instance of RSis optionally substituted C1-6alkyl. In certain embodiments, at least one instance of RSis unsubstituted C1-6alkyl. In certain embodiments, at least one instance of RSis optionally substituted C1-3alkyl. In certain embodiments, at least one instance of RSis unsubstituted C1-3alkyl. In certain embodiments, at least one instance of RSis methyl.

[0308] In certain embodiments, at least one instance of RSis C1-6haloalkyl. In certain embodiments, at least one instance of RSis optionally substituted C3-7cycloalkyl. In certain embodiments, at least one instance of RSis optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of RSis optionally substituted C1-6 acyl. In certain embodiments, at least one instance of RSis a sulfur protecting group.

[0309] As defined herein, each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

[0310] In certain embodiments, at least one instance of RS1is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of RS1is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of RS1is optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of RS1is unsubstituted C1-3 alkyl. In certain embodiments, at least one instance of RS1is methyl.

[0072] 72 / 167 12728106_1

[0311] In certain embodiments, at least one instance of RS1is C1-6 haloalkyl. In certain embodiments, at least one instance of RS1is optionally substituted C3-7 cycloalkyl. In certain embodiments, at least one instance of RS1is optionally substituted 3-7 membered heterocyclyl.

[0312] In certain embodiments of the compounds of Formula (I), the group represented by the following formula: one of the following formulae:

[0073] 73 / 167 12728106_1 .

[0074] 74 / 167 12728106_1 Pharmaceutical Compositions, Kits, and Administration

[0313] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof) and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a 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.

[0314] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound 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.

[0315] 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.

[0316] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or 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.

[0317] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0318] 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, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the 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).

[0075] 75 / 167 12728106_1

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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), 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.

[0323] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). 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

[0076] 76 / 167 12728106_1 container and the second container are combined to form a single unit dosage form. 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 and / or preventing a disease, disorder, or condition in a subject in need thereof.

[0324] 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 provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses

[0325] As described in some aspects, compounds provided herein can act as voltage-gated potassium channel potentiators (e.g., Kv7.2 / Kv7.3 potentiators) and are therefore useful, e.g., for the treatment of diseases, disorders, and conditions.

[0326] In one aspect, provided herein are methods of potentiating a Kv7 potassium channel in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the Kv7 potassium channel is Kv7.2. In certain embodiments, the Kv7 potassium channel is Kv7.3. In certain embodiments, the Kv7 potassium channel is Kv7.2 / Kc7.3. In certain embodiments, the compound or composition is selective for one or more of Kv7.2-Kv7.5 over Kv7.1. In certain embodiments, the compound or composition is selective for one or more of Kv7.2 / Kv7.3 over Kv7.1.

[0327] Also provided herein are compounds disclosed herein, and a pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in potentiating a Kv7 potassium channel in a subject.

[0328] In another aspect, provided herein are methods of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is associated with Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 dysfunction. In certain embodiments, the disease, disorder, or condition is associated with Kv7.2 dysfunction. In certain embodiments, the disease, disorder, or condition is associated with Kv7.3 dysfunction. In certain embodiments, the disease, disorder, or condition is associated with Kv7.2 / Kc7.3 dysfunction.

[0329] Also provided herein are compounds disclosed herein, and a pharmaceutically acceptable salts,

[0077] 77 / 167 12728106_1 stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject.

[0330] In another aspect, provided herein are methods of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0331] Also provided herein are compounds disclosed herein, and a pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof.

[0332] In certain embodiments, the disease, disorder, or condition is a seizure disorder. “Seizure disorders” refers to seizures and disorders associated with seizures such as partial onset seizures (also known as focal onset seizures), photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West’s syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox- Gastaut syndrome (LGS), epilepsy with myoclonic-absences, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsies, Rasmussen’s syndrome, ring chromosome 20 syndrome, reflex epilepsies, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early infantile epileptic encephalopathy, early onset epileptic encephalopathy, generalized epilepsy with febrile seizures +, Rett syndrome, multiple sclerosis, Alzheimer’s disease, autism, ataxia, hypotonia, paroxysmal dyskinesia, generalized onset seizures, or primary generalized tonic-clonic seizures, or a combination thereof. In certain embodiments, the seizure disorder refers to generalized onset seizures. In some embodiments, the generalized onset seizures are primary generalized tonic-clonic seizures. In some embodiments, the seizure disorder is primary generalized tonic-clonic seizures.

[0333] In certain embodiments, the term “seizure disorder” refers to focal onset epilepsy, also known as partial onset epilepsy. In some embodiments, the seizure disorder is photosensitive epilepsy. In some embodiments, the seizure disorder is self-induced syncope. In some embodiments, the seizure disorder is intractable epilepsy. In some embodiments, the seizure disorder is Angelman syndrome. In some embodiments, the seizure disorder is benign rolandic epilepsy. In some embodiments, the seizure disorder is CDKL5 disorder. In some embodiments, the seizure disorder is childhood and juvenile absence epilepsy. In some embodiments, the seizure disorder is Dravet syndrome. In some embodiments, the seizure disorder is frontal lobe epilepsy. In some embodiments, the seizure disorder is Glut1 deficiency syndrome. In some embodiments, the seizure disorder is hypothalamic hamartoma. In some embodiments, the seizure disorder is infantile spasms / West’s syndrome. In some embodiments, the seizure disorder is juvenile myoclonic epilepsy. In some embodiments, the seizure disorder is Landau-

[0078] 78 / 167 12728106_1 Kleffner syndrome. In some embodiments, the seizure disorder is Lennox-Gastaut syndrome (LGS). In some embodiments, the seizure disorder is epilepsy with myoclonic-absences. In some embodiments, the seizure disorder is Ohtahara syndrome. In some embodiments, the seizure disorder is Panayiotopoulos syndrome. In some embodiments, the seizure disorder is PCDH19 epilepsy. In some embodiments, the seizure disorder is progressive myoclonic epilepsies. In some embodiments, the seizure disorder is Rasmussen’s syndrome. In some embodiments, the seizure disorder is ring chromosome 20 syndrome. In some embodiments, the seizure disorder is reflex epilepsies. In some embodiments, the seizure disorder is temporal lobe epilepsy. In some embodiments, the seizure disorder is Lafora progressive myoclonus epilepsy. In some embodiments, the seizure disorder is neurocutaneous syndromes. In some embodiments, the seizure disorder is tuberous sclerosis complex. In some embodiments, the seizure disorder is early infantile epileptic encephalopathy. In some embodiments, the seizure disorder is early onset epileptic encephalopathy. In some embodiments, the seizure disorder is generalized epilepsy. In some embodiments, the seizure disorder is generalized epilepsy with febrile seizures +. In some embodiments, the seizure disorder is Rett syndrome. In some embodiments, the seizure disorder is multiple sclerosis. In some embodiments, the seizure disorder is Alzheimer’s disease. In some embodiments, the seizure disorder is autism. In some embodiments, the seizure disorder is ataxia. In some embodiments, the seizure disorder is hypotonia. In some embodiments, the seizure disorder is paroxysmal dyskinesia. In some embodiments, the seizure disorder is generalized onset seizures. In some embodiments, the seizure disorder is focal onset seizures (also known as partial onset seizures).

[0334] In certain embodiments, the disease, disorder, or condition is a depressive disorder. “Depressive disorders” are mood disorders characterized by depressed mood. In certain embodiments, the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof. Also contemplated by the disclosure is treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, social phobia, agoraphobia, agoraphobia with panic disorder, hypochondriasis, post-traumatic stress disorder (PTSD), treatment-resistant bipolar disorder, generalized anxiety disorder, attention-deficit / hyperactivity disorder (ADHD), bipolar I disorder, bipolar II disorder, manic disorder, cyclothymic disorder and bipolar disorder not otherwise specified, dysthymic disorder, depressive disorder not otherwise specified, minor depression, recurrent brief depressive disorder, depressive-type psychosis, impulse-control disorders, schizophrenia, schizophreniform disorder, schizoaffective disorder, Parkinson’s disease, dementia, Alzheimer’s disease, Huntington’s disease, Tourette’s syndrome, aggression, and substance use and / or abuse, or a combination thereof.

[0335] In some embodiments, the depressive disorder is major depressive disorder (MDD). In some embodiments, the depressive disorder is disruptive mood dysregulation disorder. In some embodiments, the depressive disorder is persistent depressive disorder. In some embodiments, the depressive disorder is

[0079] 79 / 167 12728106_1 bipolar spectrum disorder. In some embodiments, the depressive disorder is postpartum depression. In some embodiments, the depressive disorder is premenstrual dysphoric disorder (PMDD). In some embodiments, the depressive disorder is seasonal affective disorder (SAD). In some embodiments, the depressive disorder is atypical depression. In some embodiments, the depressive disorder is treatment- resistant depression (TRD). In some embodiments, the depressive disorder is depression associated with agitation or anxiety. In some embodiments, the depressive disorder is adjustment disorder with depressed mood. In some embodiments, the depressive disorder is prolonged depressive reaction.

[0336] In certain embodiments, the disease, disorder, or condition is pain. “Pain” as used herein refers to all categories of pain and includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain, orofacial pain, burn pain, burning mouth syndrome, somatic pain, visceral pain, myofacial pain, dental pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and post-operative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, familial hemiplegic migraine, conditions associated with cephalic pain, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, pain following stroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia, and combinations thereof.

[0337] In certain embodiments, the disease, disorder, or condition is anhedonia. “Anhedonia” as used herein refers to markedly diminished interest or pleasure in all, or almost all activities. Anhedonia of mild degree is sometimes referred to as hypohedonia. Social anhedonia is a type of anhedonia. “Social anhedonia” as used herein refers to a disinterest in social contact and a lack of pleasure in social situations. Social anhedonia is characterized by social withdrawal and typically manifests as an indifference to social interactions with other people. This trait is considered to be a central characteristic, as well as a predictor, of schizophrenia spectrum disorders.

[0338] In another aspect, provided herein are compounds disclosed herein, and a pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as medicaments. In certain embodiments, the medicament is for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject (e.g., Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 dysfunction, e.g., Kv7.2 / Kc7.3 dysfunction). In certain embodiments, the medicament is for treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject.

[0339] Also provided herein are methods of potentiating a Kv7 potassium channel in a cell in vitro comprising contacting the cell with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the Kv7 potassium channel is Kv7.2. In certain embodiments, the Kv7 potassium channel is Kv7.3. In certain embodiments, the Kv7 potassium channel is Kv7.2 / Kc7.3. In

[0080] 80 / 167 12728106_1 certain embodiments, the compound or composition is selective for one or more of Kv7.2-Kv7.5 over Kv7.1. In certain embodiments, the compound or composition is selective for one or more of Kv7.2 / Kv7.3 over Kv7.1.

[0340] Provided herein are methods of potentiating a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) in a subject or in a cell in vitro. In certain embodiments, the activity of the Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100%, relative to control. In certain embodiments, the activity of the Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) is increased by at least 1- fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400- fold, at least 500-fold, or at least 1000-fold, relative to control. ADDITIONAL EMBODIMENTS

[0341] Additional embodiments are provided according to the following numbered Embodiments: Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1and R2are each independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8 alkyl, C3-10 cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6 alkyl, C3-7 cycloalkyl, or a nitrogen protecting group, or RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted;

[0081] 81 / 167 12728106_1 L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C6-10 aryl, or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10 aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6 acyl, or two R5attached to the same carbon atom are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6alkyl, C1-6haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor - N(RN)2; m and n are both 0, or m and n are both 1; each instance of R’ is independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O; each instance of RN1, RL, and RNis independently H, C1-6alkyl, C3-7cycloalkyl, C1-6acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted. Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m and n are

[0082] 82 / 167 12728106_1 both 0. Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m and n are both 1. Embodiment 4. The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RN1is H. Embodiment 5. The compound of Embodiment 1, wherein the compound is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 6. The compound of Embodiment 1, wherein the compound is of Formula (I-a-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 7. The compound of Embodiment 1, wherein the compound is of Formula (I-a-2): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 8. The compound of Embodiment 1, wherein the compound is of Formula (I-a-4): 12728106_1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 9. The compound of Embodiment 1, wherein the compound is of Formula (I-a-6): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 10. The compound of Embodiment 1, wherein the compound is of Formula (I-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 11. The compound of Embodiment 1, wherein the compound is of Formula (I-b-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 12. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is CRZ. Embodiment 13. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is CH. Embodiment 14. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is N. Embodiment 15. The compound of any one of the preceding Embodiments, or a

[0083] 84 / 167 12728106_1 pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CRZ. Embodiment 16. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CH. Embodiment 17. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is N. Embodiment 18. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is optionally substituted C1-6 alkyl. Embodiment 19. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1unsubstituted C1-3alkyl. Embodiment 20. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is methyl. Embodiment 21. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is halogen. Embodiment 22. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is F or Cl. Embodiment 23. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is optionally substituted C1-6alkyl. Embodiment 24. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is unsubstituted C1-3 alkyl. Embodiment 25. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is methyl. Embodiment 26. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is halogen. Embodiment 27. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is F.

[0084] 85 / 167 12728106_1 Embodiment 28. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR’R”-. Embodiment 29. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-. Embodiment 30. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C1-8 alkyl. Embodiment 31. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is unsubstituted C1-4alkyl. Embodiment 32. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is tert-butyl. Embodiment 33. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C3-10cycloalkyl. Embodiment 34. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C3-6cycloalkyl. Embodiment 35. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C3-6cycloalkyl optionally substituted with one or more F. Embodiment 36. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is: . Embodiment 37. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted 3-7 membered heterocyclyl. Embodiment 38. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring N atoms. Embodiment 39. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or

[0085] 86 / 167 12728106_1 prodrug thereof, wherein R3is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more F. Embodiment 40. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is: . Embodiment 41. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L is a bond. Embodiment 42. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L is -O-. Embodiment 43. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted phenyl. Embodiment 44. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is of the formula: , wherein: each instance of R4ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5. Embodiment 45. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. Embodiment 46. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is selected from:

[0086] 87 / 167 12728106_1 Embodiment 47. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -CH2-. Embodiment 48. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -O-. Embodiment 49. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -NRX-. Embodiment 50. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis optionally substituted C1-6alkyl. Embodiment 51. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis unsubstituted C1-3alkyl. Embodiment 52. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis methyl. Embodiment 53. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis optionally substituted phenyl. Embodiment 54. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl. Embodiment 55. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis selected from: Embodiment 56. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R6is H. Embodiment 57. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R6is -OH or -F. Embodiment 58. The compound of any one of the preceding Embodiments, or a

[0087] 88 / 167 12728106_1 pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0. Embodiment 59. The compound of Embodiment 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Embodiment 60. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof. Embodiment 61. A pharmaceutical composition comprising a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 62. A method of potentiating a Kv7 potassium channel in a subject comprising administering to the subject a compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Embodiment 63. A method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Embodiment 64. The method of Embodiment 62 or 63, wherein the method enhances opening of a Kv7 potassium channel. Embodiment 65. The method of any one of Embodiments 62-64, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Embodiment 66. The method of any one of Embodiments 62-65, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3. Embodiment 67. A method of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Embodiment 68. The method of any one of Embodiments 62-67, wherein the subject is a human. Embodiment 69. A compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in potentiating a Kv7 potassium channel in a subject. Embodiment 70. A compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject.

[0088] 89 / 167 12728106_1 Embodiment 71. The compound for use of Embodiment 69 or 70, wherein the compound enhances opening of a Kv7 potassium channel. Embodiment 72. The compound for use of any one of Embodiments 69-71, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Embodiment 73. The compound for use of any one of Embodiments 69-72, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3. Embodiment 74. A compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject. Embodiment 75. The compound for use of any one of Embodiments 69-74, wherein the subject is a human. Embodiment 76. A compound of any one of Embodiments 1-60, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0342] Further additional embodiments are provided according to the following numbered Embodiments: Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1and R2are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8 alkyl, C3-10 cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6alkyl, C3-7cycloalkyl, or a nitrogen protecting group, or RYand R3are joined

[0089] 90 / 167 12728106_1 together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted; L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C6-10 aryl, 5-10 membered heteroaryl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10 aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6acyl, or two R5attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6alkyl, C1-6haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor -N(RN)2; m and n are both 1; each instance of R’ is independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O; each instance of RN1, RL, and RNis independently H, C1-6alkyl, C3-7cycloalkyl, C1-6acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

[0090] 91 / 167 12728106_1 Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is H, C6-10 aryl, or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted. Embodiment 3. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 4. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- a-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 5. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 6. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0091] 92 / 167 12728106_1 Embodiment 7. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- a-6): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 8. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- a-9): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 9. The compound of Embodiment 1 or 2, wherein the compound is of Formula (I- a-10): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 10. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is CRZ. Embodiment 11. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is CH. Embodiment 12. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is N.

[0092] 93 / 167 12728106_1 Embodiment 13. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CRZ. Embodiment 14. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CH. Embodiment 15. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CCl or CF. Embodiment 16. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is N. Embodiment 17. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is optionally substituted C1-6alkyl. Embodiment 18. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1unsubstituted C1-3alkyl. Embodiment 19. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is methyl. Embodiment 20. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is halogen. Embodiment 21. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is F or Cl. Embodiment 22. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is C1-6 haloalkyl or -ORO. Embodiment 23. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -CF3 or -OCF3. Embodiment 24. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is optionally substituted C1-6 alkyl. Embodiment 25. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or

[0093] 94 / 167 12728106_1 prodrug thereof, wherein R2is unsubstituted C1-3 alkyl. Embodiment 26. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is methyl. Embodiment 27. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is halogen. Embodiment 28. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is F. Embodiment 29. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR’R”-. Embodiment 30. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-. Embodiment 31. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C1-8alkyl. Embodiment 32. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is unsubstituted C1-4alkyl. Embodiment 33. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is tert-butyl. Embodiment 34. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C3-10cycloalkyl. Embodiment 35. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C3-6 cycloalkyl. Embodiment 36. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C3-6 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl. Embodiment 37. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C3-6 cycloalkyl optionally substituted with one or more F.

[0094] 95 / 167 12728106_1 Embodiment 38. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is: Embodiment 39. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted 3-7 membered heterocyclyl. Embodiment 40. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring N atoms. Embodiment 41. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more F. Embodiment 42. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is: . Embodiment 43. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L is a bond. Embodiment 44. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L is -O-. Embodiment 45. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted phenyl. Embodiment 46. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is of the formula: , wherein:

[0095] 96 / 167 12728106_1 each instance of R4ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5. Embodiment 47. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. Embodiment 48. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is phenyl optionally substituted with one or more instances of halogen and / or -ORO. Embodiment 49. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is selected from: , Embodiment 50. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 5-6 membered heteroaryl. Embodiment 51. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 5-6 membered heteroaryl having one or two ring heteroatoms independently selected from N and S. Embodiment 52. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted thiazolyl, optionally substituted pyridyl, or optionally substituted imidazolyl. Embodiment 53. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is thiazolyl, pyridyl, or imidazolyl, wherein each is optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl.

[0096] 97 / 167 12728106_1 Embodiment 54. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is selected from: Embodiment 55. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -CH2-. Embodiment 56. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -O-. Embodiment 57. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -NRX-. Embodiment 58. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis optionally substituted C1-6alkyl. Embodiment 59. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis unsubstituted C1-3 alkyl. Embodiment 60. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis methyl. Embodiment 61. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis optionally substituted phenyl. Embodiment 62. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6 alkyl. Embodiment 63. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis selected from:

[0097] 98 / 167 12728106_1 Embodiment 64. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R6is H. Embodiment 65. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R6is -OH, -F, or methyl. Embodiment 66. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0. Embodiment 67. The compound of Embodiment 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Embodiment 68. The compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt thereof. Embodiment 69. A pharmaceutical composition comprising a compound of any one of the preceding Embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof. Embodiment 70. A method of potentiating a Kv7 potassium channel in a subject comprising administering to the subject a compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Embodiment 71. A method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Embodiment 72. The method of Embodiment 70 or 71, wherein the method enhances opening of a Kv7 potassium channel. Embodiment 73. The method of any one of Embodiments 70-72, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Embodiment 74. The method of any one of Embodiments 70-73, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3. Embodiment 75. A method of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Embodiment 76. The method of any one of Embodiments 70-75, wherein the subject is a human.

[0098] 99 / 167 12728106_1 Embodiment 77. A compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in potentiating a Kv7 potassium channel in a subject. Embodiment 78. A compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject. Embodiment 79. The compound for use of Embodiment 77 or 78, wherein the compound enhances opening of a Kv7 potassium channel. Embodiment 80. The compound for use of any one of Embodiments 77-79, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Embodiment 81. The compound for use of any one of Embodiments 77-80, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3. Embodiment 82. A compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject. Embodiment 83. The compound for use of any one of Embodiments 77-82, wherein the subject is a human. Embodiment 84. A compound of any one of Embodiments 1-68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament. EXAMPLES

[0343] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological 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 in their scope.

[0344] The examples provided below include procedures, intermediates, and characterization data useful, e.g., for the preparation of compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc. are included herein as aspects of the present disclosure. Synthesis of Compounds Example 1. N-(2,6-dimethyl-4-(7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide

[0099] 100 / 167 12728106_1

[0345] N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide was prepared according to the procedure described on page 52 of WO 2008 / 024398.

[0346] To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.050 g, 0.168 mmol) and 7-phenyl-1,4-oxazepane (0.043 g, 0.201 mmol, hydrochloride) in dioxane (2.0 mL) was added potassium tert-butoxide (0.056 g, 0.499 mmol), 2-(2-ditert-butylphosphanylphenyl)-N,N-dimethylaniline (0.013 g, 0.033 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.015 g, 0.016 mmol) under nitrogen. The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 56%–76% B over 10 min). The desired fraction was collected and lyophilized to afford 0.026 g of N-(2,6-dimethyl-4-(7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (37% yield) as an off-white solid:1H NMR (400 MHz, MeOD-d4) δ 7.31–7.25 (m, 4H), 7.23–7.17 (m, 1H), 6.55 (s, 2H), 4.44 (dd, J = 3.2, 10.8 Hz, 1H), 4.10 (td, J = 3.2, 12.0 Hz, 1H), 3.90–3.82 (m, 2H), 3.82–3.74 (m, 1H), 3.72–3.62 (m, 1H), 3.61–3.51 (m, 1H), 2.39–2.31 (m, 1H), 2.29 (s, 2H), 2.18 (s, 6H), 2.06–1.96 (m, 1H), 1.14 (s, 9H); MS (ES+) m / z 395.3 (M+1). Examples 2 and 3 Step 3. Preparation of N-(2,6-dimethyl-4-(7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide and isolation of individual enantiomers

[0347] N-(2,6-dimethyl-4-(7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (0.210 g, 0.495 mmol) was purified by Chiral SFC (Sample preparation: Add methanol and dichloromethane 25 mL into sample; Instrument: Waters 80Q; Column: Daicel Chiral pak IC column, 250 × 30 mm I.D., mobile Phase: 35% methanol (0.1% ammonium hydroxide) in Supercritical carbon dioxide; Flow Rate: 65

[0100] 101 / 167 12728106_1 g / min; Cycle Time: 4.0 min, total time: 140 min; Single injection volume: 1.0 mL; Back Pressure: 100 bar to keep the carbon dioxide in Supercritical flow; UV: 220 nm). The desired fraction (peak 1, retention time = 1.997 min) was collected and lyophilized to afford 0.072 g of N-(2,6-dimethyl-4-(7- phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (36% yield, 98% purity, 99% ee) as an off- white solid.

[0348] Peak 1:1H NMR (400 MHz, MeOD-d4) δ 7.30–7.25 (m, 4H), 7.24–7.18 (m, 1H), 6.55 (s, 2H), 4.44 (dd, J = 3.6, 10.8 Hz, 1H), 4.10 (td, J = 3.2, 12.4 Hz, 1H), 3.91–3.75 (m, 3H), 3.72–3.63 (m, 1H), 3.61– 3.52 (m, 1H), 2.39–2.27 (m, 3H), 2.19 (s, 6H), 2.01 (tdd, J = 5.6, 11.2, .4 Hz, 1H), 1.14 (s, 9H); MS (ES+) m / z 395.2 (M + 1).

[0349] The desired fraction (peak 2, retention time = 2.085 min) was collected and lyophilized to give the product 2 (0.0700 g, 98% purity, 90% ee). The product 2 was purified by Chiral SFC (Instrument: Waters 80Q Preparative SFC system; Column: Daicel Chiral pak IC column, 250 × 30 mm I.D., 5 µm particle size; Mobile Phase: Phase A for Supercritical carbon dioxide and Phase B for ethanol (0.1% ammonium hydroxide); Isocratic elution: 35% Phase B in Supercritical carbon dioxide; Flow rate: 65g / min; cycle time: 4.5 min; Back Pressure: 100 bar to keep the carbon dioxide in Supercritical flow; UV: 220 nm). The desired fraction (peak 2, retention time = 2.086 min) was collected and lyophilized to afford 0.060 g of N-(2,6-dimethyl-4-(7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (30% yield, 98% purity, 99% ee) as an off-white solid.

[0350] Peak 2:1H NMR (400 MHz, MeOD-d4) δ 7.29–7.25 (m, 4H), 7.24–7.17 (m, 1H), 6.55 (s, 2H), 4.44 (dd, J = 3.2, 10.8 Hz, 1H), 4.10 (td, J = 3.2, 12.0 Hz, 1H), 3.91–3.73 (m, 3H), 3.71–3.62 (m, 1H), 3.61– 3.50 (m, 1H), 2.38–2.26 (m, 3H), 2.18 (s, 6H), 2.07–1.95 (m, 1H), 1.14 (s, 9H); MS (ES+) m / z 395.2 (M + 1).

[0351] The following further examples (Table 2) were prepared analogously to Examples 1-3 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC). Table 2

[0101] 102 / 167 12728106_1 a Examples 4 and 5 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. b Examples 6 and 7 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. c Examples 8 and 9 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. d Examples 20 and 21 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. e Examples 22 and 23 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. f Examples 18 and 19 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.

[0102] 103 / 167 12728106_1 Examples 10 and 11. (R)-N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3- dimethylbutanamide and (S)- N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3- yl)-3,3-dimethylbutanamide (single enantiomers with unknown absolute stereochemistry; stereochemistry has been arbitrarily defined)

[0352] To a solution of 3-(4-fluorophenyl)-3-oxo-propanenitrile (15.0 g, 91.9 mmol) in tetrahydrofuran (306.0 mL) was added borane (1 M in tetrahydrofuran, 184.0 mL) at 25 °C over 0.5 h under a nitrogen atmosphere. The mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. The reaction was quenched with methanol (100 mL), the mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (220 g SepaFlash® Silica Flash Column, eluent of 0–24% methanol (10% ammonium hydroxide) / dichloromethane gradient at 100 mL / min) to afford 3.8 g of 3-amino-1-(4- fluorophenyl)propan-1-ol (22% yield) as yellow oil:1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 5.6, 8.0 Hz, 2H), 7.01 (t, J = 8.4 Hz, 2H), 4.92 (dd, J = 2.4, 8.4 Hz, 1H), 3.08 (td, J = 4.8, 12.4 Hz, 1H), 2.94 (ddd, J = 4.0, 9.2, 12.4 Hz, 1H), 2.74 (s, 2H), 1.87–1.78 (m, 1H), 1.77–1.65 (m, 1H).

[0353] To a solution of 3-amino-1-(4-fluorophenyl)propan-1-ol (3.7 g, 19.7 mmol) in dichloromethane (80.0 mL) was added trimethylamine (7.3 g, 72.4 mmol) and 2-chloroacetyl chloride (2.2 g, 19.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. Water (30 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3.8 g of 2-chloro-N-(3-(4-fluorophenyl)-3- hydroxypropyl)acetamide as yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ 7.38–7.29 (m, 2H), 7.18 (s, 1H), 7.09–6.99 (m, 2H), 4.76 (dd, J = 5.2, 7.6 Hz, 1H), 4.05 (s, 2H), 3.67 (dt, J = 7.2, 13.6 Hz, 1H), 3.34 (qd, J = 5.2, 14.0 Hz, 1H), 3.15–3.04 (m, 1H), 1.98–1.84 (m, 2H).

[0103] 104 / 167 12728106_1

[0354] To a solution of 2-chloro-N-(3-(4-fluorophenyl)-3-hydroxypropyl)acetamide (6.8 g, 24.9 mmol) in tetrahydrofuran (700.0 mL) was added sodium tert-butoxide (4.8 g, 49.8 mmol). The mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (3 × 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase chromatography (0.1% formic acid) and concentrated to afford 1.2 g of 7-(4- fluorophenyl)-1,4-oxazepan-3-one (21% yield) as a yellow solid. Step 4. Preparation of 7-(4-fluorophenyl)-1,4-oxazepane

[0355] To a solution of 7-(4-fluorophenyl)-1,4-oxazepan-3-one (0.49 g, 2.32 mmol) in tetrahydrofuran (10.0 mL) was added dropwise lithium aluminum hydride (2.5 M in tetrahydrofuran, 1.4 mL) at 0 °C over 15 min under nitrogen atmosphere. The mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. The reaction was quenched with saturated sodium potassium tartrate solution (15 mL). The reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.37 g of 7-(4-fluorophenyl)-1,4-oxazepane (69% yield) as yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 5.2, 8.4 Hz, 2H), 7.06–6.98 (m, 2H), 4.73 (dd, J = 4.4, 9.6 Hz, 1H), 4.03 (td, J = 4.0, 12.8 Hz, 1H), 3.81–3.68 (m, 1H), 3.15–2.97 (m, 4H), 2.25–2.15 (m, 1H), 2.02–1.95 (m, 1H).

[0356] To a solution of 6-bromo-2,4-dimethyl-pyridin-3-amine (5.0 g, 24.9 mmol) in dichloromethane (50.0 mL) was added pyridine (5.9 g, 74.6 mmol), then 3,3-dimethylbutanoyl chloride (3.7 g, 27.3 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (2 × 10 mL), 1M

[0104] 105 / 167 12728106_1 hydrochloric acid (2 × 10 mL) and sodium bicarbonate (2 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 0–25% ethyl acetate / petroleum ether gradient at 80 mL / min) to afford 5.4 g of N-(6-bromo-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide (69% yield) as a white solid:1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.41 (s, 1H), 2.31 (s, 3H), 2.24 (s, 2H), 2.14 (s, 3H), 1.05 (s, 9H). Step 6. Preparation of N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3- dimethylbutanamide

[0357] To a solution of N-(6-bromo-2,4-dimethyl-3-pyridyl)-3,3-dimethyl-butanamide (0.150 g, 0.496 mmol) in dioxane (3.0 mL) was added 7-(4-fluorophenyl)-1,4-oxazepane (0.135 g, 0.588 mmol) and cesium carbonate (0.485 g, 1.490 mmol), then methanesulfonato(2-dicyclohexylphosphino-2,6- bis(dimethylamino)-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.040 g, 0.050 mmol) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0– 53% ethyl acetate / petroleum ether gradient at 60 mL / min) to afford 0.150 g of N-(6-(7-(4-fluorophenyl)- 1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide (72% yield) as a white solid:1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.37–7.29 (m, 2H), 7.15–7.05 (m, 2H), 6.42 (s, 1H), 4.48 (dd, J = 2.4, 10.4 Hz, 1H), 4.13–4.04 (m, 1H), 4.03–3.88 (m, 2H), 3.75–3.60 (m, 3H), 2.17 (s, 6H), 2.06 (s, 3H), 1.91–1.78 (m, 1H), 1.05 (s, 9H). Step 7. Preparation of (R)-N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3- dimethylbutanamide and (S)-N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3- dimethylbutanamide (SFC purification for isolation of single enantiomers with unknown absolute

[0358] N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide (0.190 g, 0.459 mmol) was purified by Chiral SFC (Instrument: Waters 80Q Preparative SFC system; Column: Daicel Chiral pak IG column, 250 mm × 25 mm I.D., 10 µm particle size; Mobile Phase: Phase

[0105] 106 / 167 12728106_1 A for Supercritical carbon dioxide and Phase B for methanol (0.1% ammonium hydroxide); Isocratic elution: 50% Phase B in Supercritical carbon dioxide; Flow rate: 70 g / min; cycle time: 5.9 min; Back Pressure: 100 bar to keep the carbon dioxide in Supercritical flow; UV: 220 nm). The desired fraction (peak 1, retention time = 1.811 min) was collected and lyophilized to give (R)-N-(6-(7-(4-fluorophenyl)- 1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide (0.0686 g, 0.154 mmol, 34% yield, 93% purity, 99% ee) as a white solid (absolute stereochemistry arbitrarily assigned):1H NMR (400 MHz, MeOD-d4) δ 7.35–7.26 (m, 2H), 7.05–6.96 (m, 2H), 6.44 (s, 1H), 4.45 (dd, J = 3.2, 10.4 Hz, 1H), 4.19–4.09 (m, 2H), 3.96–3.76 (m, 3H), 3.70–3.59 (m, 1H), 2.35–2.23 (m, 6H), 2.16 (s, 3H), 2.03–1.90 (m, 1H), 1.13 (s, 9H); MS (ES+) m / z 414.4 (M + 1).

[0359] The desired fraction (peak 1, retention time = 1.811 min) was collected and lyophilized to afford 0.069 g of N-(6-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-2,4-dimethylpyridin-3-yl)-3,3- dimethylbutanamide (34% yield, 93% purity, 99% ee) as a white solid (absolute stereochemistry arbitrarily assigned):1H NMR (400 MHz, MeOD-d4) δ 7.35–7.26 (m, 2H), 7.05–6.96 (m, 2H), 6.44 (s, 1H), 4.45 (dd, J = 3.2, 10.4 Hz, 1H), 4.19–4.09 (m, 2H), 3.96–3.76 (m, 3H), 3.70–3.59 (m, 1H), 2.35– 2.23 (m, 6H), 2.16 (s, 3H), 2.03–1.90 (m, 1H), 1.13 (s, 9H); MS (ES+) m / z 414.4 (M + 1).

[0360] The following further examples (Table 2A) were prepared analogously to the foregoing Examples (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC). Table 2A

[0106] 107 / 167 12728106_1

[0107] 108 / 167 12728106_1

[0108] 109 / 167 12728106_1

[0109] 110 / 167 12728106_1

[0110] 111 / 167 12728106_1 i Examples 25 and 26 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. j Examples 28 and 29 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. k Examples 31 and 32 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.lExamples 33 and 34 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.mExample 35 is a single enantiomer with unknown absolute stereochemistry. The absolute stereochemistry has been arbitrarily defined. n Example 36 is a single enantiomer with unknown absolute stereochemistry. The absolute stereochemistry has been arbitrarily defined.oExamples 37 and 38 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.pExamples 39 and 40 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.qExamples 41 and 42 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.rExamples 43 and 44 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.sExamples 45 and 46 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.tExamples 47 and 48 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.uExample 49 is a single enantiomer with unknown absolute stereochemistry. The absolute stereochemistry has been arbitrarily defined.vExample 50 is a single enantiomer with unknown absolute stereochemistry. The absolute stereochemistry has been arbitrarily defined.wExample 51 is a single enantiomer with unknown absolute stereochemistry. The absolute stereochemistry has been arbitrarily defined. aa Examples 62 and 63 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. bb Examples 65 and 66 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. cc Examples 67 and 68 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. dd Examples 70 and 71 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. ee Examples 72 and 73 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. ff Examples 74 and 75 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. gg Examples 76 and 77 are single enantiomers with unknown absolute stereochemistry. The absolute

[0111] 112 / 167 12728106_1 stereochemistry of each has been arbitrarily defined. hh Examples 78 and 79 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. ii Examples 80 and 81 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. jj Examples 82 and 83 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. kk Examples 82 and 83 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. Example 12. N-(4-(3-(4-fluorophenoxy)pyrrolidin-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide (+ / -) Step 1. Preparation of N-(4-(3-(4-fluorophenoxy)pyrrolidin-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0361] To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.050 g, 0.168 mmol) in dioxane (1.0 mL) was added 3-(4-fluorophenoxy)pyrrolidine (0.031 g, 0.171 mmol, hydrochloride) and cesium carbonate (0.164 g, 0.503 mmol), then methanesulfonato(2-dicyclohexylphosphino-2,6- bis(dimethylamino)-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.014 g, 0.017 mmol) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 54%–84% B over 6 min). The desired fraction was collected and lyophilized to afford 0.027 g of N-(4-(3-(4-fluorophenoxy)pyrrolidin-1-yl)-2,6- dimethylphenyl)-3,3-dimethylbutanamide (40% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.05–6.96 (m, 2H), 6.96–6.89 (m, 2H), 6.32 (s, 2H), 5.09–5.03 (m, 1H), 3.64 (dd, J = 4.8, 10.8 Hz, 1H), 3.45–3.35 (m, 3H), 2.23–2.25 (s, 4H), 2.16 (s, 6H), 1.13 (s, 9H); MS (ES+) m / z 399.3 (M + 1). Example 13: Preparation of (+ / -)-N-(4-(7-(4-fluorophenyl)-3-oxo-1,4-oxazepan-4-yl)-2,6- dimethylphenyl)-3,3-dimethylbutanamide

[0362] To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.100 g, 0.335 mmol) in 2-methylbutan-2-ol (1.0 mL) was added 7-(4-fluorophenyl)-1,4-oxazepan-3-one (0.082 g, 0.365 mmol) and cesium carbonate (0.328 g, 1.010 mmol), then methanesulfonato(2-dicyclohexylphosphino-

[0112] 113 / 167 12728106_1 2,6-bis(dimethylamino)-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.028 g, 0.035 mmol) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=5 / 1) to afford 0.012 g of racemic N-(4-(7-(4-fluorophenyl)-3-oxo-1,4-oxazepan-4-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.43 (dd, J = 5.2, 8.4 Hz, 2H), 7.12–7.05 (m, 2H), 7.02 (s, 2H), 4.79 (s, 1H), 4.66–4.62 (m, 1H), 4.43–4.40 (m, 1H), 4.21 (dd, J = 10.8, 14.8 Hz, 1H), 3.87–3.77 (m, 1H), 2.32 (s, 2H), 2.24 (s, 6H), 2.23–2.11 (m, 2H), 1.14 (s, 9H); MS (ES+) m / z 427.3 (M + 1). Example 14: N-(4-(3-(4-fluorophenoxy)pyrrolidin-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide (+ / -) Step 1. Preparation of tert-butyl 4-(4-fluorophenyl)-4-hydroxyazepane-1-carboxylate

[0363] To a solution of tert-butyl 4-oxoazepane-1-carboxylate (10.0 g, 46.9 mmol) in tetrahydrofuran (150 mL) was added dropwise (4-fluorophenyl) magnesium bromide (2 M in diethyl ether, 35.2 mL) at 0 °C under nitrogen. The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by addition saturated ammonium chloride (400 mL) at 25 °C, and then diluted with ethyl acetate (200 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent of 0–30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford 10.2 g of tert-butyl 4-(4-fluorophenyl)- 4-hydroxyazepane-1-carboxylate (56% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.51– 7.43 (m, 2H), 7.04 (dt, J = 3.2, 8.8 Hz, 2H), 3.77–3.62 (m, 3H), 3.62–3.36 (m, 1H), 2.78–2.55 (m, 1H), 2.36–2.15 (m, 1H), 2.00–1.73 (m, 4H), 1.50 (d, J = 6.8 Hz, 9H). Step 2. Preparation of N-(4-(azetidin-3-yl)-2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3- dimethylbutanamide

[0113] 114 / 167 12728106_1

[0364] A mixture of tert-butyl 4-(4-fluorophenyl)-4-hydroxyazepane-1-carboxylate (4.0 g, 10.3 mmol) and acetyl chloride (4.1 g, 51.7 mmol) in methanol (50.0 mL) was stirred at 25 °C for 12 h. The pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reversed-phase chromatography (0.1% formic acid) and concentrated under reduced pressure to afford 1.0 g of 4-(4- fluorophenyl)azepan-4-ol (37% yield, formate salt) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.59–7.48 (m, 2H), 7.14–7.01 (m, 2H), 3.51 (ddd, J = 2.0, 11.6, 13.6 Hz, 1H), 3.42–3.34 (m, 1H), 3.29– 3.13 (m, 2H), 2.39 (ddd, J = 2.4, 11.2, 15.6 Hz, 1H), 2.29–2.16 (m, 1H), 2.15–2.06 (m, 1H), 2.05–1.69 (m, 3H). Step 3. Preparation of N-(4-(4-(4-fluorophenyl)-4-hydroxyazepan-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0365] To a solution of 4-(4-fluorophenyl)azepan-4-ol (0.200 g, 0.776 mmol, formate) and N-(4-bromo- 2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.231 g, 0.775 mmol) in dioxane (3.0 mL) was added methanesulfonato(2-dicyclohexylphosphino-2,6-bis(dimethylamino)-1,1-biphenyl)(2-amino-1,1- biphenyl-2-yl)palladium(II) (0.062 g, 0.076 mmol) and sodium tert-butoxide (2 M in tetrahydrofuran, 1.2 mL) under nitrogen. The mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0–52% ethyl acetate / petroleum ether gradient @ 80 mL / min). The desired fraction was collected and concentrated in vacuo to afford 0.17 g of racemic N-(4-(4-(4- fluorophenyl)-4-hydroxyazepan-1-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (49% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.49–7.40 (m, 2H), 7.01 (t, J = 8.8 Hz, 1H), 6.48 (s, 2H), 3.73–3.61 (m, 1H), 3.57–3.49 (m, 1H), 3.48–3.39 (m, 2H), 2.45–2.32 (m, 1H), 2.30 (s, 2H), 2.19 (s, 6H), 2.17–2.09 (m, 1H), 2.06–1.75 (m, 4H), 1.15 (s, 9H); MS (ES+) m / z 427.3 (M + 1). Example 15: N-(2,6-dimethyl-4-(4-methyl-5-phenyl-1,4-diazepan-1-yl)phenyl)-3,3- dimethylbutanamide (+ / -) Step 1. Preparation of 4-methyl-5-phenyl-1,4-diazepan-2-one (+ / -)

[0114] 115 / 167 12728106_1

[0366] To a solution of 5-phenyl-1,4-diazepan-2-one (0.50 g, 2.63 mmol) in methanol (10.0 mL) was added formaldehyde (2.13 g, 26.30 mmol, 37% purity in water). The mixture was stirred at 25 °C for 0.5 h. Then sodium cyanoborohydride (0.33 g, 5.25 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (10 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (3 × 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.43 g of racemic 4-methyl-5-phenyl-1,4- diazepan-2-one (72% yield, 90% purity) as a white solid that was used without further purification:1H NMR (400 MHz, MeOD-d4) δ 7.38–7.31 (m, 4H), 7.31–7.25 (m, 1H), 3.66–3.53 (m, 1H), 3.30–3.11 (m, 4H), 2.56–2.44 (m, 1H), 2.43–2.33 (m, 1H), 2.08–1.99 (m, 3H). Step 2. Preparation of 1-methyl-7-phenyl-1,4-diazepane (+ / -)

[0367] To a solution of lithium aluminum hydride (2.5 M in tetrahydrofuran, 1.14 mL) was added 4- methyl-5-phenyl-1,4-diazepan-2-one (0.430 g, 1.89 mmol) in tetrahydrofuran (20.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction was quenched with saturated sodium potassium tartrate solution (5 mL). The reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 µm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 1%–20% B over 10 min) to afford 0.121 g of racemic 1- methyl-7-phenyl-1,4-diazepane (30% yield, 90% purity) as white oil:1H NMR (400 MHz, MeOD-d4) δ 7.55–7.43 (m, 5H), 4.48–4.29 (m, 1H), 3.97–3.70 (m, 4H), 3.68–3.46 (m, 2H), 2.87–2.71 (m, 1H), 2.70– 2.56 (m, 3H), 2.43–2.28 (m, 1H). Step 3. Preparation of N-(2,6-dimethyl-4-(4-methyl-5-phenyl-1,4-diazepan-1-yl)phenyl)-3,3- dimethylbutanamide (+ / -)

[0115] 116 / 167 12728106_1

[0368] To a solution of N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (0.150 g, 0.503 mmol) in dioxane (3.0 mL) was added 1-methyl-7-phenyl-1,4-diazepane (0.107 g, 0.506 mmol) and cesium carbonate (0.492 g, 1.510 mmol), then methanesulfonato(2-dicyclohexylphosphino-2,6- bis(dimethylamino)-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.041 g, 0.051 mmol) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient:18%–48% B over 10 min). The desired fraction was collected and lyophilized to afford 0.023 g of racemic N-(2,6-dimethyl-4-(4-methyl-5-phenyl-1,4-diazepan-1- yl)phenyl)-3,3-dimethylbutanamide (10% yield) as an off-white solid:1H NMR (400 MHz, MeOD-d4) δ 7.48–7.32 (m, 5H), 6.56 (s, 2H), 4.00–3.87 (m, 1H), 3.83–3.73 (s, 2H), 3.66–3.53 (m, 2H), 3.52–3.42 (m, 1H), 2.59–2.46 (m, 1H), 2.37 (s, 3H), 2.29 (s, 2H), 2.28–2.24 (s, 1H), 2.19 (s, 6H), 1.14 (s, 9H); MS (ES+) m / z 408.4 (M + 1). Example 16: N-(4-(4-fluoro-4-(4-fluorophenyl)azepan-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide (+ / -) Step 1. Preparation of N-(4-(4-fluoro-4-(4-fluorophenyl)azepan-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0369] To a solution of N-(4-(4-(4-fluorophenyl)-4-hydroxyazepan-1-yl)-2,6-dimethylphenyl)-3,3- dimethyl butanamide (0.120 g, 0.281 mmol) in dichloromethane (6.0 mL) was added (bis-(2- methoxyethyl)amino)sulfur trifluoride (0.096 g, 0.434 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched by addition of saturated sodium bicarbonate aqueous solution (5 mL) at 0 °C, and then extracted with dichloromethane (2 × 10 mL). The combined organic phases were concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna 150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; B%: 60%–90%, B over 10 min). The desired fraction was collected and lyophilized to afford 0.01 g of N-(4- (4-fluoro-4-(4-fluorophenyl)azepan-1-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (8% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.42–7.30 (m, 2H), 7.05 (t, J = 8.8 Hz, 2H), 6.48 (s, 2H), 3.72–3.54 (m, 2H), 3.52–3.39 (m, 2H), 2.38–2.24 (m, 3H), 2.17 (s, 6H), 2.15–2.04 (m, 3H), 2.03–1.88 (m, 2H), 1.13 (s, 9H); MS (ES+) m / z 429.3 (M + 1). Example 17: N-(4-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0116] 117 / 167 12728106_1 Step 1. Preparation of tert-butyl 4-(4-fluorophenyl)-1,4-diazepane-1-carboxylate

[0370] A mixture of tert-butyl 1,4-diazepane-1-carboxylate (1.00 g, 4.99 mmol), 1-bromo-4-fluoro- benzene (1.05 g, 5.99 mmol), palladium acetate (0.112 g, 0.499 mmol), dicyclohexyl[2-(2,4,6- triisopropylphenyl)phenyl] phosphane (0.476 g, 0.998 mmol) and sodium tert-butoxide (1.44 g, 14.9 mmol) in toluene (20.0 mL) / tertiary butanol (5.0 mL) was stirred at 100 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0–15% ethyl acetate / petroleum ether gradient at 100 mL / min) to give tert-butyl 4-(4-fluorophenyl)- 1,4-diazepane-1-carboxylate (1.40 g, 4.76 mmol, 95% yield) as a yellow solid:1H NMR (400 MHz, CDCl3) δ 6.99–6.86 (m, 2H), 6.68–6.58 (m, 2H), 3.69–3.46 (m, 6H), 3.34 (t, J = 5.6 Hz, 1H), 3.23 (t, J = 6.0 Hz, 1H), 2.02–1.92 (m, 2H), 1.52–1.35 (m, 9H). Step 2. Preparation of 1-(4-fluorophenyl)-1,4-diazepane

[0371] To a solution tert-butyl 4-(4-fluorophenyl)-1,4-diazepane-1-carboxylate (1.00 g, 3.40 mmol) in methanol (10.0 mL) was added acetyl chloride (1.33 g, 16.9 mmol) at 0 °C, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 1-(4- fluorophenyl)-1,4-diazepane (0.800 g, crude, hydrochloride) as a yellow solid:1H NMR (400 MHz, MeOD-d4) δ 7.18–6.85 (m, 4H), 3.87–3.78 (m, 2H), 3.62 (t, J = 6.0 Hz, 2H), 3.51–3.45 (m, 2H), 3.37– 3.33 (m, 2H), 2.25 (quin, J = 5.6 Hz, 2H) Step 3. Preparation of N-(4-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0372] A mixture of 1-(4-fluorophenyl)-1,4-diazepane (0.200 g, 0.866 mmol, hydrochloride), N-(4-bromo- 2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (0.232 g, 0.780 mmol), methanesulfonato(2-dicyclohexyl phosphino-2,4,6-tri-i-propyl-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (0.0745 g,

[0117] 118 / 167 12728106_1 0.0866 mmol), cesium carbonate (0.847 g, 2.60 mmol) in dioxane (10.0 mL) was stirred at 100 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0–40% ethyl acetate / petroleum ether gradient at 100 mL / min) to give N-(4-(4- (4-fluorophenyl)-1,4-diazepan-1-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.2041 g, 0.481 mmol, 55% yield, 97% purity) as an off-white solid:1H NMR (400 MHz, MeOD-d4) δ 6.95–6.86 (m, 2H), 6.77–6.68 (m, 2H), 6.49 (s, 2H), 3.70–3.60 (m, 4H), 3.45–3.37 (m, 4H), 2.28 (s, 2H), 2.16 (s, 6H), 2.08 (quin, J = 6.0 Hz, 2H), 1.13 (s, 9H); MS (ES+) m / z 412.3 (M+1). Example 24: N-(2-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-4,6-dimethylpyrimidin-5-yl)-3,3- dimethylbutanamide (+ / -) Step 1. Preparation of - 4-(4,6-dimethyl-5-nitropyrimidin-2-yl)-7-(4-fluorophenyl)-1,4-oxazepane

[0373] To a solution of 7-(4-fluorophenyl)-1,4-oxazepane (0.126 g, 0.581 mmol) in dimethyl sulfoxide (2.0 mL) was added N,N-diisopropylethylamine (0.207 g, 1.600 mmol) and 2-chloro-4,6-dimethyl-5- nitro-pyrimidine (0.100 g, 0.533 mmol). The mixture was stirred at 25 °C for 12 h. Water (20 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(4,6-dimethyl-5-nitropyrimidin-2-yl)-7-(4-fluorophenyl)-1,4- oxazepane (94% yield) as a yellow solid:1H NMR (400 MHz, CDCl3) δ 7.32–7.27 (m, 2H), 7.05–6.98 (m, 2H), 4.43 (dd, J = 3.2, 10.4 Hz, 1H), 4.35 (td, J = 2.8, 14.0 Hz, 1H), 4.24 (td, J = 3.2, 12.0 Hz, 1H), 4.11–4.05 (m, 2H), 3.89–3.73 (m, 2H), 2.51 (s, 6H), 2.35–.26 (m, 1H), 2.08–.99 (m, 1H).

[0374] A mixture of 4-(4,6-dimethyl-5-nitro-pyrimidin-2-yl)-7-(4-fluorophenyl)-1,4-oxazepane (0.21 g, 0.61 mmol), acetic acid (1.96 g, 32.6 mmol), iron powder (0.17 g, 3.02 mmol) in ethanol (8.0 mL) and

[0118] 119 / 167 12728106_1 water (0.8 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 0.08 g of 2-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-4,6- dimethylpyrimidin-5-amine (38% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.32–7.27 (m, 2H), 7.03–6.96 (m, 2H), 4.41 (dd, J = 3.2, 10.4 Hz, 1H), 4.31 (td, J = 2.8, 14.0 Hz, 1H), 4.17 (td, J = 3.2, 12.0 Hz, 1H), 4.05–3.96 (m, 1H), 3.95–3.86 (m, 1H), 3.81–3.73 (m, 1H), 3.72–3.62 (m, 1H), 2.99 (s, 2H), 2.35–2.29 (m, 7H), 2.07–1.96 (m, 1H). Step 3. Preparation of N-(2-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-4,6-dimethylpyrimidin-5-yl)-3,3- dimethylbutanamide

[0375] To a solution of 2-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-4,6-dimethylpyrimidin-5-amine (0.080 g, 0.228 mmol) in dichloromethane (1.5 mL) was added pyridine (0.054 g, 0.683 mmol) and 3,3- dimethylbutanoyl chloride (0.037 g, 0.275 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 25 mm × 10 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 46%–76% B over 10 min). The desired fraction was collected and lyophilized to afford 0.054 g of N-(2-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl)-4,6-dimethylpyrimidin-5-yl)-3,3-dimethylbutanamide (57% yield) as an off-white solid:1H NMR (400 MHz, MeOD-d4) δ 7.35–7.28 (m, 2H), 7.05–6.97 (m, 2H), 4.48 (dd, J = 3.2, 10.8 Hz, 1H), 4.25–4.11 (m, 2H), 4.09–3.92 (m, 2H), 3.86–3.74 (m, 2H), 2.33– 2.21 (m, 9H), 2.00–1.90 (m, 1H), 1.13 (s, 9H); MS (ES+) m / z 415.2 (M + 1). Example 27. N-(4-(1,1-dioxido-7-phenyl-1,4-thiazepan-4-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide Step 1. Preparation of tert-butyl 7-phenyl-1,4-thiazepane-4-carboxylate

[0376] To a solution of 7-phenyl-1,4-thiazepane (0.60 g, 2.64 mmol) in acetonitrile (10 mL) was added

[0119] 120 / 167 12728106_1 trimethylamine (0.32 g, 3.17 mmol) and 4-dimethylaminopyridin (0.32 g, 2.65 mmol), then di-tert-butyl dicarbonate (0.69 g, 3.17 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1). The desired fraction was concentrated under reduced pressure to afford 0.55 g of tert-butyl 7-phenyl-1,4-thiazepane-4-carboxylate (1.69 mmol) as colorless oil:1H NMR (400 MHz, MeOD-d4) δ 7.33–7.25 (m, 4H), 7.25–7.18 (m, 1H), 3.93–3.76 (m, 2H), 3.74–3.64 (m, 1H), 3.60–3.40 (m, 2H), 3.02–2.92 (m, 1H), 2.88–2.79 (m, 1H), 2.41–2.30 (m, 1H), 2.24–2.08 (m, 1H), 1.51 (d, J = 2.4 Hz, 9H). Step 2. Preparation of tert-butyl 7-phenyl-1,4-thiazepane-4-carboxylate 1,1-dioxide

[0377] To a solution of tert-butyl 7-phenyl-1,4-thiazepane-4-carboxylate (0.25 g, 0.77 mmol) in acetic acid (6.0 mL) was added hydrogen peroxide (1.30 g, 11.50 mmol, 30 wt%). The mixture was stirred at 25 °C for 12 h. The reaction was quenched with saturated sodium sulfite (5 mL). Water (10 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (3 × 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.15 g of tert-butyl 1,1-dioxo-7-phenyl-1,4- thiazepane-4-carboxylate (54% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.38 (s, 5H), 4.40 (ddd, J = 3.6, 6.0, 11.6 Hz, 1H), 3.89–3.69 (m, 3H), 3.68–3.47 (m, 2H), 3.47–3.38 (m, 1H), 2.70–2.48 (m, 1H), 2.28–2.11 (m, 1H), 1.52 (d, J = 2.8 Hz, 9H). Step 3. Preparation of 7-phenyl-1,4-thiazepane 1,1-dioxide

[0378] To a solution of tert-butyl 1,1-dioxo-7-phenyl-1,4-thiazepane-4-carboxylate (0.190 g, 0.525 mmol) in methanol (5.0 mL) was added acetyl chloride (0.206 g, 2.63 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford 0.15 g of 7-phenyl-1,4-thiazepane 1,1-dioxide (98% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.43 (s, 5H), 4.64 (dd, J = 3.2, 11.6 Hz, 1H), 4.06–3.94 (m, 1H), 3.75–3.59 (m, 4H), 3.53 (ddd, J = 1.6, 10.8, 14.8 Hz, 1H), 2.74–2.61 (m, 1H), 2.48 (tddd, J = 1.6, 3.2, 5.2, 16.8 Hz, 1H). Step 4. Preparation of N-(4-(1,1-dioxido-7-phenyl-1,4-thiazepan-4-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0120] 121 / 167 12728106_1

[0379] The reaction was carried out in 2 batches on 0.050 g and 0.085 g scale. To a solution of N-(4- bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (0.085 g, 0.285 mmol) in dioxane (5.0 mL) was added 7-phenyl-1,4-thiazepane 1,1-dioxide (0.092 g, 0.316 mmol, hydrochloride) and sodium tert-butoxide (0.082 g, 0.853 mmol), then 2-(2-ditert-butylphosphanylphenyl)-N,N-dimethylaniline (0.023 g, 0.058 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.026 g, 0.028 mmol) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1). The desired fraction was concentrated under reduced pressure to afford 0.117 g of N-(4-(1,1- dioxido-7-phenyl-1,4-thiazepan-4-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (58% yield) as a white solid:1H NMR (400 MHz, MeOD-d4) δ 7.34 (s, 5H), 6.56 (s, 2H), 4.15 (dd, J = 4.8, 10.8 Hz, 1H), 4.11–4.02 (m, 1H), 3.96 (td, J = 6.0, 15.2 Hz, 1H), 3.82–3.65 (m, 3H), 3.38–3.33 (m, 1H), 2.60–2.42 (m, 2H), 2.30 (s, 2H), 2.20 (s, 6H), 1.14 (s, 9H); MS (ES+) m / z 443.2 (M + 1). Example 52 and 53. N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3- dimethylbutanamide Step 1. Preparation of 3-hydroxy-3-phenylbutanenitrile

[0380] Tetrahydrofuran (20.0 mL) was cooled to -20 ˚C and n-butyllithium (2.5 M, 9.2 mL) was added. A solution of acetonitrile (0.95 g, 0.02 mmol) in dry tetrahydrofuran (5.0 mL) was added dropwise over 10 min. The mixture was stirred for 1 h at -20 ˚C and a solution of acetophenone (2.50 g, 20.80 mmol) in tetrahydrofuran (5.0 mL) was added dropwise over 10 min. The mixture was stirred at -20 ˚C for 15 min and 25 °C for another 15 min. Aqueous saturated ammonium chloride (20 mL) was added to quench the reaction. The solution was extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether : Ethyl acetate=20:1 to 3:1) to afford 1.5 g of 3-hydroxy-3-phenylbutanenitrile (40% yield) as a yellow oil:1H NMR (400 MHz, CDCl3) δ 7.55 – 7.47 (m, 2H), 7.44 – 7.38 (m, 2H), 7.37 – 7.29 (m, 2H), 7.19 – 7.09 (m, 1H), 2.84 (d, J = 4.8 Hz, 2H), 1.79 (s,

[0121] 122 / 167 12728106_1 3H). Step 2. Preparation of 4-amino-2-phenylbutan-2-ol

[0381] To a solution of 3-hydroxy-3-phenylbutanenitrile (2.50 g, 14.00 mmol) in tetrahydrofuran (50 mL) was added borane (10 M in dimethylsulfide, 4.2 mL) at 0 ˚C. The mixture was refluxed at 60 °C for 16 h under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was quenched with methanol (20.0 mL) at 0 °C and the mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Ethyl acetate to Ethyl acetate : Methanol=1:1) to afford 1.9 g of 4-amino-2- phenylbutan-2-ol (74% yield) as a yellow oil:1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.26 – 7.19 (m, 1H), 3.10 – 2.92 (m, 2H), 2.67 – 2.53 (m, 2H), 1.96 – 1.92 (m, 2H), 1.53 – 1.50 (m, 3H).

[0382] To a solution of 4-amino-2-phenylbutan-2-ol (1.90 g, 10.40 mmol) in dichloromethane (100 mL) was added trimethylamine (3.27 g, 32.30 mmol), then 2-chloroacetyl chloride (1.28 g, 11.30 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the mixture and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2.2 g of crude 2-chloro-N-(3- hydroxy-3-phenylbutyl) acetamide as a yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 – 7.21 (m, 2H), 3.95 – 3.82 (m, 2H), 3.45 (td, J = 6.4, 13.2 Hz, 1H), 3.24 – 3.14 (m, 1H), 2.18 – 2.09 (m, 1H), 2.07 – 1.97 (m, 1H), 1.62 (s, 3H).

[0383] To a solution of 2-chloro-N-(3-hydroxy-3-phenylbutyl) acetamide (2.20 g, 9.10 mmol) in tetrahydrofuran (200 mL) was added sodium tert-butoxide (1.75 g, 18.20 mmol). The mixture was stirred at 70 °C for 1 h. After being cooled to room temperature, the reaction mixture was diluted in ethyl

[0122] 123 / 167 12728106_1 acetate (20 mL), washed with brine (10 mL) and water (10 mL). The organic layer was concentrated under reduced pressure. The residue was purified by reversed phase column (0.1% formic acid conditions). The desired fraction was collected and concentrated under reduced pressure to remove acetonitrile. Then the mixture was adjusted pH=7 with sat. aqueous saturated sodium bicarbonate and diluted in ethyl acetate (500 mL). The organic layer was collected and concentrated under reduced pressure to afford 0.60 g of 7-methyl-7-phenyl-1,4-oxazepan-3-one (29% yield) as a yellow oil:1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 4.4 Hz, 4H), 7.33 – 7.28 (m, 1H), 6.05 (br s, 1H), 4.26 – 4.13 (m, 1H), 4.07 – 3.97 (m, 1H), 3.66 – 3.55 (m, 1H), 3.31 – 3.18 (m, 1H), 2.61 – 2.39 (m, 2H), 1.48 (s, 3H). Step 5. Preparation of 7-methyl-7-phenyl-1,4-oxazepane

[0384] To a mixture of aluminum chloride (0.18 g, 1.31 mmol) in tetrahydrofuran (15.0 mL) was added dropwise lithium aluminum hydride (2.5 M in tetrahydrofuran, 1.65 mL) at 0°C under nitrogen atmosphere. The mixture was stirred at 0 °C for 20 min. 7-Methyl-7-phenyl-1,4-oxazepan-3-one (0.50 g, 2.19 mmol) was added and the reaction mixture was stirred at 25°C for another 12 h under nitrogen atmosphere. The reaction was quenched with sodium potassium tartrate solution (1 M in water, 15 mL) at 0 °C under nitrogen atmosphere. Water (10 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.49 g of crude 7-methyl-7-phenyl-1,4-oxazepane as a yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ 7.42 – 7.38 (m, 2H), 7.38 – 7.31 (m, 3H), 7.26 – 7.22 (m, 1H), 3.87 – 3.76 (m, 1H), 3.54 (ddd, J = 2.0, 8.8, 13.2 Hz, 1H), 3.10 – 2.91 (m, 4H), 2.47 – 2.39 (m, 1H), 2.27 – 2.17 (m, 1H), 1.43 (s, 3H). Step 6. Preparation of N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3- dimethylbutanamide

[0385] To a solution of 7-methyl-7-phenyl-1,4-oxazepane (0.25 g, 1.18 mmol) in dioxane (15 mL) was added N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.43 g, 1.35 mmol) and sodium tert- butoxide (0.35 g, 3.59 mmol), then 2-(2-ditert-butylphosphanylphenyl)-N,N-dimethylaniline (0.08 g, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol) was added under nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through a pad of Celite. The filtrate was

[0123] 124 / 167 12728106_1 concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether : Ethyl acetate=10:1 to 3:1). The crude product was further purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 µm; mobile phase: [water (formic acis)-acetonitrile]; gradient:54% – 74% B over 10 min) to afford 0.17 g of N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4- oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (34% yield) as a white solid:1H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, 2H), 7.38 – 7.32 (m, 2H), 7.26 – 7.21 (m, 1H), 6.51 – 6.46 (m, 3H), 3.94 – 3.80 (m, 1H), 3.65 (ddd, J = 1.6, 8.8, 13.6 Hz, 1H), 3.61 – 3.41 (m, 4H), 2.47 – 2.30 (m, 2H), 2.26 (s, 2H), 2.18 (s, 6H), 1.45 (s, 3H), 1.14 (s, 9H). Step 7. Preparation of N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3- dimethylbutanamide & N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-

[0386] N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (0.170 g, 0.395 mmol) was purified by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm,10 µm); mobile phase: [carbon dioxide-methanol (0.1% ammonium hydroxide)]; B%:25%, isocratic elution mode; Flow rate: 60 mL / min; cycle time: 4.05 min; Back Pressure:100 bar to keep the carbon dioxide in Supercritical flow; UV 220 nm).

[0387] The desired fraction (peak 1, retention time = 1.233 min) was collected and lyophilized to give (S)- N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (0.0705 g, 0.171 mmol, 43% yield, 99% purity, 99% ee.) as a white solid:1H NMR (400 MHz, CDCl3) 7.44 – 7.38 (m, 2H), 7.38 – 7.31 (m, 2H), 7.26 – 7.21 (m, 1H), 6.53 – 6.44 (m, 3H), 3.96 – 3.83 (m, 1H), 3.71 – 3.58 (m, 1H), 3.58 – 3.41 (m, 4H), 2.48 – 2.29 (m, 2H), 2.26 (s, 2H), 2.18 (s, 6H), 1.87 (s, 1H), 1.49 – 1.41 (m, 3H), 1.14 (s, 9H); MS (ES+) m / z 409.3 (M + 1).

[0388] The desired fraction (peak 2, retention time = 1.437 min ) was collected and lyophilized to give (R)-N-(2,6-dimethyl-4-(7-methyl-7-phenyl-1,4-oxazepan-4-yl)phenyl)-3,3-dimethylbutanamide (0.0712 g, 0.171 mmol, 43% yield, 98% purity, 98% ee.) as a yellow solid:1H NMR (400 MHz, CDCl3) δ 7.45 – 7.38 (m, 2H), 7.38 – 7.32 (m, 2H), 7.26 – 7.19 (m, 1H), 6.53 – 6.44 (m, 3H), 3.93 – 3.82 (m, 1H), 3.70 – 3.59 (m, 1H), 3.58 – 3.41 (m, 4H), 2.48 – 2.31 (m, 2H), 2.26 (s, 2H), 2.18 (s, 6H), 1.48 – 1.43 (m, 3H), 1.14 (s, 9H); MS (ES+) m / z 409.3 (M + 1).

[0389] The following further examples (Table 2B) were prepared analogously to Examples 52 and 53 (as described above), substituting appropriate starting materials where necessary and making appropriate changes to experimental conditions informed by common general knowledge. Purification was performed either by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC).

[0124] 125 / 167 12728106_1 Table 2B x Examples 52 and 53 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. y Examples 54 and 55 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. z Examples 56 and 57 are single enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined. Example 58: N-(4-(6,6-difluoro-7-phenyl-1,4-oxazepan-4-yl)-2-fluoro-6-methylphenyl)-3,3- dimethylbutanamide Step 1. Preparation of ethyl 2,2-difluoro-3-hydroxy-3-phenyl-propanoate

[0390] To tetrahydrofuran (500 mL) was added zinc dust (61.60 g, 0.94 mol) and cuprous chloride (18.60 g, 0.19 mol, 4.51 mL). The mixture was stirred at 65 °C for 1 hr under nitrogen. Then ethyl 2-bromo- 2,2-difluoro-acetate (95.6 g, 471 mmol, 60.7 mL) was added. The mixture was stirred at 65 °C for 1 hr under nitrogen. Then benzaldehyde (20.0 g, 188 mmol, 19.0 mL) was added, the mixture was stirred at 65 °C for 1 hr under nitrogen. The reaction mixture was cooled to 25 °C and filtered. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (2 x 200 mL), dried over sodium sulfate, filtered and concentrated under

[0125] 126 / 167 12728106_1 reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate) to afford 10 g of ethyl 2,2-difluoro-3-hydroxy-3-phenyl-propanoate (23.0% yield) as a yellow oil:1H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.47 (m, 5H), 5.10 - 5.23 (m, 1H), 4.82 (d, J = 12.4 Hz, 1H), 4.29 - 4.36 (m, 1H), 2.80 (s, 1H), 1.25 - 1.32 (m, 3H); MS (ES-) m / z 201.0 (M - 1). Step 2. Preparation of 2,2-difluoro-3-hydroxy-3-phenyl-propanamide

[0391] To a solution of ethyl 2,2-difluoro-3-hydroxy-3-phenyl-propanoate (10.0 g, 43.4 mmol) in MeOH (30 mL) was added NH3.H2O (16.3 g, 130 mmol, 28% purity). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced. The crude residue was purified by reversed- phase HPLC (0.1% NH3.H2O) to afford 2.3 g of 2,2-difluoro-3-hydroxy-3-phenyl-propanamide (26% yield) was obtained as a yellow solid:1H NMR (400 MHz, CDCl3) δ ppm 7.36 - 7.52 (m, 5H), 6.06 - 6.47 (m, 1H), 5.50 - 5.82 (m, 1H), 5.26 (dd, J = 16.4, 7.6 Hz, 1H), 2.95 - 3.35 (m, 1H); MS (ES-) m / z 200.0 (M - 1). Step 3. Preparation of 3-amino-2,2-difluoro-1-phenyl-propan-1-ol

[0392] To a solution of 2,2-difluoro-3-hydroxy-3-phenyl-propanamide (2.30 g, 11.40 mmol) in tetrahydrofuran (5 mL) was added Lithium Aluminum Hydride (2.5 M, 9.15 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition saturated sodium potassium tartrate (30 mL) at 0 °C, and then extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1.6 g of crude amino-2,2-difluoro-1-phenyl-propan-1-ol (1.60 g, crude) as a yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ ppm 7.33 - 7.52 (m, 5H), 4.99 (J = 13.2, 7.6 Hz, 1H), 2.91 - 3.27 (m, 2H); MS (ES-) m / z 186.1 (M - 1). Step 4. Preparation of 2-chloro-N-(2,2-difluoro-3-hydroxy-3-phenyl-propyl)acetamide

[0393] To a solution of 3-amino-2,2-difluoro-1-phenyl-propan-1-ol (1.60 g, 8.55 mmol) in dichloromethane (10 mL) was added triethylamine (2.59 g, 25.60 mmol) and 2-chloroacetyl chloride (1.16 g, 10.2 mmol, 817 μL) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse-

[0126] 127 / 167 12728106_1 phase HPLC (0.1% NH3•H2O) to afford 1.0 g of crude 2-chloro-N-(2,2-difluoro-3-hydroxy-3-phenyl- propyl) acetamide as a brown oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ ppm 7.33 - 7.55 (m, 5H), 6.97 (s, 1H), 4.84 (dd, J = 16.4, 5.6 Hz, 1H), 4.01 - 4.27 (m, 3H), 3.50 - 3.80 (m, 2H); LCMS: m / z = 262.0 (M-H). Step 5. Preparation of 6,6-difluoro-7-phenyl-1,4-oxazepan-3-one

[0394] To a solution of 2-chloro-N-(2,2-difluoro-3-hydroxy-3-phenyl-propyl) acetamide (1.00 g, 3.79 mmol) in tetrahydrofuran (20 mL) was added sodium tert-butoxide (0.73 g, 7.59 mmol). The mixture was stirred at 70 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Dichloromethane: Methanol = 10: 1, P1: Rf = 0.63, Dichloromethane / Methanol = 500 / 1 to 5 / 1) to afford 0.16 g of 6,6-difluoro-7-phenyl-1,4- oxazepan-3-one (18% yield) was obtained as a yellow oil: MS (ES-) m / z 226.1 (M - 1)

[0395] To a solution of 6,6-difluoro-7-phenyl-1,4-oxazepan-3-one (0.16 g, 0.70 mmol) in tetrahydrofuran (5 mL) was added Lithium Aluminum Hydride (2.5 M, 0.56 mL) dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 2 hrs under nitrogen. The reaction mixture was quenched by addition saturated sodium potassium tartrate 10 mL at 0 °C, and then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.12 g of 6,6-difluoro-7-phenyl-1,4-oxazepane (120 mg, crude) as a yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.42 (m, 5H), 4.82 - 4.93 (m, 1H), 4.18 - 4.30 (m, 1H), 3.71 - 3.85 (m, 1H), 3.47 (td, J = 15.2, 4.4 Hz, 1H), 3.20 - 3.35 (m, 1H), 2.98 - 3.16 (m, 2H). Step 7. Preparation of N-[4-(6,6-difluoro-7-phenyl-1,4-oxazepan-4-yl)-2-fluoro-6-methyl-phenyl]-3,3- dimethyl-butanamide

[0127] 128 / 167 12728106_1

[0396] To a solution of 6,6-difluoro-7-phenyl-1,4-oxazepane (0.05 g, 0.24 mmol) in dioxane (5 mL) was added potassium tert-butoxide (0.08 g, 0.71 mmol), N-(4-bromo-2-fluoro-6-methyl-phenyl)-3,3- dimethyl-butanamide (0.09 g, 0.31 mmol), 2-(2-dicyclohexylphosphanylphenyl)-N, N-dimethyl-aniline (0.02 g, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 23.5 μmol). The mixture was stirred at 90 °C for 12 hrs under nitrogen. The reaction mixture was concentrated under reduced pressure The crude residue was purified by reversed-phase HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150*25*10um; mobile phase: [water( NH4HCO3)-ACN];gradient:52%-76% B over 12 min) to afford 0.008 g of N-[4-(6,6-difluoro-7-phenyl-1,4-oxazepan-4-yl)-2-fluoro-6-methyl-phenyl]-3,3-dimethyl- butanamide (7% yield) was obtained as a white solid:1H NMR: EC16504-273-p1az1 (400 MHz, MeOD) δ 7.25 - 7.34 (m, 5H), 6.50 - 6.77 (m, 2H), 4.55 (d, J = 4.8 Hz, 1H), 4.53 - 4.64 (m, 1H), 4.36 (ddd, J = 16.0, 11.6, 4.0 Hz, 1H), 4.20 (dd, J = 12.4, 3.6 Hz, 1H), 3.85 - 4.07 (m, 3H), 3.52 (ddd, J = 14.8, 11.2, 4.0 Hz, 1H), 2.29 (s, 2H), 2.23 (s, 3H), 1.13 (s, 9H); LCMS 435.3 (M+H)+. Example 87. N-(4-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl-5,5,7-d3)-2,6-dimethylphenyl)-3,3- dimethylbutanamide Step 1. Preparation of 3-amino-1,3,3-trideuterio-1-(4-fluorophenyl)propan-1-ol

[0397] The three reactions were carried out in parallel on 2.00 g scale. To a cold (0 °C) solution of lithium aluminum deuteride (1.40 g, 36.90 mmol) in tetrahydrofuran (30.0 mL) was added a solution of 3-(4- fluorophenyl)-3-oxo-propanenitrile (2.00 g, 12.30 mmol) in tetrahydrofuran (10.0 mL) under nitrogen. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with sodium sulfate decahydrate (3.00 g) at 0 °C. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0–20% methanol (10% ammonium hydroxide) / dichloromethane gradient at 100 mL / min) to afford 1.80 g of 3- amino-1,3,3-trideuterio-1-(4-fluorophenyl)propan-1-ol (17% yield) as yellow oil:1H NMR (400 MHz, MeOD-d4) δ 7.45–7.31 (m, 2H), 7.12–6.97 (m, 2H), 1.89–1.74 (m, 2H). Step 2. Preparation of 2-chloro-N-(3-(4-fluorophenyl)-3-hydroxypropyl-1,1,3-d3)acetamide

[0128] 129 / 167 12728106_1

[0398] To a cold (0 °C) solution of 3-amino-1,3,3-trideuterio-1-(4-fluorophenyl)propan-1-ol (1.00 g, 3.49 mmol) and triethylamine (1.41 g, 13.90 mmol) in dichloromethane (5.0 mL) was added 2-chloroacetyl chloride (0.40 g, 3.49 mmol). The mixture was stirred at 25 °C for 1 h. Water (10 mL) was added to the mixture and then the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.80 g of crude 2-chloro-N-(3-(4-fluorophenyl)-3-hydroxypropyl-1,1,3- d3)acetamide as yellow oil that was used without further purification:1H NMR (400 MHz, CDCl3) δ 7.39–7.29 (m, 2H), 7.17–7.09 (m, 1H), 7.08–7.00 (m, 2H), 4.07 (d, J = 1.2 Hz, 2H), 2.95 (s, 1H), 1.91 (s, 2H). Step 3. Preparation of 7-(4-fluorophenyl)-1,4-oxazepan-3-one-5,5,7-d3

[0399] To a solution of 2-chloro-N-(3-(4-fluorophenyl)-3-hydroxypropyl-1,1,3-d3)acetamide (1.20 g, 4.83 mmol) in tetrahydrofuran (240 mL) was added sodium tert-butoxide (0.93 g, 9.65 mmol) at 50 °C and the mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove tetrahydrofuran. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 mm × 40 mm × 15 µm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 23%–53% B over 15 min). The desired fraction was collected and lyophilized to afford 0.20 g of 7-(4-fluorophenyl)-1,4-oxazepan-3-one-5,5,7-d3(20% yield) as a white solid:1H NMR (400 MHz, CDCl3) δ 7.38–7.30 (m, 1H), 7.13–7.01 (m, 1H), 6.14 (s, 1H), 4.46 (d, J = 15.6 Hz, 1H), 4.32–4.19 (m, 1H), 2.26 (d, J = 14.8 Hz, 1H), 2.08 (d, J = 14.8 Hz, 1H). Step 4. Preparation of 7-(4-fluorophenyl)-1,4-oxazepane-5,5,7-d3

[0400] To a solution of 7-(4-fluorophenyl)-1,4-oxazepan-3-one-5,5,7-d3(0.25 g, 1.18 mmol) in tetrahydrofuran (12.0 mL) was added lithium aluminum hydride (2.5 M in tetrahydrofuran, 0.70 mL) at 0 °C under nitrogen and the mixture was stirred at 25 °C for 1 h. The reaction was quenched with sodium potassium tartrate solution (1 M, 5.0 mL) at 0 °C under nitrogen atmosphere. Water (30 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.25 g of crude 7-(4-fluorophenyl)-1,4-oxazepane-5,5,7-d3as yellow oil that

[0129] 130 / 167 12728106_1 was used without further purification:1H NMR (400 MHz, CDCl3) δ 7.37–7.30 (m, 2H), 7.09–6.98 (m, 2H), 4.04 (td, J = 4.0, 12.8 Hz, 1H), 3.75 (ddd, J = 4.4, 7.2, 12.8 Hz, 1H), 3.15–3.02 (m, 2H), 2.19 (d, J = 14.8 Hz, 1H), 1.96 (d, J = 14.8 Hz, 1H). Step 5. Preparation of N-(4-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl-5,5,7-d3)-2,6-dimethylphenyl)-3,3- dimethylbutanamide

[0401] The two reactions were carried out on 0.100 g and 0.150 g scale. A mixture of 7-(4-fluorophenyl)- 1,4-oxazepane-5,5,7-d3 (0.150 g, 0.756 mmol), N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl- butanamide (0.225 g, 0.756 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.069 g, 0.076 mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.060 g, 0.151 mmol) and sodium tert- butoxide (0.181 g, 1.890 mmol) in dioxane (10.0 mL) was stirred 90 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0–35% ethyl acetate / petroleum ether gradient at 80 mL / min). The desired fraction was collected and lyophilized to afford 0.238 g of N-(4-(7-(4-fluorophenyl)-1,4-oxazepan-4-yl-5,5,7-d3)-2,6-dimethylphenyl)-3,3- dimethyl butanamide (45% yield) as an off-white solid:1H NMR (400 MHz, MeOD-d4) δ 7.32–7.26 (m, 2H), 7.04–6.97 (m, 2H), 6.54 (s, 2H), 4.13–4.04 (m, 1H), 3.91–3.80 (m, 2H), 3.60–3.49 (m, 1H), 2.35– 2.27 (m, 3H), 2.18 (s, 6H), 1.96 (d, J = 14.4 Hz, 1H), 1.14 (s, 9H); MS (ES+) m / z 416.3 (M + 1). Example 124. N-(2,6-dimethyl-4-(7-(5-(trifluoromethyl)isoxazol-3-yl)-1,4-oxazepan-4-yl)phenyl)- 3,3-dimethylbutanamide...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1and R2are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8 alkyl, C3-10 cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6 alkyl, C3-7 cycloalkyl, or a nitrogen protecting group, or RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted; L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C1-6acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7152 / 167 12728106_1membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6 acyl, or two R5are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6 alkyl, C1-6 haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor -N(RN)2; or R4and R6are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted; m and n are both 1; each instance of R’ is independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O; each instance of RN1, RL, and RNis independently H, C1-6alkyl, C3-7cycloalkyl, C1-6acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C1-6acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, C1-6acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein: R1and R2are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, -SRS, -S(=O)2RS1, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R3is C1-8 alkyl, C3-10 cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”)w-Ar1, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1is C6-10 aryl or 5-10153 / 167 12728106_1membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted; Z1and Z2are each independently CRZor N; each instance of RZis independently H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; Y is a bond, -CR’R”-, -O-, or -NRY-; RYis H, C1-6 alkyl, C3-7 cycloalkyl, or a nitrogen protecting group, or RYand R3are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein the alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted; L is a bond, -CR’R”-, -O-, or -NRL-; provided that when X is -O-, -NRX-, or -S-, or R6is -OROor -N(RN)2, then L is not -O- or -NRL-; R4is H, C6-10aryl, 5-10 membered heteroaryl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted; X is -CR’R”-, -O-, -NRX-, -S-, or -S(=O)2-; RXis H, C1-6alkyl, C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, C1-6acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or acyl is optionally substituted; provided that exactly one of R4and RXis C6-10aryl or 5-10 membered heteroaryl; each instance of R5is independently halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, -CN, -ORO, -N(RN)2, or C1-6acyl, or two R5attached to the same carbon atom are joined together with the intervening atoms to form C3-7cycloalkyl or 3-7 membered heterocyclyl, or two R5attached to the same carbon atom are taken together to form =O, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl, is independently optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits; R6is H, halogen, C1-6alkyl, C1-6haloalkyl, -ORO, or -N(RN)2, wherein the alkyl is optionally substituted; provided that when X is -O-, -NRX-, or -S-, or L is -O- or -NRL-, then R6is not -OROor -N(RN)2; m and n are both 1; each instance of R’ is independently H, halogen, C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, or 3-7 membered heterocyclyl, each instance of R” is independently H, halogen, C1-6 alkyl, -ORO, or -N(RN)2, or R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted, or R’ and R” attached to the same carbon atom are taken together to form =O; each instance of RN1, RL, and RNis independently H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 acyl, or a nitrogen protecting group, or two RNattached to the same nitrogen atom are joined together with the intervening atoms to form 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, acyl, or heterocyclyl is independently optionally substituted; each instance of ROis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered154 / 167 12728106_1heterocyclyl, C1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; each instance of RSis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C1-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; and each instance of RS1is independently C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.

3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is H, C6-10 aryl, or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted.

4. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

5. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-1):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

6. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-2):155 / 167 12728106_1or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

7. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-4):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

8. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-6):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

9. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-9):or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

10. The compound of any one of claims 1-3, wherein the compound is of Formula (I-a-10):156 / 167 12728106_1or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is CRZ.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is CH.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z1is N.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CRZ.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CH.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is CCl or CF.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2is N.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is optionally substituted C1-6alkyl.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1unsubstituted C1-3 alkyl.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is methyl.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is halogen.157 / 167 12728106_122. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is F or Cl.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is C1-6 haloalkyl or -ORO.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -CF3 or -OCF3.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is -CN.

26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is optionally substituted C3-6cycloalkyl.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is unsubstituted C3-6cycloalkyl.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R1is cyclopropyl.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is optionally substituted C1-6 alkyl.

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is unsubstituted C1-3 alkyl.

31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is methyl.158 / 167 12728106_132. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is halogen.

33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R2is F.

34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR’R”-.

35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-.

36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C1-8alkyl.

37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is unsubstituted C1-4alkyl.

38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is tert- butyl.

39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C1-6alkyl substituted with one or more F.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is -CF3,41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C3-10cycloalkyl.159 / 167 12728106_142. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted C3-6 cycloalkyl.

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C3-6 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is C3-6 cycloalkyl optionally substituted with one or more F.

45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is:

46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted 3-7 membered heterocyclyl.

47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring N atoms.

48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more F.

49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R3is:.160 / 167 12728106_150. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L is a bond.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein L is -O-.

52. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted phenyl.

53. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is of the formula:, wherein: each instance of R4ais independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN)2, or C1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.

54. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl.

55. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is phenyl optionally substituted with one or more instances of halogen and / or -ORO.

56. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is selected from:,161 / 167 12728106_157. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 5-6 membered heteroaryl.

58. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 5-6 membered heteroaryl having one or two ring heteroatoms independently selected from O, N and S.

59. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted thiazolyl, optionally substituted pyridyl, optionally substituted imidazolyl, or optionally substituted isoxazolyl.

60. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is thiazolyl, pyridyl, imidazolyl, or isoxazolyl, wherein each is optionally substituted with one or more instances of halogen, unsubstituted C1-6alkyl, and / or C1-6haloalkyl.

61. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is selected from:.

62. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted C3-7 cycloalkyl.

63. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is C3-6162 / 167 12728106_1cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C1-6 alkyl, and / or C1-6 haloalkyl.

64. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is C3-6 cycloalkyl optionally substituted with one or more F and / or -CF3.

65. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is:

66. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted 3-7 membered heterocyclyl.

67. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is:.

68. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is optionally substituted C1-6 alkyl or C1-6 haloalkyl, or R4and R6are joined together with the intervening atoms to form optionally substituted C3-6 cycloalkyl.

69. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is unsubstituted C1-6 alkyl or C1-6 haloalkyl, or R4and R6are joined together with the intervening atoms to form unsubstituted C3-6 cycloalkyl.

70. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R4is hydrogen, methyl, tert-butyl, -CF2H or -CF3, or R4and R6are joined together with the intervening atoms to form:.163 / 167 12728106_171. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -CH2-.

72. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -O-.

73. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X is -NRX-.

74. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis optionally substituted C1-6alkyl.

75. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis unsubstituted C1-3alkyl.

76. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis methyl.

77. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis optionally substituted phenyl.

78. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis phenyl optionally substituted with one or more instances of halogen and / or unsubstituted C1-6alkyl.

79. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein RXis selected from:

80. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R6is H.164 / 167 12728106_181. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R6is -OH, -F, or methyl.

82. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

83. The compound of claim 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.

84. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

85. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

86. A method of potentiating a Kv7 potassium channel in a subject comprising administering to the subject a compound of any one of claims 1-84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

87. A method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject in need thereof comprising administering to the subject a compound of any one of claims 1-84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

88. The method of claim 86 or 87, wherein the method enhances opening of a Kv7 potassium channel.

89. The method of any one of claims 86-88, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.

5.

90. The method of any one of claims 86-89, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

91. A method of treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject in need thereof comprising administering to the subject a compound of any one of claims 1-84, or a165 / 167 12728106_1pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

92. The method of any one of claims 86-91, wherein the subject is a human.

93. A compound of any one of claims 1-84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in potentiating a Kv7 potassium channel in a subject.

94. A compound of any one of claims 1-84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a subject.

95. The compound for use of claim 93 or 94, wherein the compound enhances opening of a Kv7 potassium channel.

96. The compound for use of any one of claims 93-95, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.

5.

97. The compound for use of any one of claims 93-96, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

98. A compound of any one of claims 1-84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject.

99. The compound for use of any one of claims 93-98, wherein the subject is a human.

100. A compound of any one of claims 1-84, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use as a medicament.166 / 167 12728106_1

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