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WO2025231323A1 - Composés hétéroaryle bicycliques et leurs utilisations - Google Patents

Composés hétéroaryle bicycliques et leurs utilisations

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Publication number
WO2025231323A1
WO2025231323A1 PCT/US2025/027423 US2025027423W WO2025231323A1 WO 2025231323 A1 WO2025231323 A1 WO 2025231323A1 US 2025027423 W US2025027423 W US 2025027423W WO 2025231323 A1 WO2025231323 A1 WO 2025231323A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
certain embodiments
cycloalkyl
compound
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/027423
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English (en)
Other versions
WO2025231323A8 (fr
Inventor
Christoph Martin Dehnhardt
Ashik Ajij SAYYAD
Paul Scott CHARIFSON
Hong Wang
Julien A. DELBROUCK
Stephen Jones BARIGYE
Shaoyi Sun
Qi Jia
Wei Gong
Michael Philip Clark
Kristen BURFORD
Stephen Kenneth JACKSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xenon Pharmaceuticals Inc
Original Assignee
Xenon Pharmaceuticals Inc
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Publication date
Application filed by Xenon Pharmaceuticals Inc filed Critical Xenon Pharmaceuticals Inc
Publication of WO2025231323A1 publication Critical patent/WO2025231323A1/fr
Publication of WO2025231323A8 publication Critical patent/WO2025231323A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • SUMMARY [004] 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).
  • pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same.
  • the disclosure provides methods of preparing the compounds and pharmaceutical compositions described herein, and intermediates useful thereto.
  • compounds of Formula (I) and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, wherein Z, R 2 , R N1 , Y, R 3 , L, R 4 , X 5 , X 6 , and X 7 are as defined herein.
  • a compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X 7 is NR N 5a , R 5b , R 6a , and R 6b are as defined herein.
  • a compound of Formula (I) is of Formula (I ): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one of X 5 and X 6 is N or O.
  • the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 6a is as defined herein.
  • the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 5a is as defined herein.
  • a compound disclosed herein is selected from those recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.
  • pharmaceutical compositions comprising a compound of 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.
  • 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.
  • an effective amount e.g., therapeutically effective amount
  • 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.
  • a Kv7 potassium channel e.g., Kv7.2/Kv7.3
  • Methods of treating a disease, disorder, or condition associated with Kv7 potassium channel 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.
  • 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 derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • Methods of potentiating a Kv7 potassium channel e.g., Kv7.2/Kv7.3
  • 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.
  • 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).
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • 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”).
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • 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. [021] 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.
  • C 1-6 alkyl encompasses, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • 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.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1–6 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 (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • C 1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl,
  • alkyl groups include n-heptyl (C 7 ), 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).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1–12 alkyl (such as unsubstituted C 1–6 alkyl, e.g., ⁇ CH 3 (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)).
  • unsubstituted C 1–12 alkyl such as unsubstituted C 1–6 alkyl, e.g.
  • the alkyl group is a substituted C 1–12 alkyl (such as substituted C 1–6 alkyl, e.g., –CH 2 F, –CHF 2 , –CF 3 , –CH 2 CH 2 F, –CH 2 CHF 2 , –CH 2 CF 3 , or benzyl (Bn)).
  • 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.
  • the haloalkyl moiety has 1 to 20 carbon atoms (“C 1–20 haloalkyl”).
  • the haloalkyl moiety has 1 to 10 carbon atoms (“C 1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C 1–9 haloalkyl”).
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C 1–7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C 1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C 1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1–4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C 1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1–2 haloalkyl”). 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.
  • haloalkyl groups include –CHF 2 , ⁇ CH 2 F, ⁇ CF 3 , ⁇ CH 2 CF 3 , ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
  • 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.
  • 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.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–20 heteroalkyl”).
  • 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”).
  • a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–11 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 (“C 1–9 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 (“C 1–8 heteroalkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C 1–7 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 (“C 1–6 heteroalkyl”). 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 (“C 1–5 heteroalkyl”). 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 (“C 1–4 heteroalkyl”).
  • a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C 1–3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C 1–2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C 1 heteroalkyl”). 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 (“C 2-6 heteroalkyl”).
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • 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 (“C 2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C 2–12 alkenyl”).
  • an alkenyl group has 2 to 11 carbon atoms (“C 2–11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C 2 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 C 2–4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • 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.
  • 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.
  • 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 (“C 2–20 heteroalkenyl”). 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 (“C 2–12 heteroalkenyl”). 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 (“C 2–11 heteroalkenyl”).
  • 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 (“C2–10 heteroalkenyl”). 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 (“C 2–9 heteroalkenyl”). 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 (“C 2–8 heteroalkenyl”).
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C 2–7 heteroalkenyl”). 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 (“C 2–6 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 (“C 2–5 heteroalkenyl”).
  • a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C 2–4 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 (“C 2–3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C 2 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 (“C 2–6 heteroalkenyl”).
  • each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
  • alkynyl 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 triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 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 (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”).
  • an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 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 C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), 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.
  • 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.
  • 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.
  • 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 (“C 2–20 heteroalkynyl”). 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 (“C 2–10 heteroalkynyl”). 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 (“C 2–9 heteroalkynyl”).
  • a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C 2–8 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 (“C 2–7 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 (“C 2–6 heteroalkynyl”).
  • a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C 2–5 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 (“C 2–4 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 (“C 2–3 heteroalkynyl”).
  • a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C 2 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“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.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C 3-13 carbocyclyl”).
  • a carbocyclyl group has 3 to 12 ring carbon atoms (“C 3-12 carbocyclyl”).
  • a carbocyclyl group has 3 to 11 ring carbon atoms (“C 3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 ), and the like.
  • 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.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • Cycloalkyl refers to a saturated carbocyclyl group.
  • a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”).
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7 cycloalkyl”).
  • 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 (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • heterocyclyl 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”).
  • 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.
  • 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.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • 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.
  • a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).
  • 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”).
  • 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”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • 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]
  • 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 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has 6-10 ring carbon atoms (“C 6-10 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 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.
  • 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 ⁇ 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”).
  • 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 ⁇ 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.
  • 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).
  • 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.
  • 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.
  • 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”).
  • 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”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • 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. [039] 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.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • halo or “halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • sil refers to the group –Si(R aa ) 3 , wherein R aa is as defined herein.
  • a group is optionally substituted unless expressly provided otherwise.
  • 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” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • 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.
  • 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.
  • 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.
  • 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.
  • the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, or –NO 2 .
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1–6 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb ) 2 , –CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1–6 alkyl, 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-
  • each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a nitrogen protecting group.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • 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, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each nitrogen protecting group 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-nitro
  • each nitrogen protecting group 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 carb
  • each nitrogen protecting group 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),
  • Ts p-toluenesulfonamide
  • each nitrogen protecting group 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-di
  • a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds
  • At least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or an oxygen protecting group.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • 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, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • each oxygen protecting group 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-methoxy
  • an oxygen protecting group is silyl.
  • 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),
  • At least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C 1-6 alkyl or a sulfur protecting group.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
  • 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 – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , 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.
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , 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.
  • 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
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • salts 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • 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,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • 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.
  • 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,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 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.
  • 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.
  • 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.
  • tautomerizations include keto-to- enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • 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. [074] 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.
  • a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, 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 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
  • 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.
  • 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.
  • 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.
  • composition and “formulation” are used interchangeably.
  • 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.
  • 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)).
  • 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.
  • patient refers to a human subject in need of treatment of a disease, disorder, or condition.
  • administer 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.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease.
  • 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.
  • 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.
  • 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.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • 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).
  • 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.
  • a 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.
  • 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.
  • a therapeutically effective amount is an amount sufficient for potentiating a Kv7 potassium channel in a subject.
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • 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.
  • a prophylactically effective amount is an amount sufficient for potentiating a Kv7 potassium channel in a subject.
  • Voltage-gated potassium channels 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.
  • alpha subunits form the actual conductance pore.
  • 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.
  • 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.
  • “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” 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.
  • Kv7 potassium channels such as Kv7.2/Kv7.3
  • Kv7 potassium channels such as Kv7.2/Kv7.3
  • 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.
  • X 5 is N, CR 5a , or CR 5a R 5b X 6 is N, O, CR 6a , or CR 6a R 6b X 7 is absent, or is N, NR N , O, S, CR 7a , or CR 7a R 7b provided that at least one of X 5 , X 6 , and X 7 is N, NR N Z is CR Z or N; each instance of R Z and R 2 is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N )
  • a compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X 7 is NR N , O, or S.
  • a compound of Formula (I) is of Formula (I-a-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein X 7 is NR N , O, or S.
  • a compound of Formula (I) is of Formula (I-a-2): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-a-3): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-a-4): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.
  • a compound of Formula (I) is of Formula (I-a-5): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-a-6): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.
  • a compound of Formula (I) is of Formula (I-a-7): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I-a-7) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-a-8): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.
  • a compound of Formula (I-a-8) is of one of the following formulae: or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-a-9): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a 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.
  • a compound of Formula (I) is of Formula (I-a-10): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.
  • a 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.
  • a compound of Formula (I) is of Formula (I ): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one of X 5 and X 6 is N or O.
  • a compound of Formula (I) is of Formula (I -1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one of X 5 and X 6 is N or O.
  • a compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-b-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-b-2): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted
  • a compound of Formula (I) is of Formula (I-b-3): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-b-4): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-c-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-c-2): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted
  • a compound of Formula (I) is of Formula (I-c-3): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • a compound of Formula (I) is of Formula (I-c-4): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted
  • 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.
  • 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.
  • a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof.
  • a compound provided herein is a compound of Formula (I) or any subgenus or species thereof, as a free base.
  • 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.
  • a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
  • a compound disclosed herein is selected from the compounds recited in Table 1, and pharmaceutically acceptable salts thereof.
  • a compound disclosed herein is selected from the compounds recited in Table 1 (in free base form). Table 1
  • X 6 is N, O, CR 6a , or CR 6a R 6b , as valency permits. [127] In certain embodiments, X 6 is N. [128] In certain embodiments, X 6 is O. [129] In certain embodiments, X 6 is CR 6a . In certain embodiments, X 6 is CH. In certain embodiments, X 6 is CMe. [130] In certain embodiments, X 6 is CR 6a R 6b . In certain embodiments, X 6 is CH 2 . In certain embodiments, X 6 is C(Me)H.
  • X 7 is absent, or is N, NR N , O, S, CR 7a , or CR 7a R 7b , as valency permits. [132] In certain embodiments, X 7 is absent. [133] In certain embodiments, X 7 is N. In certain embodiments, X 7 is NR N . [134] In certain embodiments, X 7 is O. [135] In certain embodiments, X 7 is S. [136] In certain embodiments, X 7 is CR 7a . In certain embodiments, X 7 is CR 7a R 7b . In certain embodiments, X 7 is CH 2 .
  • At least one of X 5 , X 6 , and X 7 is N, NR N , O, or S.
  • at least one of X 5 , X 6 , and X 7 is N, NR N , or O. In certain embodiments, at least one of X 5 , X 6 , and X 7 is N or O.
  • at least one of X 5 and X 6 is N or O.
  • at least one of X 5 and X 6 is N.
  • Z is CR Z or N.
  • Z is CR Z . In certain embodiments, Z is CH.
  • Z is CCl. In certain embodiments, Z is CF. In certain embodiments, Z is N. In certain embodiments, Z is CH or N.
  • R Z is H. [144] In certain embodiments, R Z is halogen. In certain embodiments, R Z is F. In certain embodiments, R Z is Cl. [145] In certain embodiments, R Z is optionally substituted C 1-6 alkyl. In certain embodiments, R Z is C 1-6 haloalkyl. In certain embodiments, R Z is optionally substituted C 3-7 cycloalkyl. In certain embodiments, R Z is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R Z is optionally substituted C 6-10 aryl. In certain embodiments, R Z is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R Z is -CN.
  • R 2 is H.
  • R 2 is halogen.
  • R 2 is F or Cl. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Cl. [149] In certain embodiments, R 2 is optionally substituted C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted C1-6 alkyl. In certain embodiments, R 2 is optionally substituted C1-3 alkyl. In certain embodiments, R 2 is unsubstituted C 1-3 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. [150] In certain embodiments, R 2 is C 1-6 haloalkyl. [151] In certain embodiments, R 2 is optionally substituted C 3-7 cycloalkyl.
  • R 2 is optionally substituted C 3-6 cycloalkyl. In certain embodiments, R 2 is unsubstituted C 3-6 cycloalkyl. In certain embodiments, R 2 is optionally substituted C 3-4 cycloalkyl. In certain embodiments, R 2 is unsubstituted C 3-4 cycloalkyl. In certain embodiments, R 2 is optionally substituted C 3 cycloalkyl. In certain embodiments, R 2 is cyclopropyl. [152] In certain embodiments, R 2 is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R 2 is optionally substituted C 6-10 aryl.
  • R 2 is optionally substituted 5-10 membered heteroaryl.
  • R 2 is -CN.
  • R 2 is -OR O .
  • R 2 is -OR O , wherein R O is optionally substituted C 1-6 alkyl.
  • R 2 is -OR O , wherein R O is optionally substituted C 1-3 alkyl.
  • R 2 is - OR O , wherein R O is unsubstituted C 1-3 alkyl.
  • R 2 is -OMe.
  • R 2 is -OR O , wherein R O is C 1-6 haloalkyl. In certain embodiments, R 2 is - OR O , wherein R O is C 1-3 haloalkyl. In certain embodiments, R 2 is -OR O , wherein R O is C 1 haloalkyl. In certain embodiments, R 2 is -OCF 3 . [157] In certain embodiments, R 2 is -N(R N ) 2 . In certain embodiments, R 2 is optionally substituted C 1-6 acyl. In certain embodiments, R 2 is -SR S . In certain embodiments, R 2 is -SMe.
  • R 3 is C 1-8 alkyl, C 3-10 cycloalkyl, 3-7 membered heterocyclyl, or -(CR’R”) w -Ar 1 , wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; and Ar 1 is C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted. [159] In certain embodiments, R 3 is optionally substituted C 1-8 alkyl.
  • R 3 is unsubstituted C 1-8 alkyl. In certain embodiments, R 3 is optionally substituted C 1-4 alkyl. In certain embodiments, R 3 is unsubstituted C 1-4 alkyl. In certain embodiments, R 3 is tert-butyl. [160] In certain embodiments, [161] In certain embodiments, R 3 is C 1-6 alkyl substituted with one or more halogen. In certain embodiments, R 3 is C 1-6 alkyl substituted with one or more F. In certain embodiments, R 3 is C 1-3 alkyl substituted with one or more F.
  • R 3 is -CF 3 , -CF 2 Me, -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CF 2 Me -CH(Me)CF 3 , or -C(Me) 2 CF 3 . In certain embodiments, R 3 is -CF 3 or -CH 2 CF 3 . [162] In certain embodiments, R 3 is C 1-6 alkyl substituted with one or more -CN. In certain embodiments, R 3 is C1-3 alkyl substituted with one or more -CN. In certain embodiments, R 3 is -C(Me)2CN. [163] In certain embodiments, R 3 is optionally substituted C 3-10 cycloalkyl.
  • R 3 is optionally substituted C 3-8 cycloalkyl. In certain embodiments, R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of halogen and/or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of halogen and/or unsubstituted C 1-3 alkyl. In certain embodiments, R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of F and/or methyl.
  • R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of halogen, C 1-6 haloalkyl, and/or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of halogen, C 1-3 haloalkyl, and/or unsubstituted C 1-3 alkyl. In certain embodiments, R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of F, -CF 3 , and/or methyl. In certain embodiments, R 3 is C 3-8 cycloalkyl optionally substituted with one or more instances of F.
  • R 3 is optionally substituted C 3-5 cycloalkyl. In certain embodiments, R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of halogen and/or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of halogen and/or unsubstituted C 1-3 alkyl. In certain embodiments, R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of F and/or methyl.
  • R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of halogen, C 1-6 haloalkyl, and/or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of halogen, C 1-3 haloalkyl, and/or unsubstituted C 1-3 alkyl. In certain embodiments, R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of F, -CF 3 , and/or methyl. [166] In certain embodiments, R 3 is C 3-5 cycloalkyl optionally substituted with one or more instances of F.
  • R 3 is C 3-5 cycloalkyl substituted with one or more instances of F. In certain embodiments, R 3 is C 4 cycloalkyl (cyclobutyl) substituted with one or more instances of F. [167] In certain embodiments, R 3 is selected from: [168] In certain embodiments, R 3 is selected from: , [169] In certain embodiments, R 3 is R 3 is: [170] In certain embodiments, R 3 is: . In certain embodiments, R 3 is selected from: [171] In certain embodiments, R 3 is optionally substituted C 6-10 aryl. In certain embodiments, R 3 is optionally substituted phenyl.
  • R 3 is phenyl optionally substituted with one or more instances of halogen and/or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is phenyl optionally substituted with one or more instances of halogen. In certain embodiments, R 3 is phenyl optionally substituted with one or more instances of F. In certain embodiments, R 3 is phenyl substituted with one or more instances of F. [172] In certain embodiments, R 3 is selected from: [173] In certain embodiments, R 3 is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R 3 is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring N atoms.
  • R 3 is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more halogen. In certain embodiments, R 3 is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and optionally substituted with one or more F. In certain embodiments, R 3 is 3-6 membered heterocyclyl having 1 or 2 ring N atoms and substituted with one or more F. In certain embodiments, R 3 is azetidinyl substituted with one or more F. [174] In certain embodiments, R 3 is optionally substituted 3-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N and O.
  • R 3 is 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 C 1-6 haloalkyl.
  • R 3 is 3-6 membered heterocyclyl having 1 ring N atom, wherein the heterocyclyl is optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl.
  • R 3 is 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 -CF 3 .
  • R 3 is 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 - CF 3 .
  • R 3 is selected from: , [176]
  • R 3 is or -(CR’R”) w -Ar 1 .
  • w is 0, 1, or 2. In certain embodiments, w is 0.
  • w is 1. In certain embodiments, w is 2. [178] As defined herein, Ar 1 is C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted. In certain embodiments, Ar 1 is optionally substituted C 6-10 aryl. [179] In certain embodiments, Ar 1 is optionally substituted 5-10 membered heteroaryl. In certain embodiments, Ar 1 is optionally substituted 5-6 membered heteroaryl. In certain embodiments, Ar 1 is optionally substituted 5-membered heteroaryl. In certain embodiments, Ar 1 is optionally substituted 5- membered heteroaryl having 1 or 2 ring nitrogen atoms.
  • Ar 1 is optionally substituted 5-membered heteroaryl having 2 ring nitrogen atoms. In certain embodiments, Ar 1 is optionally substituted pyrazole. In certain embodiments, Ar 1 is pyrazole optionally substituted with one or more instances of C 1-6 alkyl and/or halogen. In certain embodiments, Ar 1 is pyrazole optionally substituted with one or more instances of methyl and/or Cl. In certain embodiments, R 3 is [180] As defined herein, Y is a bond, -CR’R”-, -O-, or -NR Y -. [181] In certain embodiments, Y is a bond. [182] In certain embodiments, Y is -CR’R”-.
  • Y is -CH 2 -. In certain embodiments, Y is -CH(Me)-. In certain embodiments, Y is -CH(OR O )-. In certain embodiments, Y is -CH(OH)-. [183] In certain embodiments, Y is -O-. [184] In certain embodiments, Y is -NR Y -. In certain embodiments, Y is -NH-. [185] As defined herein, R Y is H, C 1-6 alkyl, C 3-7 cycloalkyl, or a nitrogen protecting group, wherein the alkyl or cycloalkyl is optionally substituted. [186] In certain embodiments, R Y is H.
  • R Y is optionally substituted C 1-6 alkyl. In certain embodiments, R Y is optionally substituted C 3-7 cycloalkyl. In certain embodiments, R Y is a nitrogen protecting group. [188] In other embodiments, R Y and R 3 are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl. In some embodiments, R Y and R 3 are joined together with the intervening atoms to form optionally substituted 4-6 membered heterocyclyl. [189] In certain embodiments, Y is -CR’R”- and R 3 is optionally substituted C 1-8 alkyl.
  • Y is -CR’R”- and R 3 is optionally substituted C 1-4 alkyl.
  • Y is - CH 2 - and R 3 is unsubstituted C 1-4 alkyl.
  • Y is -CH 2 - and R 3 is tert-butyl.
  • Y is -CH(OH)- and R 3 is unsubstituted C 1-4 alkyl.
  • Y is - CH(OH)- and R 3 is tert-butyl.
  • L is a bond or -(CR L1 R L2 ) m -, wherein m is 1 or 2.
  • m is 1. In certain embodiments, m is 2. [192] In certain embodiments, L is a bond. [193] In certain embodiments, L is -CR L1 R L2 -. In certain embodiments, L is -CH 2 -. [194] As defined herein, each instance of R L1 is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl, wherein each alkyl or cycloalkyl is independently optionally substituted. [195] In certain embodiments, at least one instance of R L1 is H. In certain embodiments, each instance of R L1 is H.
  • At least one instance of R L1 is halogen. In certain embodiments, at least one instance of R L1 is optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R L1 is C 1-6 haloalkyl. In certain embodiments, at least one instance of R L1 is optionally substituted C 3-7 cycloalkyl.
  • each instance of R L2 is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl, wherein each alkyl or cycloalkyl is independently optionally substituted. [198] In certain embodiments, at least one instance of R L2 is H.
  • R L1 and R L2 attached to the same carbon atom are joined together with the intervening atoms to form C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is independently optionally substituted.
  • R L1 and R L2 attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted C 3-7 cycloalkyl.
  • R L1 and R L2 attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl.
  • R 4 is C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted.
  • R 4 is C 6-10 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted.
  • R 4 is optionally substituted C 1-6 alkyl. In certain embodiments, R 4 is unsubstituted C 1-6 alkyl. In certain embodiments, R 4 is optionally substituted C 1-3 alkyl. In certain embodiments, R 4 is unsubstituted C 1-3 alkyl. In certain embodiments, R 4 is isopropyl. [206] In certain embodiments, R 4 is C 1-6 haloalkyl. [207] In certain embodiments, R 4 is optionally substituted C 6-10 aryl. In certain embodiments, R 4 is optionally substituted C 6 aryl (i.e., optionally substituted phenyl).
  • R 4 is phenyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and/or -OR O . In certain embodiments, R 4 is phenyl optionally substituted with one or more instances of F, Cl, methyl, -CF 3 , and/or -OCF 3 . [208] In certain embodiments, R 4 is of the formula: , wherein R 4a and s are as defined herein. [209] As defined herein, s is 0, 1, 2, 3, 4, or 5. [210] In certain embodiments, s is 0, 1, 2, or 3. In certain embodiments, s is 0, 1 or 2.
  • s is 0 or 1. 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.
  • R 4 is of one of the following formulae: [212] As defined herein, each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1- 6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted. [213] In certain embodiments, at least one instance of R 4a is halogen.
  • At least one instance of R 4a is F. In certain embodiments, at least one instance of R 4a is Cl. [214] In certain embodiments, at least one instance of R 4a is optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 4a is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R 4a is optionally substituted C 1-3 alkyl. In certain embodiments, at least one instance of R 4a is unsubstituted C 1-3 alkyl. In certain embodiments, at least one instance of R 4a is methyl. [215] In certain embodiments, at least one instance of R 4a is C 1-6 haloalkyl.
  • At least one instance of R 4a is C 1-3 haloalkyl. In certain embodiments, at least one instance of R 4a is C 1 haloalkyl. In certain embodiments, at least one instance of R 4a is -CF 3 . [216] In certain embodiments, at least one instance of R 4a is optionally substituted C 3-7 cycloalkyl. In certain embodiments, at least one instance of R 4a is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R 4a is optionally substituted C 6-10 aryl. In certain embodiments, at least one instance of R 4a is optionally substituted 5-10 membered heteroaryl.
  • At least one instance of R 4a is -CN. [217] In certain embodiments, at least one instance of R 4a is -OR O . [218] In certain embodiments, at least one instance of R 4a is -OR O , wherein R O is C 1-6 haloalkyl. In certain embodiments, at least one instance of R 4a is -OR O , wherein R O is C 1-3 haloalkyl. In certain embodiments, at least one instance of R 4a is -OR O , wherein R O is C 1 haloalkyl. In certain embodiments, at least one instance of R 4a is -OCF 3 .
  • At least one instance of R 4a is -OR O , wherein R O is optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 4a is -OR O , wherein R O is optionally substituted C 1-3 alkyl. In certain embodiments, at least one instance of R 4a is -OR O , wherein R O is unsubstituted C 1-3 alkyl. In certain embodiments, at least one instance of R 4a is -OMe. [220] In certain embodiments, at least one instance of R 4a is -N(R N ) 2 . In certain embodiments, at least one instance of R 4a is C 1-6 acyl.
  • each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -OR O , wherein each alkyl is independently optionally substituted.
  • each instance of R 4a is independently halogen, unsubstituted C 1-6 alkyl, or C 1-6 haloalkyl.
  • each instance of R 4a is independently F, Cl, methyl, -CF 3 , or -OCF 3 .
  • R 4 is selected from: [223]
  • R 4 is selected from: [224]
  • R 4 is optionally substituted C 3-7 cycloalkyl.
  • R 4 is optionally substituted C 3-6 cycloalkyl. In certain embodiments, R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl. In certain embodiments, R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of halogen and/or C 1-6 haloalkyl. In certain embodiments, R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of F and/or -CF 3 .
  • R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of halogen. In certain embodiments, R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of F. In certain embodiments, R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of C 1-6 haloalkyl. In certain embodiments, R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of -CF 3 . [227] In certain embodiments, R 4 is selected from: . [228] In certain embodiments, R 4 is optionally substituted 5-10 membered heteroaryl.
  • R 4 is optionally substituted 5- or 6-membered heteroaryl.
  • R 4 is optionally substituted 5- or 6-membered heteroaryl having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S.
  • R 4 is optionally substituted 5- or 6-membered heteroaryl having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl.
  • R 4 is optionally substituted 5- or 6-membered heteroaryl having 1or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R 4 is optionally substituted 5- or 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl.
  • R 4 is optionally substituted 5- or 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of F, methyl, and/or -CF 3 .
  • R 4 is optionally substituted 5-membered heteroaryl.
  • R 4 is optionally substituted 5-membered heteroaryl having 1or 2 ring heteroatoms independently selected from O, N, and S.
  • R 4 is optionally substituted 5- membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl.
  • R 4 is optionally substituted 5-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of F, methyl, and/or -CF 3 .
  • R 4 is optionally substituted 6-membered heteroaryl.
  • R 4 is optionally substituted 6-membered heteroaryl having 1or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R 4 is optionally substituted 6- membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl. In certain embodiments, R 4 is optionally substituted 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from O, N, and S, wherein the heteroaryl is optionally substituted with one or more instances of F, methyl, and/or -CF 3 .
  • R 4 is optionally substituted pyridyl. In certain embodiments, R 4 is pyridyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl. In certain embodiments, R 4 is pyridyl optionally substituted with one or more instances of F and/or -CF 3 . [234] In certain embodiments, R 4 is optionally substituted isoxazolyl. In certain embodiments, R 4 is isoxazolyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C1-6 haloalkyl.
  • R 4 is isoxazolyl optionally substituted with one or more instances of methyl and/or -CF 3 .
  • R 4 is optionally substituted oxazolyl.
  • R 4 is oxazolyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1- 6 haloalkyl.
  • R 4 is oxazolyl optionally substituted with one or more instances of - CF 3 .
  • R 4 is optionally substituted thiazolyl.
  • R 4 is thiazolyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1- 6 haloalkyl. In certain embodiments, R 4 is thiazolyl optionally substituted with one or more instances of - CF 3 . [237] In certain embodiments, R 4 is optionally substituted thiophenyl. In certain embodiments, R 4 is thiophenyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl. In certain embodiments, R 4 is thiophenyl optionally substituted with one or more instances of -CF 3 .
  • R 4 is of one of the following formulae: defined herein.
  • p is 0, 1, 2, 3, or 4, as valency permits. In certain embodiments, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0, 1, 2 or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. [240] In certain embodiments, R 4 is of one of the following formulae: [241] In certain embodiments, R 4 is of the formula: .
  • each instance of R 4b is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1- 6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted.
  • at least one instance of R 4b is halogen.
  • at least one instance of R 4b is F.
  • At least one instance of R 4b is optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 4b is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 4b is optionally substituted C1-3 alkyl. In certain embodiments, at least one instance of R 4b is unsubstituted C 1-3 alkyl. In certain embodiments, at least one instance of R 4b is methyl. [245] In certain embodiments, at least one instance of R 4b is C 1-6 haloalkyl. In certain embodiments, at least one instance of R 4b is C 1-3 haloalkyl.
  • At least one instance of R 4b is C 1 haloalkyl. In certain embodiments, at least one instance of R 4b is -CF 3 . [246] In certain embodiments, at least one instance of R 4b is C 3-7 cycloalkyl. In certain embodiments, at least one instance of R 4b is 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R 4b is C 6-10 aryl. In certain embodiments, at least one instance of R 4b is 5-10 membered heteroaryl. In certain embodiments, at least one instance of R 4b is -CN. In certain embodiments, at least one instance of R 4b is -OR O .
  • At least one instance of R 4b is -N(R N ) 2 . In certain embodiments, at least one instance of R 4b is C 1-6 acyl. [247] In certain embodiments, each instance of R 4b is independently halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each alkyl is independently optionally substituted. In certain embodiments, each instance of R 4b is independently halogen, unsubstituted C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, each instance of R 4b is independently F, methyl, or -CF 3 .
  • R 4 is selected from: [249] In certain embodiments, R 4 is: .
  • R 5a is H.
  • R 5a is halogen. In certain embodiments, R 5a is F. In certain embodiments, R 5a is Cl. [253] In certain embodiments, R 5a is optionally substituted C 1-6 alkyl. In certain embodiments, R 5a is unsubstituted C 1-6 alkyl. In certain embodiments, R 5a is optionally substituted C 1-3 alkyl. In certain embodiments, R 5a is unsubstituted C 1-3 alkyl. In certain embodiments, R 5a is methyl. [254] In certain embodiments, R 5a is C 1-6 haloalkyl. In certain embodiments, R 5a is C 1-3 haloalkyl.
  • R 5a is H, optionally substituted C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, R 5a is H, unsubstituted C 1-3 alkyl, or C 1 haloalkyl. In certain embodiments, R 5a is H, methyl, or -CF 3 .
  • R 5b is H.
  • R 5b is halogen.
  • R 5a is F.
  • R 5b is Cl.
  • R 5b is optionally substituted C 1-6 alkyl. In certain embodiments, R 5b is unsubstituted C 1-6 alkyl. In certain embodiments, R 5b is optionally substituted C 1-3 alkyl. In certain embodiments, R 5b is unsubstituted C 1-3 alkyl. In certain embodiments, R 5b is methyl. [261] In certain embodiments, R 5b is C 1-6 haloalkyl. In certain embodiments, R 5b is C 1-3 haloalkyl. In certain embodiments, R 5b is C 1 haloalkyl. In certain embodiments, R 5b is -CF 3 .
  • R 5a and R 5b are joined together with the intervening atoms to form C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted.
  • R 5a and R 5b are joined together with the intervening atoms to form optionally substituted C 3-7 cycloalkyl.
  • R 5a and R 5b are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl.
  • R 6a is H.
  • R 6a is halogen.
  • R 6a is F.
  • R 6a is Cl.
  • R 6a is optionally substituted C 1-6 alkyl. In certain embodiments, R 6a is unsubstituted C1-6 alkyl. In certain embodiments, R 6a is optionally substituted C1-3 alkyl. In certain embodiments, R 6a is unsubstituted C 1-3 alkyl. [270] In certain embodiments, R 6a is methyl. [271] In certain embodiments, R 6a is C1-6 haloalkyl. In certain embodiments, R 6a is C1-3 haloalkyl. In certain embodiments, R 6a is C 1 haloalkyl. In certain embodiments, R 6a is -CF 3 .
  • R 6a is H, halogen, optionally substituted C 1-6 alkyl, or C 1-6 haloalkyl. In certain embodiments, R 6a is H, halogen, unsubstituted C 1-3 alkyl, or C 1 haloalkyl. In certain embodiments, R 6a is H, methyl, F, Cl, or -CF 3 .
  • R 6b is H.
  • R 6b is halogen.
  • R 6b is F.
  • R 6b is Cl.
  • R 6b is optionally substituted C 1-6 alkyl. In certain embodiments, R 6b is unsubstituted C 1-6 alkyl. In certain embodiments, R 6b is optionally substituted C 1-3 alkyl. In certain embodiments, R 6b is unsubstituted C 1-3 alkyl. In certain embodiments, R 6b is methyl. [278] In certain embodiments, R 6b is C 1-6 haloalkyl. In certain embodiments, R 6b is C 1-3 haloalkyl. In certain embodiments, R 6b is C 1 haloalkyl. In certain embodiments, R 6b is -CF 3 .
  • R6a is H or unsubstituted C1-3 alkyl 6b is H. In certain embodiments, R6a is H or methyl 6b is H. [281] In certain embodiments, R 6a and R 6b are both H. [282] In certain embodiments, R 6a is methyl, and R 6b is H. [283] In certain embodiments, R 6a and R 6b are joined together with the intervening atoms to form C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted.
  • R 7a is H.
  • R 7a is halogen.
  • R 7a is F.
  • R 7a is Cl.
  • R 7a is optionally substituted C 1-6 alkyl. In certain embodiments, R 7a is unsubstituted C 1-6 alkyl. In certain embodiments, R 7a is optionally substituted C 1-3 alkyl. In certain embodiments, R 7a is unsubstituted C 1-3 alkyl. In certain embodiments, R 7a is methyl. [289] In certain embodiments, R 7a is C 1-6 haloalkyl. In certain embodiments, R 7a is C 1-3 haloalkyl. In certain embodiments, R 7a is C 1 haloalkyl. In certain embodiments, R 7a is -CF 3 .
  • R 7b is H.
  • R 7b is halogen.
  • R 7b is F.
  • R 7b is Cl.
  • R 7b is optionally substituted C 1-6 alkyl. In certain embodiments, R 7b is unsubstituted C 1-6 alkyl. In certain embodiments, R 7b is optionally substituted C 1-3 alkyl. In certain embodiments, R 7b is unsubstituted C 1-3 alkyl. In certain embodiments, R 7b is methyl. [295] In certain embodiments, R 7b is C 1-6 haloalkyl. In certain embodiments, R 7b is C 1-3 haloalkyl. In certain embodiments, R 7b is C 1 haloalkyl. In certain embodiments, R 7b is -CF 3 .
  • R 7a is methyl, and R 7b is H.
  • R 7a and R 7b are joined together with the intervening atoms to form C 3-7 cycloalkyl or 3-7 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted.
  • R 7a and R 7b are joined together with the intervening atoms to form optionally substituted C 3-7 cycloalkyl.
  • R 7a and R 7b are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl.
  • each instance of R’ is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.
  • at least one instance of R’ is H.
  • at least one instance of R’ is halogen.
  • at least one instance of R’ is optionally substituted C 1-6 alkyl.
  • at least one instance of R’ is C 1-6 haloalkyl.
  • At least one instance of R’ is optionally substituted C 3-7 cycloalkyl. In certain embodiments, at least one instance of R’ is optionally substituted 3-7 membered heterocyclyl.
  • each instance of R” is independently H, halogen, C 1-6 alkyl, -OR O , or -N(R N ) 2 , wherein the each alkyl is independently optionally substituted.
  • at least one instance of R” is H.
  • at least one instance of R” is halogen.
  • at least one instance of R” is optionally substituted C 1-6 alkyl.
  • At least one instance of R” is - OR O . In certain embodiments, at least one instance of R” is -N(R N ) 2 . [306] In certain embodiments, R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form C 3-7 cycloalkyl 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 C 3-7 cycloalkyl.
  • R’ and R” attached to the same carbon atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl.
  • R N1 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 acyl, or a nitrogen protecting group, wherein the alkyl, cycloalkyl, or acyl is optionally substituted.
  • R N1 is H.
  • R N1 is optionally substituted C 1-6 alkyl.
  • R N1 is optionally substituted C 3-7 cycloalkyl.
  • R N1 is optionally substituted C 1-6 acyl. In certain embodiments, R N1 is a nitrogen protecting group.
  • each R N is independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 acyl, or a nitrogen protecting group, or two R N attached 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.
  • at least one instance of R N is H. In certain embodiments, each instance of R N is H.
  • At least one instance of R N is optionally substituted C 1-6 alkyl. [313] In certain embodiments, at least one instance of R N is optionally substituted C 3-7 cycloalkyl. In certain embodiments, at least one instance of R N is optionally substituted C 1-6 acyl. In certain embodiments, at least one instance of R N is a nitrogen protecting group. [314] In certain embodiments, two R N attached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, two R N attached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 4-6 membered heterocyclyl.
  • each instance of R O is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 1-6 acyl, or an oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.
  • at least one instance of R O is H.
  • each instance of R O is H.
  • at least one instance of R O is optionally substituted C 1-6 alkyl.
  • at least one instance of R O is C 1-6 haloalkyl.
  • At least one instance of R O is C 1-3 haloalkyl. In certain embodiments, at least one instance of R O is C 1 haloalkyl. In certain embodiments, at least one instance of R O is -CF 3 . [319] In certain embodiments, at least one instance of R O is optionally substituted C 3-7 cycloalkyl. In certain embodiments, at least one instance of R O is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R O is optionally substituted C 1-6 acyl. In certain embodiments, at least one instance of R O is an oxygen protecting group.
  • each instance of R S is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 1-6 acyl, or a sulfur protecting group, wherein each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted.
  • at least one instance of R S is H.
  • at least one instance of R S is optionally substituted C 1-6 alkyl.
  • at least one instance of R S is unsubstituted C 1-6 alkyl.
  • At least one instance of R S is optionally substituted C 1-3 alkyl. In certain embodiments, at least one instance of R S is unsubstituted C 1-3 alkyl. In certain embodiments, at least one instance of R S is methyl. [323] In certain embodiments, at least one instance of R S is C 1-6 haloalkyl. In certain embodiments, at least one instance of R S is optionally substituted C 3-7 cycloalkyl. In certain embodiments, at least one instance of R S is optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R S is optionally substituted C 1-6 acyl. In certain embodiments, at least one instance of R S is a sulfur protecting group.
  • each instance of R S1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3-7 membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is independently optionally substituted.
  • at least one instance of R S1 is optionally substituted C 1-6 alkyl.
  • at least one instance of R S1 is unsubstituted C 1-6 alkyl.
  • at least one instance of R S1 is optionally substituted C 1-3 alkyl.
  • at least one instance of R S1 is unsubstituted C 1-3 alkyl.
  • At least one instance of R S1 is methyl. [326] In certain embodiments, at least one instance of R S1 is C1-6 haloalkyl. In certain embodiments, at least one instance of R S1 is optionally substituted C 3-7 cycloalkyl. In certain embodiments, at least one instance of R S1 is optionally substituted 3-7 membered heterocyclyl.
  • compositions comprising a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof) and one or more pharmaceutically acceptable carriers and/or excipients.
  • a compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., via blood and/or lymph supply
  • direct administration to an affected site.
  • 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).
  • 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.
  • 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.
  • 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. [335] 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).
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • 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.
  • 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
  • bioavailability improve safety
  • reduce drug resistance, reduce and/or modify metabolism inhibit excretion, and/or modify distribution in a subject or cell.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • 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).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • 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.
  • the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating and/or preventing a disease, disorder, or condition in a subject in need thereof.
  • kits 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).
  • the information included in the kits is prescribing information.
  • the kits provide instructions for treating a disease in a subject in need thereof.
  • 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.
  • 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.
  • Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5.
  • 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. [341] Also provided herein are compounds), 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.
  • 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.
  • the disease, disorder, or condition is associated with Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5 dysfunction.
  • the disease, disorder, or condition is associated with Kv7.2 dysfunction.
  • the disease, disorder, or condition is associated with Kv7.3 dysfunction.
  • the disease, disorder, or condition is associated with Kv7.2/Kc7.3 dysfunction.
  • 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.
  • 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
  • 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. [347] 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.
  • 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- Kleffner syndrome.
  • 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.
  • LGS Lennox-Gastaut syndrome
  • 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.
  • 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). [348] In certain embodiments, the disease, disorder, or condition is a depressive disorder. “Depressive disorders” are mood disorders characterized by depressed mood.
  • 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.
  • MDD major depressive disorder
  • PMDD premenstrual dysphoric disorder
  • SAD seasonal affective disorder
  • TRD treatment-resistant depression
  • depression associated with agitation or anxiety adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.
  • the depressive disorder is major depressive disorder (MDD).
  • the depressive disorder is disruptive mood dysregulation disorder.
  • the depressive disorder is persistent depressive disorder.
  • the depressive disorder is bipolar spectrum disorder.
  • the depressive disorder is postpartum depression.
  • 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.
  • PMDD premenstrual dysphoric disorder
  • SAD seasonal affective disorder
  • the depressive disorder is atypical depression.
  • the depressive disorder is treatment- resistant depression (TRD).
  • the depressive disorder is depression associated with agitation or anxiety.
  • the depressive disorder is adjustment disorder with depressed mood. In some embodiments, the depressive disorder is prolonged depressive reaction.
  • OCD obsessive-compulsive disorder
  • 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.
  • OCD obsessive-compulsive disorder
  • PTSD post-traumatic stress disorder
  • ADHD attention-deficit/hyperactivity disorder
  • bipolar I disorder bipolar II disorder
  • 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-
  • 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.
  • 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).
  • the medicament is for treating a seizure disorder, a depressive disorder, pain, or anhedonia in a subject.
  • Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and/or Kv7.5.
  • the Kv7 potassium channel is Kv7.2.
  • the Kv7 potassium channel is Kv7.3.
  • the Kv7 potassium channel is Kv7.2/Kc7.3.
  • 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.
  • a Kv7 potassium channel e.g., Kv7.2/Kv7.3
  • the activity of the Kv7 potassium channel 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.
  • the activity of the Kv7 potassium channel 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 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: X 5 is N, CR 5a , or CR 5a R 5b X 6 is N, O, CR 6a , or CR 6a R 6b X 7 is absent, or is N, NR N , O, S, CR 7a , or CR 7a R 7b of X 5 , X 6 , and X 7 is N, NR N Z is CR Z or N; each instance of R Z and R 2 is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N )2, -SR S , -S( O)2R
  • E mbodiment 2 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, wherein X 7 is NR N , O, or S.
  • Embodiment 3 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, wherein X 7 is NR N , O, or S.
  • 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 5 The compound of Embodiment 1, wherein the compound is of Formula (I-a-3): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 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 7 The compound of Embodiment 1, wherein the compound is of Formula (I-a-5): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and s is 0, 1, 2, 3, 4, or 5.
  • E mbodiment 9 The compound of Embodiment 1, wherein the compound is of Formula (I ): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one of X 5 and X 6 is N or O.
  • E mbodiment 10 The compound of Embodiment 1, wherein the compound is of Formula (I -1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one of X 5 and X 6 is N or O.
  • Embodiment 11 The compound of Embodiment 1, wherein the compound is of Formula (I ): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein at least one of X 5 and X 6 is N or O.
  • 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 12 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 13 Embodiment 13
  • each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 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 14 The compound of Embodiment 1, wherein the compound is of Formula (I-c): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • Embodiment 15 The compound of Embodiment 1, wherein the compound is of Formula (I-c-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • Embodiment 16 The compound of Embodiment 1, wherein the compound is of Formula (I-c-1): or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.
  • each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 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 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 Z is CR Z .
  • 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 R Z is H.
  • 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 Z is CH.
  • 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 Z is N.
  • 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 R 2 is optionally substituted C 1-6 alkyl.
  • Embodiment 22 Embodiment 22.
  • 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 R 2 is methyl.
  • 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 R 2 is methyl.
  • 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 Y is -CR’R”-.
  • 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 Y is -CH 2 -.
  • Embodiment 26 Embodiment 26.
  • 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 R 3 is unsubstituted C 1-4 alkyl.
  • 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 R 3 is unsubstituted C 1-4 alkyl.
  • 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 R 3 is tert-butyl.
  • 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 R 5a is H or optionally substituted C 1-6 alkyl.
  • Embodiment 30 Embodiment 30.
  • 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 R 5a is H or unsubstituted C 1-3 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 R 5a is H or methyl.
  • 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 R 5a is H or methyl.
  • 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 R 6a is H or unsubstituted C 1-3 alkyl.
  • 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 R 6a is H or unsubstituted C 1-3 alkyl.
  • 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 R 6a is H or methyl.
  • 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 R 6b is H.
  • 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 R 6b is H.
  • 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 L is -CH 2 -.
  • 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 L is -CH 2 -.
  • 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 R 4 is optionally substituted phenyl.
  • 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 R 4 is phenyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and/or -OR O .
  • Embodiment 43 Embodiment 43.
  • R 4 is of the formula: , wherein: each instance of R 4a is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -ORO, -N(RN) 2 , or C 1-6 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 s is 0, 1, 2, or 3; or s is 0, 1 or 2; or s is 0 or 1; or s is 0; or s is 1; or s is 2; or s is 3.
  • 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 R 4 is of one of the following formulae: Embodiment 47.
  • 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 R 4 is optionally substituted C 3-7 cycloalkyl.
  • 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 R 4 is C 3-6 cycloalkyl optionally substituted with one or more instances of halogen, unsubstituted C 1-6 alkyl, and/or C 1-6 haloalkyl.
  • Embodiment 54 Embodiment 54.
  • 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 R 4 is selected from: Embodiment 56.
  • 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 R 4 is optionally substituted 5- or 6-membered heteroaryl.
  • 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 R 4 is optionally substituted 5- or 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, O, and S.
  • Embodiment 58 Embodiment 58.
  • each instance of R 4b is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OR O , -N(R N ) 2 , or C 1-6 acyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; and p is 0, 1, 2, 3, or 4, as valency permits.
  • 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 p is 0 or 1.
  • 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 R 4 is of one of the following formulae: Embodiment 63.
  • 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 each instance of R 4a is independently F, methyl, or -CF 3 .
  • 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 R 4 is selected from: Embodiment 67.
  • Embodiment 1 wherein the compound is selected from Examples 1-12, 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 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 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, iso
  • 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 is a Kv7 potassium channel.
  • 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.
  • 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 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 The compound for use of Embodiment 82.
  • 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.
  • tert-butyl 7-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [360] To a degassed (with nitrogen) mixture of tert-butyl (2-((3-bromo-5-methylpyridin-2- yl)oxy)ethyl)carbamate (21.5 g, 64.9 mmol) and cesium carbonate (31.7 g, 97.4 mmol) in dioxane (250 mL) was added tris(dibenzylideneacetone)dipalladium (2.97 g, 3.25 mmol) and 2- dicyclohexylphosphino-2 ,4 ,6 -triisopropylbiphenyl (3.09 g, 6.49 mmol).
  • reaction mixture was allowed to warm to ambient temperature and stirred for 16 h, then stirred at to 80°C for 4 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL); dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with a gradient of 0 to 50% of ethyl acetate in heptane to provide the title compound in 64% yield (1.89 g) as colorless solid.
  • Example 7 Example 7 and related compounds can be prepared according to the following general scheme.
  • Examples 11 and 12 Examples 11 and 12 and related compounds can be prepared according to the following general scheme.
  • Examples 11 and 12 and related compounds can be prepared according to the following general scheme.
  • the following Examples were prepared analogously to Examples 7, 11, and 12, 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, C-18 reverse-phase chromatography, or reverse-phase preparative HPLC.
  • Step 8 Preparation of (S)-N-(7-chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-yl)-3,3-bis(methyl-d 3 )butanamide and (R)-N-(7-chloro-1-(3,5- difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-3,3-bis(methyl- d 3 )butanamide [387] N-(7-chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)-3,3-bis(methyl-
  • Step 4 Preparation of 5-chloro-2,6-dimethyl-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H- imidazo[4,5-b]pyridine [396] To a solution of 6-chloro-5-methyl-N3-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyridine-2,3- diamine (2.00 g, 6.31 mmol) in AcOH (20 mL) was added 1,1,1-trimethoxyethane (3.79 g, 31.60 mmol, 3.97 mL). The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure.
  • TREX HEK 293 or HEK 293 cells were stably transfected with either an inducible or non-inducible expression vector containing the full- length cDNA coding for the desired human K V 7.2/K V 7.3 or in combination with another full-length cDNA for a second desired human K V 7 potassium channel.
  • Potassium channel-expressing cell lines were induced with tetracycline (1 g/mL), if required, and plated on 384-well poly-D-lysine (PDL)-coated plates in culture media (DMEM, containing 10% FBS and 1% L-glutamine).
  • a Hamamatsu FDSS ⁇ Cell was used to perform a 1:1 addition of K challenge buffer (150 mM NaCl, 10 mM HEPES, 2 mM CaCl 2 , 10 mM KCl, 1 mM MgCl 2 , 10 mM glucose, adjusted with Tris to pH 7.4 for human K V 7.2/K V 7.3, and simultaneously read plates at excitation wavelength of 530 nm and emission wavelength of 558 nm.
  • K challenge buffer 150 mM NaCl, 10 mM HEPES, 2 mM CaCl 2 , 10 mM KCl, 1 mM MgCl 2 , 10 mM glucose, adjusted with Tris to pH 7.4 for human K V 7.2/K V 7.3, and simultaneously read plates at excitation wavelength of 530 nm and emission wavelength of 558 nm.
  • Non-potassium channel-mediated potassium influx was determined in the presence of DMSO, and maximal influx was determined in the presence of a
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.
  • certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.
  • any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [403] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

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Abstract

L'invention concerne des composés, y compris des composés de l'une quelconque des formules décrites dans la description (par exemple, formule (I)), et des sels pharmaceutiquement acceptables, des stéréoisomères, des tautomères, des solvates, des hydrates, des dérivés marqués de manière isotopique, et des promédicaments de ceux-ci. Les composés selon l'invention peuvent agir en tant que potentialisateurs des canaux potassiques voltage-dépendants (par exemple les canaux potassiques Kv7 tels que Kv7.2/Kv7.3) et sont donc utiles dans le traitement et/ou la prévention de maladies, de troubles et d'affections (par exemple des maladies, des troubles et des affections associés au dysfonctionnement du canal potassique Kv7).
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