Heteroaryl amine compounds and uses thereof

Abstract

Provided herein are compounds, including compounds of any of the formulae described herein (e.g., Formula (I), e.g., Formula (I'')) and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. The 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).(I'').

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 520,171, filed August 17, 2023, and U.S. Provisional Patent Application No. 63 / 567,980, filed March 21, 2024, pursuant to 35 USC § 119(e), the entire contents of which are incorporated herein by reference. Background Technology

[0003] Voltage-gated potassium channels, including Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), are important in controlling neuronal excitability. Kv7.2 / Kv7.3 are fundamental to neuronal “M-currents,” named, based on their initial characterization, as neuronal currents reduced in response to muscarinic / cholinergic agonists (see Brown, DA et al., Nature (1980), 283: 673-676). M-currents are non-inactivating hyperpolarizing currents known to act as brakes on neuronal overexcitation. Thus, a decrease in Kv7.2-mediated M-currents (e.g., via inherited loss of function) can cause neuronal depolarization and increased membrane and neuronal excitability, leading to action potential bursts, manifested as, for example, epileptic seizures. In contrast, an increase in Kv7.2-mediated M-currents can cause cell membrane hyperpolarization, thereby reducing neuronal excitability and preventing the initiation and propagation of action potential bursts and the resulting epileptic seizures. Enhancing the open state of Kv7.2 / Kv7.3 channels in neurons favors a hyperpolarized resting state, which reduces fast action potential spikes (i.e., sudden discharges). This enhancement can provide a stabilizing effect on excitable, especially hyperexcitable, neurons and can therefore be used to treat certain epileptic seizure conditions. Clinically, this enhancement has been shown to be effective in treating seizure conditions in adults with epilepsy, such as partial-onset seizures, using the known Kv7.2 / Kv7.3 enhancer retigabine (ezogabine).

[0004] Despite significant progress in this field, there remains a substantial need for improved compounds and methods to enhance voltage-gated potassium channels, including voltage-gated potassium channels Kv7.2 / Kv7.3. Such compounds and methods could be used to treat diseases, conditions, and disorders involving potassium channel dysfunction. Summary of the Invention

[0005] This document provides compounds comprising any of the formulas described herein (e.g., formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. The 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 intended for the treatment and / or prevention of diseases, conditions, and disorders (e.g., diseases, conditions, and disorders associated with Kv7 potassium channel dysfunction). This document also provides pharmaceutical compositions comprising the compounds provided herein, and kits comprising said pharmaceutical compositions. Additionally, this disclosure provides methods for preparing the compounds and pharmaceutical compositions described herein, as well as intermediates useful thereto.

[0006] In one aspect, this paper provides compounds of formula (I):

[0007] (I),

[0008] and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, of which X 1 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 R 1 R 2 R 3 R 5 Y, R N1 m, n, and p are as defined in this paper.

[0009] In some embodiments, the compound of formula (I) is a compound of formula (I''):

[0010] (I''),

[0011] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments of formula (I''), Z 3 For N and Z 6 Let S be the value of Z. In some embodiments of formula (I''), Z is the value of Z. 3 For S and Z 6 For N. In some implementations of equation (I''), Z 3 For N and Z 6 For O. In some embodiments of formula (I''), Z 3 For O and Z 6 Let N be the number of elements in the array.

[0012] In some embodiments, the compound of formula (I) is the compound of formula (Ia):

[0013] (Ia),

[0014] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0015] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0016] (Ib),

[0017] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0018] In some embodiments, the compound of formula (I) is the compound of formula (If):

[0019] (If),

[0020] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0021] In some embodiments, for example, the compounds disclosed herein are selected from those listed in Tables 1A-1C (hereinafter), and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs.

[0022] In another aspect, this document provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In some embodiments, the pharmaceutical compositions provided herein comprise an effective amount (e.g., a therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0023] As described herein, the compounds and pharmaceutical compositions provided herein can enhance voltage-gated potassium channels (e.g., Kv7.2 / Kv7.3 potassium channels) and are therefore suitable for the treatment and / or prevention of diseases, conditions and disorders in subjects, including, for example, indications involving Kv7 potassium channel dysfunction.

[0024] In other respects, this document provides methods and uses for the compounds and pharmaceutical compositions provided herein, including but not limited to the following:

[0025] (a) A method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0026] (b) A method of treating a subject in need of a disease, condition or disorder associated with dysfunction of a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3), comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0027] (c) A method of treating a subject with epileptic seizure disorder, depression, pain or anhedonia, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0028] (d) A method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in in vitro cells, comprising administering to said cells a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0029] In another aspect, this document provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In yet another aspect, this document provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof, for use as pharmaceuticals and / or for the preparation of pharmaceuticals.

[0030] In another aspect, this document provides kits comprising the compounds disclosed herein, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives or prodrugs thereof, or pharmaceutical compositions thereof. The kits described herein may comprise single-dose or multiple-dose compounds or pharmaceutical compositions thereof. The kits described herein may be used in any of the methods or uses provided herein, and optionally further include instructions for using the kit (e.g., instructions for using the compounds or compositions included in the kit).

[0031] This document also provides methods for preparing the compounds disclosed herein, their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, and pharmaceutical compositions thereof. Synthetic intermediates that can be used to prepare the compounds and compositions are also provided herein.

[0032] As described below, details of certain embodiments of this disclosure are set forth in the specific embodiments. Other embodiments of this disclosure will become apparent from the definitions, examples, abstract, and claims.

[0033] definition

[0034] Chemical definition

[0035] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner pages, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0036] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further covers compounds that are substantially free of other isomers and alternatively, mixtures of various isomers.

[0037] Unless otherwise provided, the formulas and structures described herein include compounds excluding isotopically enriched atoms, and also include compounds containing isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the structures of the present invention (hydrogen replaced by deuterium or tritium, ...) 19 F was 18 F replacement or carbonization 13 C or 14 (Except for carbon substitution enriched with C) within the scope of this disclosure. Such compounds can be used as analytical tools or probes, for example, in bioassays. In some embodiments, one or more hydrogen atoms of the compound are replaced with deuterium (“deuterated derivatives”).

[0038] The term "isotope" refers to a variant of a particular chemical element such that, although all isotopes of a given element have the same number of protons per atom of the element, those isotopes have different numbers of neutrons.

[0039] When a range of values ​​is listed (“range”), it encompasses every value within the range and its subranges. Unless otherwise specified, a range includes the values ​​at both ends of the range. For example, “C” 1-6 "Alkyl" encompasses C1, C2, C3, C4, C5, C6, 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.

[0040] The phrase “at least one instance” is used to refer to one, two, three, four or more instances, but also includes, for example, one to four, one to three, one to two, two to four, two to three or three to four instances, including endpoints.

[0041] The term "aliphatic" refers to alkyl, alkenyl, ynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic group" refers to heteroalkyl, heteroalkenyl, heteroynyl, and heterocyclic groups.

[0042] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, dibutyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and n-dodecyl (C9). 12 ), etc. Unless otherwise stated, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C 1-12 Alkyl groups (such as unsubstituted C4) 1-6 Alkyl groups, such as -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, such as unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), and unsubstituted butyl (Bu, such as unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted dibutyl (sec-Bu or s-Bu), and unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C. 1-12 Alkyl groups (such as substituted C4 groups) 1-6 Alkyl groups, such as –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3 or benzyl (Bn)).

[0043] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen (e.g., fluorine, bromine, chlorine, or iodine). "Haloalkyl" is a subset of haloalkyl groups and refers to an alkyl group in which all hydrogen atoms are independently replaced by a halogen (e.g., fluorine, bromine, chlorine, or iodine). In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C"). 1-20 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C10”). 1-10 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1”). 1-9 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1”). 1-8 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1”). 1-7Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1”). 1-6 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1”). 1-5 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1”). 1-4 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C10”). 1-3 (Halogenated moiety). In some embodiments, the halogenated moiety has 1 to 2 carbon atoms (“C2”). 1-2 (Haloalkyl). In some embodiments, all hydrogen atoms of the haloalkyl group are independently replaced by fluorine to provide a "perfluoroalkyl". In some embodiments, all hydrogen atoms of the haloalkyl group are independently replaced by chlorine to provide a "perchloroalkyl". Examples of haloalkyl groups include –CHF2, –CH2F, –CF3, –CH2CF3, –CF2CF3, –CF2CF2CF3, –CCl3, –CFCl2, –CF2Cl, etc.

[0044] The term "heteroalkyl" refers to an alkyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroalkyl group is an alkyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, and sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroalkyl group refers to a saturated group ("C") having 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain. 1-20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C…”). 1-12 (“heteroalkyl”). In some embodiments, the 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, the heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–10 (“heteroalkyl”). In some embodiments, the 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, the 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”). In some embodiments, the 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, the 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, the 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, the 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). In some embodiments, the heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain (“C…”). 1–3 (Heteroalkyl). In some embodiments, the heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain (“C…”). 1–2 In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“C1 heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms within the parent chain (“C1 heteroalkyl”). 2-6 (Heteroalkyl). Unless otherwise stated, each instance of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”).

[0045] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group having 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, the alkenyl group has 2 to 20 carbon atoms ("C..."). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 12 carbon atoms (“C”). 2–12 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 11 carbon atoms (“C”). 2–11 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2–10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2–9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2–8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2–5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”).2–3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. One or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenes include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenes include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl is independently unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In alkenes, the stereochemical C=C double bond is not specified (e.g., -CH=CHCH3 or ...). It can be in (E)- or (Z)- configuration.

[0046] The term "heteroalkenyl" refers to an alkenyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or located at one or more end positions of the parent chain. In some embodiments, a heteroalkenyl is an alkenyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or located at one or more end positions of the parent chain. In some embodiments, a heteroalkenyl refers to a group ("C") having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain. 2-20 (“heterene”). In some embodiments, a heteroene group refers to a group having 2 to 12 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“C”). 2-12 (“heterenyl”). In some embodiments, a heteroene group refers to a group having 2 to 11 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“C”). 2-11 (“heterenyl”). In some embodiments, a heteroene group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“C”). 2-10 Heterene group (“Hyperene”). In some embodiments, the heteroene group has 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2-9 (“heterene”). In some embodiments, the heteroene group has 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2–8(“heterene”). In some embodiments, the heteroene group has 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2–7 Heterene group (“Hyperene”). In some embodiments, the heteroene group has 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2–6 (“heterene”). In some embodiments, the heteroene group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–5 (“heterene”). In some embodiments, the heteroene group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–4 (“heterene”). In some embodiments, the heteroene group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“C”) within the parent chain. 2–3 In some embodiments, the heteroalkenyl group has two carbon atoms, at least one double bond, and one heteroatom (“C2 heteroalkenyl”) within the parent chain. In some embodiments, the heteroalkenyl group has two to six carbon atoms, at least one double bond, and one or two heteroatoms (“C2 heteroalkenyl”) within the parent chain. 2–6 (“heterenyl”). Unless otherwise stated, each instance of a heteroalkenyl is independently either unsubstituted (“unsubstituted heteroalkenyl”) or substituted with one or more substituents (“substituted heteroalkenyl”).

[0047] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 2-20 The alkynyl group (“acetylation”) has 2 to 10 carbon atoms in some embodiments. 2-10 The alkynyl group (“Alynyl”) has 2 to 9 carbon atoms in some embodiments. 2-9 The alkynyl group (“acetylation”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“acetylation”) has 2 to 6 carbon atoms in some embodiments. 2-6 The alkynyl group (“H”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C”). 2-5 The alkynyl group (“H”) has 2 to 4 carbon atoms in some embodiments. 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Additional examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of the alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (“substituted alkynyl”).

[0048] The term "heteroyne" refers to an alkynyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or located at one or more terminal positions of the parent chain. In some embodiments, a heteroyne is an alkynyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, and sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or located at one or more terminal positions of the parent chain. In some embodiments, a heteroyne refers to a group having 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("C..."). 2–20 (“C-Hydynyl”). In some embodiments, a C-Hydynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain. 2–10 (“heteroyne group”). In some embodiments, the heteroyne group has 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms (“C…”) within the parent chain. 2–9 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms (“C”) within the parent chain. 2–8 (“heteroyne group”). In some embodiments, the heteroyne group has 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms (“C…”) within the parent chain. 2–7 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms (“C”) within the parent chain. 2–6 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–5 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–4 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“C”) within the parent chain. 2–3In some embodiments, the heteroyne group has two carbon atoms, at least one triple bond, and one heteroatom within the parent chain (“C2 heteroyne group”). In some embodiments, the heteroyne group has two to six carbon atoms, at least one triple bond, and one or two heteroatoms within the parent chain (“C2 heteroyne group”). 1–6 (“Zyrynyl”). Unless otherwise stated, each instance of a zyrynyl group is independently either unsubstituted (“unsubstituted zyrynyl”) or substituted with one or more substituents (“substituted zyrynyl”).

[0049] The term "carbocyclic" or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C"). 3-14 A group consisting of a carbocyclic group (“C”) and a non-aromatic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 14 cyclic carbon atoms (“C”). 3-14 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 13 cyclic carbon atoms (“C”). 3-13 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 12 cyclic carbon atoms (“C”). 3-12 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 11 cyclic carbon atoms (“C”). 3-11 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 10 cyclic carbon atoms (“C”). 3-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 4 to 6 cyclic carbon atoms (“C”). 4-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 6 cyclic carbon atoms (“C”). 5-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6 Carbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C3-10 Carbocyclic groups include the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 ), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-10 Carbocyclic and cycloundecyl (C 11 ), spiro[5.5]undecyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or polycyclic (e.g., containing fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”) or tricyclic systems (“tricyclic carbocyclic”)) and may be saturated or may contain one or more carbon-carbon double or triple bonds. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the carbon number continues to specify the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group includes 0, 1, or 2 C=C double bonds in the carbocyclic system, where the valence allows.

[0050] "Cycloalkyl" refers to a saturated carbocyclic group. In some embodiments, the cycloalkyl group has 3 to 14 cyclic carbon atoms ("C"). 3-14 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”). 4-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”).5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”).

[0051] The term "heterocyclic group" or "heterocycle" refers to a group having a 3- to 14-membered non-aromatic ring system with a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorus ("3-14-membered heterocyclic group"). In some embodiments, the heterocyclic group is a group having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Where the valence allows, the linking point may be attached to the cyclic carbon atom or the cyclic heteroatom of the heterocyclic group. For example, in a heterocyclic group containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, where the valence allows. The heterocyclic group may be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. A heterocyclic polycyclic system may include one or more heteroatoms in one or two rings. "Hypercyclic group" also includes ring systems in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or ring systems in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring. In such cases, the number of ring members continues to specify the number of ring members in the heterocyclic ring system. Unless otherwise stated, each instance of a heterocyclic group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclic group, wherein one, two, or three atoms in the heterocyclic system are independently oxygen, nitrogen, or sulfur, where the valence allows.

[0052] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0053] Exemplary 3-membered heterocyclic groups containing one heteroatom include azirropropyl, ethylene oxide, and thiopyrropropyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include azirrobutyl, oxetanebutyl, and thiopyranebutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include dioxetanepentyl, oxetanethiopentyl, and dithiopyranepentyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include piperazine, morpholino, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include triazine. Exemplary 7-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromanyl, octahydroisochromanyl, decahydronaphthidyl, decahydro-1,8-naphthidyl, octahydropyrrolo[3,2-b]pyrrole, indololinyl, phthalimide, naphthimide, chromanyl, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyrano[3,2-b]pyrrole, and chromenyl. [4-b]pyrrolithyl, 5,6-dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-dihydrofurano[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthidyl, etc.

[0054] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a ring array) that provides 6-14 ring carbon atoms and zero heteroatoms ("C") in the aromatic ring system. 6-14 Aryl group (“Aryl”). In some embodiments, the aryl group has 6-10 cyclic carbon atoms (“C”). 6-10Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein a linking group or dot is located on the aryl ring, and in such cases, the number of ring members continues to specify the number of ring atoms in the aryl ring system. Unless otherwise stated, each instance of an aryl is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0055] The term "heteroaryl" refers to a group comprising a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the ring array), providing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorus ("5-14 membered heteroaryl"). In some embodiments, "heteroaryl" is a group comprising a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the ring array), providing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Where valence permits, the linking point may be attached to the cyclic carbon atom or the cyclic heteroatom of the heteroaryl. For example, in a heteroaryl containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, where valence permits. A heteroaryl polycyclic system may include one or more heteroatoms in one or two rings. "Hyperaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, wherein the connection point is on the heteroaryl ring, and in such cases, the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in such cases, the number of ring members specifies the number of ring members in the fused polycyclic (aryl / heteraryl) ring system. A polycyclic heteroaryl, in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazoyl, etc.), may have a connection point on either ring, such as a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, the heteroaryl group is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0056] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each instance of a heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”).

[0057] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyrazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azirrolyl, oxoheptanyl, and thioheptanyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenidyl, dibenzofuranyl, carbazoleyl, acridineyl, phenothiazinyl, phenothiazinyl, and phenothiazinyl.

[0058] The term "acyl" refers to an acyl group having the general formula –C(=O)R aa –C(=O)OR aa –C(=O)–O–C(=O)R aa –C(=O)SR aa–C(=O)N(R) bb )2、–C(=S)R aa –C(=S)N(R) bb )2、–C(=S)S(R aa –C(=NR) bb )R aa –C(=NR) bb OR aa –C(=NR) bb )SR aa and –C(=NR) bb )N(R bb )2 groups, wherein R aa and R bb As defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0059] The term “halogen” or “halogen” refers to fluorine (fluorinated, –F), chlorine (chlorinated, –Cl), bromine (brominated, –Br), or iodine (iodinated, –I).

[0060] The term "silyl group" refers to the group -Si(R) aa )3, where R aa As defined in this article.

[0061] Unless otherwise expressly specified, groups are optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" means substituted or unsubstituted groups (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" ynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substitution" means that at least one hydrogen atom present on a group is replaced by a permissible substituent (e.g., a substituent that, upon substitution, produces a stable compound, such as a substituent that does not spontaneously undergo transformation through rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a "substitution" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. The term "substitution" is contemplated to include substitution by all permissible substituents of an organic compound and includes any of the substituents described herein that result in the formation of a stable compound. This disclosure covers any and all such combinations to achieve a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The embodiments described herein are not in any way limited to the exemplary substituents described herein.

[0062] Exemplary substituents (e.g., carbon atom substituents) include halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, and –OR. aa –ON(R) bb )2、–N(R bb )2、–N(R bb )3 + X – –N(OR) cc )R bb –SH, –SR aa –SSR cc –C(=O)R aa –CO2H, –CHO, –C(OR) cc )2、–CO2R aa –OC(=O)R aa –OCO2R aa –C(=O)N(R) bb )2、–OC(=O)N(Rbb )2、–NR bb C(=O)R aa 、–NR bb CO2R aa 、–NR bb C(=O)N(R bb )2、–C(=NR bb )R aa 、–C(=NR bb )OR aa 、–OC(=NR bb )R aa 、–OC(=NR bb )OR aa 、–C(=NR bb )N(R bb )2、–OC(=NR bb )N(R bb )2、–NR bb C(=NR bb )N(R bb )2、–C(=O)NR bb SO2R aa 、–NR bb SO2R aa 、–SO2N(R bb )2、–SO2R aa 、–SO2OR aa 、–OSO2R aa 、–S(=O)R aa 、–OS(=O)R aa 、–Si(R aa )3、–OSi(R aa )3–C(=S)N(R bb )2、–C(=O)SR aa 、–C(=S)SR aa 、–SC(=S)SR aa 、–SC(=O)SR aa 、–OC(=O)SR aa 、–SC(=O)OR aa 、–SC(=O)R aa 、–P(=O)(R aa )2、–P(=O)(OR cc )2、–OP(=O)(R aa )2、–OP(=O)(OR cc )2、–P(=O)(N(R bb )2)2、–OP(=O)(N(R bb )2)2、–NR bbP(=O)(R aa )2、–NR bb P(=O)(OR cc )2、–NR bb P(=O)(N(R bb )2)2、–P(R cc 2. –P(OR) cc )2、–P(R cc )3 + X – –P(OR) cc )3 + X – –P(R) cc 4. –P(OR) cc 4. –OP(R) cc )2、–OP(R cc )3 + X – –OP(OR) cc 2. –OP(OR) cc )3 + X – –OP(R) cc 4. –OP(OR) cc )4、–B(R aa 2. –B(OR) cc )2、–BR aa (OR cc C 1–20 Alkyl, C 1–20 All-haloalkyl, C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20 Heterene, C 2–20 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and where X - These are balanced ions;

[0063] Or the two twin hydrogens on the carbon atom are replaced by the following groups: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa=NR bb or = NOR cc ;

[0064] in:

[0065] R aa Each instance is independently selected from C 1-20 Alkyl, C 1-20 All-haloalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Heteroalkyl, C 2-20 Heterene, C 2-20 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa The groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0066] R bb Each instance is independently selected from hydrogen, –OH, –OR aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –C(=NR) cc OR aa –C(=NR) cc )N(R cc )2、–SO2N(R cc )2、–SO2R cc –SO2OR cc –SOR aa –C(=S)N(R) cc )2、–C(=O)SR cc –C(=S)SR cc –P(=O)(R aa )2、–P(=O)(OR cc )2、–P(=O)(N(R cc )2)2、C 1–20 Alkyl, C 1–20 All-haloalkyl, C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20Heterene, C 2–20 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb The groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0067] R cc Each instance is independently selected from hydrogen, C 1–20 Alkyl, C 1–20 All-haloalkyl, C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20 Heterene, C 2–20 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc The groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0068] R dd Each instance is independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee –ON(R) ff )2、–N(R ff )2、–N(R ff )3 + X – –N(OR) ee )R ff –SH, –SR ee –SSR ee –C(=O)R ee –CO2H, –CO2R ee –OC(=O)R ee –OCO2R ee –C(=O)N(R) ff )2、–OC(=O)N(R ff )2、–NR ff C(=O)R ee –NR ff CO2Ree –NR ff C(=O)N(R ff )2、–C(=NR ff OR ee –OC(=NR) ff )R ee –OC(=NR) ff OR ee –C(=NR) ff )N(R ff )2、–OC(=NR ff )N(R ff )2、–NR ff C(=NR ff )N(R ff )2、–NR ff SO2R ee –SO2N(R) ff )2、–SO2R ee –SO2OR ee –OSO2R ee –S(=O)R ee 、–Si(R ee 3. –OSi(R) ee 3. –C(=S)N(R) ff )2、–C(=O)SR ee –C(=S)SR ee –SC(=S)SR ee –P(=O)(OR ee )2、–P(=O)(R ee )2、–OP(=O)(R ee )2、–OP(=O)(OR ee 2. C 1–10 Alkyl, C 1–10 All-haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 Neyne group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two twins dd Substituents bond to form =O or =S, and where X - These are balanced ions;

[0069] Ree Each instance is independently selected from C 1–10 Alkyl, C 1–10 All-haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 Neyne group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0070] R ff Each instance is independently selected from hydrogen, C 1–10 Alkyl, C 1–10 All-haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 Neyne group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff The groups are joined to form a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0071] R gg Each instance is independently a halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)3 + X – –NH(C 1–6 Alkyl)2 + X – –NH2(C 1–6 alkyl) + X – –NH3 + X – –N(OC) 1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl, –SS(C 1–6 Alkyl), –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6 Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)(C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC(=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups), –OC(NH)NH2, –NHC(NH)N(C 1–6 Alkyl)2, –NHC(=NH)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –SO2NH2, –SO2C 1–6 Alkyl, –SO2OC 1–6 Alkyl, –OSO2C 1–6 Alkyl, –SOC 1–6 Alkyl, –Si(C) 1–6 Alkyl)3、–OSi(C 1–6 alkyl)3–C(=S)N(C 1–6 Alkyl)2、C(=S)NH(C 1–6 Alkyl), C(=S)NH2, –C(=O)S(C 1–6 Alkyl), –C(=S)SC 1–6 Alkyl, –SC(=S)SC1–6 Alkyl group, –P(=O)(OC) 1–6 Alkyl)2、–P(=O)(C 1–6 Alkyl)2、–OP(=O)(C 1–6 Alkyl)2、–OP(=O)(OC 1–6 Alkyl)2, C 1–10 Alkyl, C 1–10 All-haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 Neyne group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic or 5-10 heteroaryl; or two twins gg Substituents can join to form =O or =S; and each X - These are balanced ions.

[0072] In some embodiments, the substituent (e.g., a carbon atom substituent) has a molecular weight of less than 250, less than 200, less than 150, less than 100, or less than 50 g / mol. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0073] In some embodiments, exemplary substituents (e.g., carbon atom substituents) include halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, and –OR. aa –N(R) bb )2、–N(R bb )3 + X – –SH, –SR aa –C(=O)R aa –CO2H, –CHO, –CO2R aa –OC(=O)R aa –OCO2R aa –C(=O)N(R) bb )2、–OC(=O)N(R bb )2、–NR bb C(=O)R aa –NR bb CO2R aa –NR bbC(=O)N(R bb )2、–NR bb SO2R aa –SO2N(R) bb )2、–SO2R aa –SO2OR aa –OSO2R aa –S(=O)R aa –OS(=O)R aa 、–Si(R aa 3. –OSi(R) aa 3. –P(=O)(R aa )2、–P(=O)(OR cc )2、–OP(=O)(R aa )2、–OP(=O)(OR cc )2、–P(=O)(N(R bb )2)2、–OP(=O)(N(R bb )2)2、–NR bb P(=O)(R aa )2、–NR bb P(=O)(OR cc )2、–NR bb P(=O)(N(R bb )2)2、–B(R aa 2. –B(OR) cc )2、–BR aa (OR cc C 1-10 Alkyl, C 1-10 All-haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 membered heteroaryl, of which X - These are balanced ions;

[0074] Or the two twin hydrogens on the carbon atom are replaced by the following groups: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc ;

[0075] R aa Each instance is independently selected from C 1-10 Alkyl, C 1-10 All-haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa Groups combine to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings;

[0076] R bb Each instance is independently selected from hydrogen, –OH, –OR aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –C(=NR) cc OR aa –C(=NR) cc )N(R cc )2、–SO2N(R cc )2、–SO2R cc –SO2OR cc –SOR aa –P(=O)(R aa )2、–P(=O)(OR cc )2、–P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 All-haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb Groups combine to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings; and

[0077] R cc Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 All-haloalkyl, C 2-10alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc Groups combine to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings.

[0078] In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, –OR aa –SR aa –N(R) bb )2, –CN, –NO2, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2、–OC(=O)R aa –OCO2R aa –OC(=O)N(R) bb )2、–NR bb C(=O)R aa –NR bb CO2R aa Or –NR bb C(=O)N(R bb 2. In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C atom. 1–10 Alkyl, –OR aa –SR aa –N(R) bb )2, –CN, –NO2, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2、–OC(=O)R aa –OCO2R aa –OC(=O)N(R) bb )2、–NR bb C(=O)R aa –NR bb CO2R aa Or –NR bb C(=O)N(R bb )2, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted. 1-6Alkyl, oxygen-protecting groups (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 sulfur-protecting groups (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinylthioyl, 2-pyridinylthioyl, or triphenylmethyl), when attached to a sulfur atom; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl groups, or nitrogen-protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In some embodiments, each carbon atom substituent is independently halogenated, substituted (e.g., substituted with one or more halogens), or unsubstituted. 1-6 Alkyl, -OR aa -SR aa -N(R) bb 2. -CN or -NO2. In some embodiments, each carbon atom substituent is independently a halogenated, substituted (e.g., substituted by one or more halogen moieties), or unsubstituted C. 1–6 Alkyl, –OR aa –SR aa –N(R) bb 2. –CN, –SCN, or –NO2, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–6 Alkyl, oxygen-protecting groups (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 sulfur-protecting groups (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinylthioyl, 2-pyridinylthioyl, or triphenylmethyl), when attached to a sulfur atom; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–10 Alkyl groups, or nitrogen-protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0079] In some embodiments, each nitrogen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, –C(=O)R aa –CO2R aa –C(=O)N(R) bb)2 or nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2 or nitrogen protecting group, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens) or unsubstituted. 1-6 Alkyl or oxygen protecting groups, when attached to an oxygen atom; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or nitrogen protecting group.

[0080] In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen protecting groups include –OH, –OR, etc. aa –N(R) cc )2、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa –C(=NR) cc )R aa –C(=NR) cc OR aa –C(=NR) cc )N(R cc )2、–SO2N(R cc )2、–SO2R cc –SO2OR cc –SOR aa –C(=S)N(R) cc )2、–C(=O)SR cc –C(=S)SR cc C 1–10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20 Heterene, C 2–20 Neyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aralkyl, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd As defined herein, nitrogen protecting groups are those well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0081] For example, in some embodiments, at least one nitrogen protecting group is an amide (e.g., including a nitrogen protecting group (e.g., -C(=O)R) aa (The part directly connected to the nitrogen atom). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridinecarboxamide, 3-pyridylcarboxamide, N-benzoylphenylpropanamide derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0082] For example, in some embodiments, at least one nitrogen protecting group is a carbamate group (e.g., including nitrogen protecting groups (e.g., –C(=O)OR)). aa(The portion directly connected to the nitrogen atom). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: methyl carbamate, ethyl carbamate, 9-enyl methyl carbamate (Fmoc), 9-(2-sulfonyl)enyl methyl carbamate, 9-(2,7-dibromo)fluoroenyl methyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl methyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trichloroethyl carbamate, etc. Methyl silyl ethyl ester (Teoc), 2-phenyl ethyl carbamate (hZ), 1-(1-adamantyl)-1-methyl ethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methyl ethyl carbamate (t-Bumeoc), 2-(2¢- and 4¢-pyridyl)ethyl carbamate (Pyo c) Ethyl 2-(N,N-dicyclohexylformamido)carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-- Bromobenzyl ester, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinyl benzyl carbamate (Msz), 9-anthrayl methyl carbamate, diphenyl carbamate, 2-methylthioethyl carbamate, 2-methanesulfonyl ethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiaalkyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphoethyl carbamate (Peoc), 2-triphenylphosphoisopropyl carbamate (Ppoc), 1-carbamate1-Dimethyl-2-cyanoethyl ester, m-chloro-p-acyloxybenzyl ester of carbamate, p-(dihydroxyboryl)benzyl ester of carbamate, 5-benzisoxazolyl methyl ester of carbamate, 2-(trifluoromethyl)-6-chromone methyl ester of carbamate (Tcroc), m-nitrophenyl ester of carbamate, 3,5-dimethoxybenzyl ester of carbamate, o-nitrobenzyl ester of carbamate, 3,4-dimethoxy-6-nitrobenzyl ester of carbamate, phenyl (o-nitro) carbamate Phenyl methyl ester, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyyl vinyl carbamate, o-(N,N-dimethylformamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamide)propyl carbamate, 1 1-Dimethylpropynyl ester, di(2-pyridyl)methyl ester of carbamate, 2-furanylmethyl ester of carbamate, 2-iodoethyl ester of carbamate, isoboronyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl ester of carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, amino 1-Methyl-1-(3,5-dimethoxyphenyl)ethyl formate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0083] In some embodiments, at least one nitrogen protecting group is a sulfonamide (e.g., including a nitrogen protecting group (e.g., –S(=O)2R)). aa(The portion directly connected to the nitrogen atom). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide... Amines (Mbs), 2,4,6-trimethylbenzenesulfonamides (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamides (iMds), 2,2,5,7,8-pentamethylchromane-6-sulfonamides (Pmc), methanesulfonamides (Ms), β-trimethylsilyl ethyl sulfonamides (SES), 9-anthracitesulfonamides, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamides (DNMBS), benzylsulfonamides, trifluoromethylsulfonamides, and benzyl sulfonamides.

[0084] In some embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of: phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylpropanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazine adduct (STABASE), 5 -substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptanamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N -9-Phenylenylamine (PhF), N-2,7-dichloro-9-pyrenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N-p-nitrobenzylamine, N-salamiylamine, N-5-chlorosalamiylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclo Hexenylamine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphamides (Dpp), dimethylthiophosphamides (Mpt), diphenylthiophosphamides (Ppt), dialkyl aminophosphates, dibenzyl aminophosphates, diphenyl aminophosphates, benzyl sulfenamides, o-nitro-o-phenylsulfenamides (Nps), 2,4-dinitrophenylsulfenamides, pentachlorophenylsulfenamides, 2-nitro-4-methoxyphenylsulfenamides, triphenylmethylsulfenamides, and 3-nitropyridinesulfenamides (Npys). In some embodiments, two examples of the nitrogen protecting group together with the nitrogen atom to which the nitrogen protecting group is attached are N,N'-isopropylidene diamine.

[0085] In some embodiments, the nitrogen protecting group is benzyl (Bn), tert-butoxycarbonyl (BOC), carboxybenzyloxy (Cbz), 9-enylamethoxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (Tr), toluenesulfonyl (Ts), p-bromobenzenesulfonyl (Bs), nitrobenzenesulfonyl (Ns), methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), or dansyl (Ds).

[0086] In some embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0087] In some embodiments, each oxygen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2 or oxygen protecting group. In some embodiments, each oxygen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2 or oxygen protecting group, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or oxygen protecting groups, when attached to an oxygen atom; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or nitrogen protecting group. In some embodiments, each oxygen atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or oxygen protecting group.

[0088] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include –R aa –N(R) bb )2、–C(=O)SR aa –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2、–C(=NRbb )R aa –C(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–S(=O)R aa –SO2R aa 、–Si(R aa 3. –P(R) cc )2、–P(R cc )3 + X – –P(OR) cc 2. –P(OR) cc )3 + X – –P(=O)(R aa )2、–P(=O)(OR cc )2 and –P(=O)(N(R bb )2)2, where X – R aa R bb and R cc As defined herein, oxygen protecting groups are those well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0089] In some embodiments, each oxygen protecting group, together with the oxygen atom to which it is attached, is selected from the group consisting of: methoxy, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl) )Ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-Bromotetrahydropyranyl, Tetrahydrothiaranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl (MTHP), 4-Methoxytetrahydrothiaranyl, 4-Methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-bridged methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxy Ethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl, N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenyl methyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthaliminophenyl)methyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 4,4'-dimethoxy-3"'-[N-(imidazolylmethyl)]triphenylmethyl ether (IDTr-OR), 4,4'-dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]tribenzyl ether (IETr-OR), 1,1-Bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)oxanthracene, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiacyclopentan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl Diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxovalerate (acetylpropionate), 4,4-(ethylidene dithio)valerate (acetylpropionyl dithioacetal), tertylvalerate, adamantyl ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-monomethyl carbonate ( Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-epoxybenzyl ester Nitrobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, dichlorophenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate, alkyl N,N,N',N'-Tetramethyldiaminophosphate, alkyl N-phenylcarbamate, borate, dimethylphosphonothioyl, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (methanesulfonate), benzyl sulfonate, and toluenesulfonate (Ts).

[0090] In some embodiments, the oxygen protecting group is silyl. In some embodiments, the oxygen protecting group is tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (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), or 1-ethoxyethyl. (EE), 2-methoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), allyl, p-methoxybenzyl (PMB), tert-butyl, benzyl (Bn), allyl or pivaloyl (Piv).

[0091] In some embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0092] In some embodiments, each sulfur atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2 or sulfur protecting group. In some embodiments, each sulfur atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2 or sulfur protecting group, wherein R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl groups, or oxygen protecting groups, when attached to an oxygen atom; and each Rbb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or nitrogen protecting group. In some embodiments, each sulfur atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or sulfur protecting group.

[0093] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). In some embodiments, each sulfur protecting group is selected from the group consisting of: –R aa –N(R) bb )2、–C(=O)SR aa –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2、–C(=NR bb )R aa –C(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–S(=O)R aa –SO2R aa 、–Si(R aa 3. –P(R) cc )2、–P(R cc )3 + X – –P(OR) cc 2. –P(OR) cc )3 + X – –P(=O)(R aa )2、–P(=O)(OR cc )2 and –P(=O)(N(R bb )2)2, where R aa R bb and R cc As defined herein, sulfur protecting groups are those well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0094] In some embodiments, the sulfur protecting group is acetaminomethyl, t-Bu, 3-nitro-2-pyridinethioyl, 2-pyridine-thioyl or triphenylmethyl.

[0095] A "balanced ion" or "anionic balance ion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic balance ions can be monovalent (e.g., including one form of negative charge). Anionic balance ions can also be polyvalent (e.g., including more than one form of negative charge), such as divalent or trivalent. Exemplary balance ions include halide ions (e.g., F). – Cl – ,Br – I – NO3 – ClO4 – OH – H2PO4 – HCO3 – 、 HSO4 – Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 – PF4 – PF6 – AsF6 – SbF6 – B[3,5-(CF3)2C6H3]4] – B(C6F5)4 – BPh4 – Al(OC(CF3)3)4 – and carborane anions (e.g., CB) 11 H 12 – or (HCB) 11 Me5Br6) – Exemplary balanced ions that may be multivalent include CO3. 2- HPO4 2- PO4 3- B4O7 2- SO4 2- S2O3 2- Carboxylate anions (such as tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipic acid, pimelic acid, succinate, azelaic acid, sebacic acid, salicylate, phthalate, aspartate, glutamate, etc.) and carborane.

[0096] These and other exemplary substituents are described in more detail in the detailed descriptions, embodiments, and claims. The embodiments provided herein are not in any way limited to the exemplary list of substituents described above.

[0097] Other definitions

[0098] The following are more general terms used throughout this application.

[0099] As used herein, the term "salt" means any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds produced by the neutralization reaction of acids and bases. A salt consists of one or more cations (positively charged ions) and one or more anions (negative ions), such that the salt is electrically neutral (without net charge). Salts of the compounds disclosed herein include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts formed by reacting amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactose, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other salts include ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0100] The term "pharmaceutically acceptable salt" refers to those salts that, to the extent of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by reacting amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 – Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0101] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers."

[0102] Stereoisomers that are not mirror images of each other are called diastereomers, and those stereoisomers that are non-overlapping mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarization and is specified as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0103] The term "tautomer" or "tautomer" refers to two or more interconvertible compounds resulting from at least one formal migration of hydrogen atoms and at least one change in valence (e.g., from single to double, triple to single, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone to enol, amide to imide, lactam to lactimide, enamine to imide, and enamine to (different enamines) tautomerization.

[0104] The term "solvent" refers to a compound (including its salts) that typically associates with a solvent via a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, solvates will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0105] The term "hydrate" refers to a solvate in which a compound is associated with water. Typically, the number of water molecules in a hydrate is in a definite ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R×x H₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R×0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R×2H₂O) and hexahydrates (R×6H₂O)).

[0106] The term "prodrug" refers to a compound having a cleavable group and being converted into the compound described herein by solvent decomposition or under physiological conditions, which has pharmaceutical activity in vivo. See, for example, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985. Prodrugs include acid derivatives, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the acidic groups side-attached to the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Other derivatives of the compounds described herein are active in both their acidic and acid derivative forms, but the acid-sensitive form often provides advantages in subjects such as solubility, tissue compatibility, or delayed release.

[0107] Throughout this disclosure, references to “the compound” and “a compound” are intended to encompass the compound or group of compounds, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Isotopically labeled derivatives are also included.

[0108] The terms “composition” and “formulation” are used interchangeably.

[0109] The term "subject" intended for administration refers to a human being (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird, such as a chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any developmental stage. The non-human animal can be a transgenic or genetically engineered animal. The term "patient" refers to a human subject who requires treatment for a disease, symptom, or illness.

[0110] The terms “administer,” “administering,” or “administration” mean the implantation, absorption, ingestion, injection, inhalation, provision, or other introduction of a compound or combination thereof described herein into or onto a subject.

[0111] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have been acquired or observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen). Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0112] The terms "prevent," "preventing," or "prevention" refer to preventive treatment of a subject who does not have or has had the disease but is at risk of developing it, or who has the disease, or who does not have the disease but is at risk of disease relapse. In some implementations, the subject has a higher risk of developing the disease or a higher risk of disease relapse compared to the average healthy member of the population.

[0113] The terms “illness,” “disease,” and “symptom” are used interchangeably.

[0114] The “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. The effective amount of a compound described herein may vary depending on factors such as: the desired biological endpoint, the severity of side effects, the disease or condition, the identity of the specific compound, pharmacokinetics and pharmacodynamics, the condition being treated, the mode of administration, route of administration and desired or required frequency, the species, age, and health or general condition of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is for prophylactic treatment. In some embodiments, the effective amount is the amount of the compound described herein in a single dose. In some embodiments, the effective amount is the combined amount of the compound described herein in multiple doses. In some embodiments, the effective amount is an amount sufficient to enhance Kv7 potassium channels (e.g., in a subject or in in vitro cells).

[0115] The "therapeuticly effective amount" of the compounds described herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease or to delay or minimize one or more symptoms associated with said disease. Therapeuticly effective amount of a compound means an amount in which a therapeutic agent, alone or in combination with other therapies, provides therapeutic benefit in the treatment of a disease. The term "therapeuticly effective amount" may encompass amounts that improve overall therapy, reduce or avoid symptoms, signs, or causes of a disease, and / or enhance the therapeutic efficacy of another therapeutic agent. In some embodiments, the therapeutically effective amount is an amount sufficient to treat a subject's disease, condition, or disorder (e.g., a disease, condition, or disorder associated with Kv7 potassium channel dysfunction). In some embodiments, the therapeutically effective amount is an amount sufficient to enhance Kv7 potassium channels in a subject.

[0116] The “preventive effective amount” of the compounds described herein is an amount sufficient to prevent a disease, or one or more symptoms associated with said disease, or to prevent its recurrence. The preventive effective amount of a compound means the amount by which a therapeutic agent, alone or in combination with other agents, provides a preventive benefit in preventing a disease. The term “preventive effective amount” may also encompass an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. In some embodiments, the preventive effective amount is an amount sufficient to prevent a subject’s disease, condition, or disorder (e.g., a disease, condition, or disorder associated with Kv7 potassium channel dysfunction). In some embodiments, the preventive effective amount is an amount sufficient to enhance Kv7 potassium channels in a subject.

[0117] Voltage-gated potassium channels (VGKCs) are transmembrane channels that are specific to potassium and sensitive to voltage changes in cell membrane potential. They play a crucial role in returning depolarized cells to a resting state during action potentials. In VGKCs, the α subunit forms the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane core, the α subunits of voltage-gated potassium channels are divided into 12 families (Kv1-12), with Kv7 being one family. The Kv7 family of voltage-gated potassium channels consists of five members (Kv7.1-7.5) encoded by the KCNQ1-5 genes. Of these, Kv7.2 / Kv7.3 is the active heterotetramer, which is the major active Kv7 current (M-current) in neurons. Kv7 potassium channels can be members selected from Kv7.1, Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5.

[0118] "Potassium channel enhancer" 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., a voltage-gated potassium channel, such as a Kv7 potassium channel), for example, by promoting ion transport across the potassium channel. For the purposes of this disclosure, "potentiating," "potentiation," etc., refer to restoring, enhancing, or increasing the activity or effect of a potassium channel. Detailed Implementation

[0119] This document provides compounds, including compounds of any of the formulas described herein (e.g., formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. The 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 suitable for the treatment and / or prevention of diseases, conditions, and disorders (e.g., diseases, conditions, and disorders associated with Kv7 potassium channel dysfunction). This document also provides pharmaceutical compositions comprising the compounds provided herein, and kits comprising said pharmaceutical compositions. Additionally, this disclosure provides methods for preparing the compounds and pharmaceutical compositions described herein, as well as intermediates useful thereto.

[0120] compound

[0121] This article provides compounds of formula (I):

[0122] (I),

[0123] and its pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs, wherein:

[0124] X 1 It can be C or N;

[0125] Z 3 Z 4 and Z 6 Each independently for CR 4 , N, NR N S or O;

[0126] Z 5 For key, CR 4 , N, NR N S or O;

[0127] The condition is Z 3 Z 4 Z 5 and Z 6 At least one of them is N, NR N S or O, and Z 3 Z 4 Z 5 and Z 6 No more than one of them is S or O;

[0128] R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0129] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0130] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0131] R Y For H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0132] Z 1 and Z 2 Each independently for CR Z Or N;

[0133] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0134] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0135] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0136] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0137] m is 1 or 2;

[0138] n is 0, 1, or 2;

[0139] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O;

[0140] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom NThey combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently;

[0141] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0142] R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and

[0143] R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0144] In some embodiments, the compound of formula (I) is a compound of formula (I′):

[0145] (I'),

[0146] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0147] In some embodiments, the compound of formula (I) is a compound of formula (I''):

[0148] (I''),

[0149] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In certain embodiments of formula (I''):

[0150] Z 3 For N and Z 6 S;

[0151] Z 3 For S and Z 6 Let N be the number of people in the group.

[0152] Z3 For N and Z 6 For O; or

[0153] Z 3 For O and Z 6 Let N be the number of elements in the array.

[0154] In some implementations of formula (I′′), Z 3 For N and Z 6 For S, or Z 3 For S and Z 6 Let N be the number of elements. In some implementations of equation (I′′), Z is the number of elements. 3 For N and Z 6 Let S be the value of Z. In some embodiments of equation (I′′), Z is the value of Z. 3 For S and Z 6 Let N be the number of elements in the array.

[0155] In some implementations of formula (I′′), Z 3 For N and Z 6 For O, or Z 3 For O and Z 6 Let N be the number of elements. In some implementations of equation (I′′), Z is the number of elements. 3 For N and Z 6 For O. In some embodiments of equation (I′′), Z 3 For O and Z 6 Let N be the number of elements in the array.

[0156] In some embodiments, the compound of formula (I) is the compound of formula (Ia):

[0157] (Ia),

[0158] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0159] In some embodiments, the compound of formula (I) is the compound of formula (Ia-1):

[0160] (Ia-1),

[0161] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0162] In some embodiments, the compound of formula (I) is a compound of formula (Ia-2):

[0163] (Ia-2),

[0164] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0165] In some embodiments, the compound of formula (I) is a compound of formula (Ia-2-i):

[0166] (Ia-2-i),

[0167] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, Z 1 For N. In some implementations, R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, R 1 and R 2 It is methyl. In some embodiments, R 1 It is halogen and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, R 1 For F and R 2 It is methyl. In some embodiments, R 2 It is halogen and R 1 For unreplaced C 1-3 Alkyl group. In some embodiments, R 2 For F and R 1 It is methyl. In some embodiments, R 1 For unreplaced C 3-6 cycloalkyl and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R 1 and R 2 It is methyl. In some embodiments, Z 1 For N, R 1 It is halogen and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For N, R 1 Let F be the integer part of the integer part, and R be the integer part of the integer part. 2It is methyl. In some embodiments, Z 1 For CH, R 1 For unreplaced C 1-3 Alkyl, and R 2 It is a halogen. In some embodiments, Z 1 For CH, R 1 It is methyl, and R 2 For F. In some implementations, Z 1 For N, R 1 For unreplaced C 3-6 Cycloalkyl, and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For N, R 1 It is cyclopropyl, and R 2 It is a methyl group.

[0168] In some embodiments, the compound of formula (I) is a compound of formula (Ia-2-ii):

[0169] (Ia-2-ii),

[0170] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, Z 1 For N. In some implementations, R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, R 1 and R 2 It is methyl. In some embodiments, R 1 It is halogen and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, R 1 For F and R 2 It is methyl. In some embodiments, R 2 It is halogen and R 1 For unreplaced C 1-3 Alkyl group. In some embodiments, R 2 For F and R 1 It is methyl. In some embodiments, R 1 For unreplaced C 3-6 cycloalkyl and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, Z1 For CH, and R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R 1 and R 2 It is methyl. In some embodiments, Z 1 For N, R 1 It is halogen and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For N, R 1 Let F be the integer part of the integer part, and R be the integer part of the integer part. 2 It is methyl. In some embodiments, Z 1 For CH, R 1 For unreplaced C 1-3 Alkyl, and R 2 It is a halogen. In some embodiments, Z 1 For CH, R 1 It is methyl, and R 2 For F. In some implementations, Z 1 For N, R 1 For unreplaced C 3-6 Cycloalkyl, and R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For N, R 1 It is cyclopropyl, and R 2 It is a methyl group.

[0171] In some embodiments, the compound of formula (I) is a compound of formula (Ia-3):

[0172] (Ia-3),

[0173] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0174] In some embodiments, the compound of formula (I) is a compound of formula (Ia-3-i):

[0175] (Ia-3-i),

[0176] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0177] In some embodiments, the compound of formula (I) is a compound of formula (Ia-4):

[0178] (Ia-4),

[0179] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0180] In some embodiments, the compound of formula (I) is a compound of formula (Ia-4-i):

[0181] (Ia-4-i),

[0182] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0183] In some embodiments, the compound of formula (I) is a compound of formula (Ia-5):

[0184] (Ia-5),

[0185] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0186] In some embodiments, the compound of formula (I) is a compound of formula (Ia-6):

[0187] (Ia-6),

[0188] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0189] In some embodiments, the compound of formula (I) is a compound of formula (Ia-7):

[0190] (Ia-7),

[0191] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0192] In some embodiments, the compound of formula (I) is a compound of formula (Ia-8):

[0193] (Ia-8),

[0194] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0195] In some embodiments, the compound of formula (I) is a compound of formula (Ia-9):

[0196] (Ia-9),

[0197] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0198] In some embodiments, the compound of formula (I) is a compound of formula (Ia-10):

[0199] (Ia-10),

[0200] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0201] In some embodiments, the compound of formula (I) is a compound of formula (Ia′):

[0202] (Ia′),

[0203] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0204] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-1):

[0205] (Ia′-1),

[0206] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0207] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-2):

[0208] (Ia′-2),

[0209] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0210] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-2-i):

[0211] (Ia′-2-i),

[0212] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0213] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-2-ii):

[0214] (Ia′-2-ii),

[0215] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0216] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-3):

[0217] (Ia′-3),

[0218] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0219] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-4):

[0220] (Ia′-4),

[0221] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0222] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-5):

[0223] (Ia′-5),

[0224] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0225] In some embodiments, the compound of formula (I) is a compound of formula (Ia′-6):

[0226] (Ia′-6),

[0227] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0228] In some embodiments, the compound of formula (I) is a compound of formula (I′′′):

[0229] (I′′′),

[0230] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0231] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0232] (Ib),

[0233] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0234] In some embodiments, the compound of formula (I) is the compound of formula (Ib-1):

[0235] (Ib-1),

[0236] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0237] In some embodiments, the compound of formula (I) is the compound of formula (Ib-2):

[0238] (Ib-2),

[0239] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0240] In some embodiments, the compound of formula (I) is a compound of formula (Ib-3):

[0241] (Ib-3),

[0242] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, R 1 and R 2 It is methyl. In some embodiments, Z 1 For CH, and R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R1 and R 2 It is a methyl group.

[0243] In some embodiments, the compound of formula (I) is a compound of formula (Ib-4):

[0244] (Ib-4),

[0245] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, R 1 and R 2 It is methyl. In some embodiments, Z 1 For CH, and R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R 1 and R 2 It is a methyl group.

[0246] In some embodiments, the compound of formula (I) is the compound of formula (Ib-5):

[0247] (Ib-5),

[0248] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0249] In some embodiments, the compound of formula (I) is the compound of formula (Ib-6):

[0250] (Ib-6),

[0251] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0252] In some embodiments, the compound of formula (I) is the compound of formula (Ic):

[0253] (Ic),

[0254] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0255] In some embodiments, the compound of formula (I) is the compound of formula (Ic-1):

[0256] (Ic-1),

[0257] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0258] In some embodiments, the compound of formula (I) is the compound of formula (Ic-2):

[0259] (Ic-2),

[0260] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0261] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0262] (Id),

[0263] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0264] In some embodiments, the compound of formula (I) is the compound of formula (Id-1):

[0265] (Id-1),

[0266] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0267] In some embodiments, the compound of formula (I) is the compound of formula (Id-2):

[0268] (Id-2),

[0269] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0270] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0271] (Ie),

[0272] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0273] In some embodiments, the compound of formula (I) is the compound of formula (Ie-1):

[0274] (Ie-1),

[0275] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0276] In some embodiments, the compound of formula (I) is the compound of formula (Ie-2):

[0277] (Ie-2),

[0278] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0279] In some embodiments, the compound of formula (I) is the compound of formula (If):

[0280] (If),

[0281] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0282] In some embodiments, the compound of formula (I) is the compound of formula (If-1):

[0283] (If-1),

[0284] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0285] In some embodiments, the compound of formula (I) is a compound of formula (If-2):

[0286] (If-2),

[0287] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0288] In some embodiments, the compound of formula (I) is a compound of formula (If-2-i):

[0289] (If-2-i),

[0290] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, R 1 and R 2 It is methyl. In some embodiments, R 1 and R 2 Independently halogenated. In some implementations, R 1 For Cl and R 2 For F. In some implementations, Z 1 For CH, and R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R 1 and R 2 It is methyl. In some embodiments, Z 1 For CH, and R 1 and R 2 Independently halogenated. In some implementations, Z 1 For CH, R 1 For Cl, and R 2 It is F.

[0291] In some embodiments, the compound of formula (I) is a compound of formula (If-2-ii):

[0292] (If-2-ii),

[0293] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug. In some embodiments, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, R 1 and R 2 It is methyl. In some embodiments, R 1 and R 2Independently halogenated. In some implementations, R 1 For Cl and R 2 For F. In some implementations, Z 1 For CH, and R 1 and R 2 Independently for unreplaced C 1-3 Alkyl group. In some embodiments, Z 1 For CH, and R 1 and R 2 It is methyl. In some embodiments, Z 1 For CH, and R 1 and R 2 Independently halogenated. In some implementations, Z 1 For CH, R 1 For Cl, and R 2 It is F.

[0294] In some embodiments, the compound of formula (I) is a compound of formula (If-3):

[0295] (If-3),

[0296] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0297] In some embodiments, the compound of formula (I) is a compound of formula (If-3-i):

[0298] (If-3-i),

[0299] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0300] In some embodiments, the compound of formula (I) is a compound of formula (If-4):

[0301] (If-4),

[0302] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0303] In some embodiments, the compound of formula (I) is a compound of formula (If-5):

[0304] (If-5),

[0305] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0306] In some embodiments, the compound of formula (I) is a compound of formula (If-6):

[0307] (If-6),

[0308] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0309] In some embodiments, the compound of formula (I) is the compound of formula (Ig):

[0310] (Ig),

[0311] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0312] In some embodiments, the compound of formula (I) is the compound of formula (Ig-1):

[0313] (Ig-1),

[0314] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0315] In some embodiments, the compound of formula (I) is the compound of formula (Ig-2):

[0316] (Ig-2),

[0317] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0318] In some embodiments, the compound of formula (I) is a compound of formula (Ig-2-i):

[0319] (Ig-2-i),

[0320] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0321] In some embodiments, the compound of formula (I) is a compound of formula (Ig-2-ii):

[0322] (Ig-2-ii),

[0323] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0324] In some embodiments, the compound of formula (I) is the compound of formula (Ig-3):

[0325] (Ig-3),

[0326] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0327] In some embodiments, the compound of formula (I) is a compound of formula (Ig-4):

[0328] (Ig-4),

[0329] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0330] In some embodiments, the compounds provided herein are compounds of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts, stereoisomers, tautomers, or solvates thereof. In some embodiments, the compounds provided herein are compounds of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof. In some embodiments, the compounds provided herein are compounds of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds provided herein are compounds of formula (I) in free base form, or any subgenus or species thereof.

[0331] In some embodiments, the compounds provided herein are compounds of formula (I) or isotopically labeled derivatives of any subgenus or species thereof, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds provided herein are compounds of formula (I) or deuterated derivatives of any subgenus or species thereof, or pharmaceutically acceptable salts thereof.

[0332] In each aspect and embodiment disclosed herein, explicit reference to a compound of formula (I) should be understood to alternatively refer to a compound of any of the disclosed subgenus or species, such as compounds of any of those in Tables 1A-1C.

[0333] In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A, and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A, and their pharmaceutically acceptable salts, stereoisomers, and tautomers. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A, and their pharmaceutically acceptable salts. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A (in free base form).

[0334] Table 1A

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343] a The absolute stereochemistry of Examples 18a and 18b has been arbitrarily defined.

[0344] b The absolute stereochemistry of Examples 19a and 19b has been arbitrarily defined.

[0345] c The absolute stereochemistry of Examples 42 and 43 has been arbitrarily defined.

[0346] d The absolute stereochemistry of Examples 103 and 105 has been arbitrarily defined.

[0347] In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B, and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B, and their pharmaceutically acceptable salts, stereoisomers, and tautomers. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B, and their pharmaceutically acceptable salts. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B (in free base form).

[0348] Table 1B

[0349]

[0350]

[0351]

[0352]

[0353]

[0354] In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C, and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C, and their pharmaceutically acceptable salts, stereoisomers, and tautomers. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C (in free base form).

[0355] Table 1C

[0356]

[0357]

[0358] The following definitions and embodiments apply to all general formulas containing the relevant groups provided herein (e.g., formula (I) or any of its sub-formulas). Any description of a list of chemical groups in any definition of a variable herein includes defining the variable as any single group or combination of the listed groups. Descriptions of embodiments of a variable herein include the embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0359] As defined in this article, X 1It is C or N. In some implementations, X 1 For C. In some implementations, X 1 Let N be the number of elements in the array.

[0360] As defined in this article, Z 3 For CR 4 , N, NR N S or O. In some implementations, Z 3 For CR 4 In some implementations, Z 3 For N. In some implementations, Z 3 For NR N In some implementations, Z 3 For S. In some implementations, Z 3 It is O.

[0361] As defined in this article, Z 4 For CR 4 , N, NR N S or O. In some implementations, Z 4 For CR 4 In some implementations, Z 4 For C-CF3. In some implementations, Z 4 For N. In some implementations, Z 4 For NR N In some implementations, Z 4 For S. In some implementations, Z 4 It is O.

[0362] As defined in this article, Z 5 For key, CR 4 , N, NR N S or O. In some implementations, Z 5 As the key. In some implementations, Z 5 For CR 4 In some implementations, Z 5 For S. In some implementations, Z 5 For O. In some implementations, Z 5 For N. In some implementations, Z 5 For NR N .

[0363] As defined in this article, Z 6 For CR 4 , N, NR N S or O. In some implementations, Z 6 For CR 4 In some implementations, Z 6For N. In some implementations, Z 6 For NR N In some implementations, Z 6 For S. In some implementations, Z 6 It is O.

[0364] As described in this article, Z 3 Z 4 Z 5 and Z 6 At least one of them is N, NR N S or O, and Z 3 Z 4 Z 5 and Z 6 No more than one of them is S or O. In some implementations, Z 3 Z 4 Z 5 and Z 6 At least two of them are independently selected from N and NR. N S and O, with condition Z 3 Z 4 Z 5 and Z 6 No more than one of them is S or O.

[0365] In some implementation schemes:

[0366] Z 3 For N and Z 6 S;

[0367] Z 3 For S and Z 6 Let N be the number of people in the group.

[0368] Z 3 For N and Z 6 For O; or

[0369] Z 3 For O and Z 6 Let N be the number of elements in the array.

[0370] In some implementations, Z 3 For N and Z 6 For S, or Z 3 For S and Z 6 For N. In some implementations, Z 3 For N and Z 6 For S. In some implementations, Z 3 For S and Z 6 Let N be the number of elements in the array.

[0371] In some implementations, Z 3 For N and Z6 For O, or Z 3 For O and Z 6 For N. In some implementations, Z 3 For N and Z 6 For O. In some implementations, Z 3 For O and Z 6 Let N be the number of elements in the array.

[0372] As defined in this article, R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted independently.

[0373] In some implementations, R 4 At least one instance of H is H.

[0374] In some implementations, R 4 At least one instance is a halogen. In some embodiments, R 4 At least one instance is Cl. In some implementations, R 4 At least one instance of F is F.

[0375] In some implementations, R 4 At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R 4 At least one instance is unsubstituted C 1-6 Alkyl group. In some embodiments, R 4 At least one instance of C is optionally replaced. 1-4 Alkyl group. In some embodiments, R 4 At least one instance is unsubstituted C 1-4 Alkyl group. In some embodiments, R 4 At least one instance of R is methyl. In some embodiments, R 4 At least one instance is tert-butyl.

[0376] In some implementations, R 4 At least one instance of C is 1-6 Halogenated groups. In some embodiments, R 4 At least one instance of C is 1-3Halogenated groups. In some embodiments, R 4 At least one example is a C1 haloalkyl group. In some embodiments, R 4 At least one instance is -CF2H.

[0377] In some implementations, R 4 At least one instance is -CF3.

[0378] In some implementations, R 4 At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R 4 At least one instance of C is optionally replaced. 3-5 Cycloalkyl. In some embodiments, R 4 At least one instance of C is optionally replaced. 3-4 Cycloalkyl. In some embodiments, R 4 At least one instance is unsubstituted C 3-4 Cycloalkyl. In some embodiments, R 4 At least one instance is cyclopropyl.

[0379] In some implementations, R 4 At least one instance of C is optionally replaced. 6-10 Aryl. In some embodiments, R 4 At least one example is an optionally substituted C6 aryl (phenyl). In some embodiments, R 4 At least one instance is an unsubstituted phenyl group.

[0380] In some implementations, R 4 At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R 4 At least one example is an optionally substituted 5-10 membered heteroaryl group. In some embodiments, R 4 At least one instance is -CN. In some implementations, R 4 At least one instance of -OR O In some implementations, R 4 At least one instance is -N(R) N 2. In some implementations, R 4 At least one instance of C is optionally replaced. 1-6 Acyl group.

[0381] In other implementations, R 4 At least one instance is -SR S In some implementations, R 4 At least one instance is -SMe.

[0382] In other implementations, R 4 At least one instance is -S(=O)2R S1 In some implementations, R 4 At least one instance is -S(=O)2Me.

[0383] As defined herein, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, where valence allows. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0384] As defined herein, m is 1 or 2. In some implementations, m is 1. In some implementations, m is 2.

[0385] As defined herein, n is 0, 1, or 2. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2.

[0386] In some implementations, both m and n are 1.

[0387] In some implementations, m is 1 and n is 0.

[0388] In some implementations, m is 1 and n is 2.

[0389] As defined in this article, R 1 H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted.

[0390] In some implementations, R 1 For H.

[0391] In some implementations, R 1 It is a halogen. In some implementations, R 1For F. In some implementations, R 1 It is Cl.

[0392] In some implementations, R 1 C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R 1 For unreplaced C 1-6 Alkyl group. In some embodiments, R 1 C is arbitrarily replaced 1-3 Alkyl group. In some embodiments, R 1 For unreplaced C 1-3 Alkyl group. In some embodiments, R 1 It is a methyl group.

[0393] In some implementations, R 1 C 1-6 Halogenated groups. In some embodiments, R 1 C 1-3 Halogenated groups. In some embodiments, R 1 It is a C1 haloalkyl group. In some embodiments, R 1 It is -CF3.

[0394] In some implementations, R 1 C is arbitrarily replaced 3-7 Cycloalkyl. In some embodiments, R 1 For unreplaced C 3-7 Cycloalkyl. In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with C 3-7 Cycloalkyl. In some embodiments, R 1 C is replaced by one or more instances of halogen. 3-7 Cycloalkyl. In some embodiments, R 1 C is replaced by one or more instances of F. 3-7 Cycloalkyl.

[0395] In some implementations, R 1 C is arbitrarily replaced 3-5 Cycloalkyl. In some embodiments, R 1 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 1 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C4 cycloalkyl groups. In some embodiments, R 1It is a C4 cycloalkyl group optionally substituted with one or more instances of halogen. In some embodiments, R 1 C4 cycloalkyl group optionally substituted with one or more instances of F.

[0396] In some implementations, R 1 It is an unsubstituted C3 cycloalkyl (cyclopropyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with cyclopropyl groups. In some embodiments, R 1 The cyclopropyl group is substituted with one or more instances of halogen. In some embodiments, R 1 The cyclopropyl group is replaced by one or more instances of F.

[0397] In some implementations, R 1 It is an unsubstituted C4 cycloalkyl (cyclobutyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl-substituted cyclobutyl groups. In some embodiments, R 1 The cyclobutyl group is substituted with one or more instances of halogen. In some embodiments, R 1 is a cyclobutyl group that is replaced by one or more instances of F.

[0398] In some implementations, R 1 It is an unsubstituted C5 cycloalkyl group (e.g., cyclopentyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with cyclopentyl groups. In some embodiments, R 1 The cyclopentyl group is substituted with one or more instances of halogen. In some embodiments, R 1 , which is a cyclopentyl group substituted by one or more instances of F.

[0399] In some implementations, R 1 It is an unsubstituted C6 cycloalkyl group (e.g., cyclohexyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl-substituted cyclohexyl groups. In some embodiments, R 1 A cyclohexyl group substituted with one or more instances of halogen. In some embodiments, R 1 For cyclohexyl groups that are replaced by one or more instances of F.

[0400] In some implementations, R 1 Optionally substituted 3-7 membered heterocyclic groups. In some embodiments, R1 It is a 3-7 membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1 Optionally substituted 3-6 membered heterocyclic groups. In some embodiments, R 1 A 3- to 6-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1 Optionally substituted 3-5 membered heterocyclic groups. In some embodiments, R 1 It is an optionally substituted 3- to 5-membered heterocyclic group having one cyclic heteroatom selected from O, N, and S. In some embodiments, R 1 It is an optionally substituted 4-membered heterocyclic group having one cyclic heteroatom selected from O, N, and S. In some embodiments, R 1 It is a optionally substituted 4-membered heterocyclic group having one independently selected cyclic heteroatom chosen from O and N. In some embodiments, R 1 It is an optionally substituted oxocyclic butyl group. In some embodiments, R 1 It is an unsubstituted oxocyclic butyl group.

[0401] In some implementations, R 1 C is arbitrarily replaced 6-10 Aryl. In some embodiments, R 1 It is an optionally substituted C6 aryl (phenyl). In some embodiments, R 1 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with phenyl groups.

[0402] In some implementations, R 1 Optionally substituted 5-10 membered heteroaryl groups. In some embodiments, R 1 It is a 5-10 membered heteroaryl group having one, two, or three independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1 Optionally substituted 5-6 membered heteroaryl groups. In some embodiments, R 1 It is a 5-6 membered heteroaryl group having 1, 2 or 3 independently substituted cyclic heteroatoms selected from O, N and S.

[0403] In some implementations, R 1 Selected from:

[0404] , , , , , and .

[0405] In some implementations, R 1 for: , or .

[0406] In some implementations, R 1 for: or .

[0407] In some implementations, R 1 For -OR O .

[0408] In some implementations, R 1 For -OR O , where R O C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R 1 For -OR O , where R O C is arbitrarily replaced 1-3 Alkyl group. In some embodiments, R 1 For -OR O , where R O For unreplaced C 1-3 Alkyl group. In some embodiments, R 1 For -OMe.

[0409] In some implementations, R 1 For -OR O , where R O C 1-6 Halogenated groups. In some embodiments, R 1 For -OR O , where R O C 1-3 Halogenated groups. In some embodiments, R 1 For -OR O , where R O It is a C1 haloalkyl group. In some embodiments, R 1 It is -OCF3.

[0410] In some implementations, Z 1 For -CN. In some implementations, R 1 -N(R) N 2. In some implementations, R 1 C is arbitrarily replaced 1-6 Acyl group.

[0411] In some implementations, R 1For -SR S In some implementations, R 1 For -SMe.

[0412] In some implementations, R 1 is -S(=O)2R S1 In some implementations, R 1 It is -S(=O)2Me.

[0413] In some implementations, R 1 Halogen, C 1-6 Halogenated or -OR O In some implementations, R 1 Halogen, C 1-6 Halogenated groups, -OR O -CN, -SR S or -S(=O)2R S1 .

[0414] In some implementations, R 1 For F, Cl, -CF3, or -OMe. In some implementations, R 1 For F, Cl, -CF3, -OMe, -OCF3, -CN, -SMe or -S(=O)2Me.

[0415] As defined in this article, R 2 H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted.

[0416] In some implementations, R 2 For H.

[0417] In some implementations, R 2 It is a halogen. In some implementations, R 2 For F. In some implementations, R 2 For Cl. In some implementations, R 2 It can be F or Cl.

[0418] In some implementations, R 2 C is arbitrarily replaced 1-6Alkyl group. In some embodiments, R 2 For unreplaced C 1-6 Alkyl group. In some embodiments, R 2 C is arbitrarily replaced 1-3 Alkyl group. In some embodiments, R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, R 2 It is a methyl group.

[0419] In some implementations, R 2 C 1-6 Halogenated groups. In some embodiments, R 2 C is arbitrarily replaced 3-7 Cycloalkyl. In some embodiments, R 2 Optionally substituted 3-7 membered heterocyclic groups. In some embodiments, R 2 C is arbitrarily replaced 6-10 Aryl. In some embodiments, R 2 Optionally substituted 5-10 membered heteroaryl groups. In some embodiments, R 2 For -CN.

[0420] In some implementations, R 2 For -OR O .

[0421] In some implementations, R 2 For -OR O , where R O C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R 2 For -OR O , where R O C is arbitrarily replaced 1-3 Alkyl group. In some embodiments, R 2 For -OR O , where R O For unreplaced C 1-3 Alkyl group. In some embodiments, R 2 For -OMe.

[0422] In some implementations, R 2 For -OR O , where R O C 1-6 Halogenated groups. In some embodiments, R 2 For -OR O , where R O C 1-3 Halogenated groups. In some embodiments, R 2For -OR O , where R O It is a C1 haloalkyl group. In some embodiments, R 2 It is -OCF3.

[0423] In some implementations, R 2 Halogen or -OR O In some implementations, R 2 It can be F, Cl, or -OMe.

[0424] In some implementations, R 2 -N(R) N 2. In some implementations, R 2 C is arbitrarily replaced 1-6 Acyl group.

[0425] In some implementations, R 2 For -SR S In some implementations, R 2 For -SMe.

[0426] In some implementations, R 2 is -S(=O)2R S1 In some implementations, R 2 It is -S(=O)2Me.

[0427] As defined in this article, R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; and Ar 1 C 6-10 Aryl or 5-10 heteroaryl, wherein the aryl or heteroaryl group is optionally substituted.

[0428] In some implementations, R 3 C is arbitrarily replaced 1-8 Alkyl group. In some embodiments, R 3 For unreplaced C 1-8 Alkyl group. In some embodiments, R 3 C is arbitrarily replaced 1-4 Alkyl group. In some embodiments, R 3 For unreplaced C 1-4 Alkyl group. In some embodiments, R 3 It is tert-butyl.

[0429] In some implementations, R 3C substituted by one or more halogens 1-6 Alkyl group. In some embodiments, R 3 C replaced by one or more F 1-6 Alkyl group. In some embodiments, R 3 C replaced by one or more F 1-3 Alkyl group. In some embodiments, R 3 -CF3, -CH2CF3 or In some implementations, R 3 It is -CH2CF3.

[0430] In some implementations, R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0431] In some implementations, R 3 C is arbitrarily replaced 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-3 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F and / or methyl. 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally replaced by one or more instances of F. 3-8 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-6 Halogenated alkyl groups and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-3 Halogenated alkyl groups and / or unsubstituted C 1-3 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F, -CF3, and / or methyl. 3-8 Cycloalkyl.

[0432] In some implementations, R 3 C is arbitrarily replaced 3-5 Cycloalkyl. In some embodiments, R3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-3 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F and / or methyl. 3-5 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-6 Halogenated alkyl groups and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-3 Halogenated alkyl groups and / or unsubstituted C 1-3 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F, -CF3, and / or methyl. 3-5 Cycloalkyl.

[0433] In some implementations, R 3 C is optionally replaced by one or more instances of F. 3-5 Cycloalkyl. In some embodiments, R 3 C is replaced by one or more instances of F. 3-5 Cycloalkyl. In some embodiments, R 3 C4 cycloalkyl (cyclobutyl) substituted by one or more instances of F.

[0434] In some implementations, R 3 Selected from:

[0435] , , , , , , ,

[0436] , , and .

[0437] In some implementations, R 3 for: In some implementations, R 3 for: In some implementations, R 3 for: .

[0438] In some implementations, R 3 for: In some implementations, R 3 Selected from: and .

[0439] In some implementations, R 3 Selected from:

[0440] , , , , , , , , , , , , and .

[0441] In some implementations, R 3 C is arbitrarily replaced 6-10 Aryl. In some embodiments, R 3 The phenyl group is optionally substituted. In some embodiments, R... 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with phenyl groups. In some embodiments, R 3 The phenyl group is optionally substituted with one or more instances of halogen. In some embodiments, R 3 A phenyl group that is optionally substituted with one or more instances of F.

[0442] In some implementations, R 3 Selected from:

[0443] , , , and .

[0444] In some implementations, R 3 Selected from:

[0445] , , ,

[0446] , , , and .

[0447] In some implementations, R 3 Optionally substituted 3-7 membered heterocyclic groups. In some embodiments, R 3 It is an optionally substituted 3-6 membered heterocyclic group having one or two ring N atoms. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and optionally substituted with one or more halogens. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and optionally substituted with one or more F atoms. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms substituted by one or more F atoms. In some embodiments, R 3 It is an nitrogen-containing heterocyclic butyl group substituted with one or more F atoms. In some embodiments, R... 3 It is a 3- to 6-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from N and O. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two independent cyclic heteroatoms selected from N and O, wherein the heterocyclic group is optionally halogenated, unsubstituted C 1-6 Alkyl and / or C 1-6 One or more instances of haloalkyl groups are substituted. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one ring N atom, wherein the heterocyclic group is optionally converted by halogen, unsubstituted C 1-6 Alkyl and / or C 1-6 One or more instances of haloalkyl groups are substituted. In some embodiments, R 3 A 3-6 membered heterocyclic group having one cyclic heteroatom selected from N and O, wherein the heterocyclic group is optionally substituted with one or more instances of F, Me, and / or -CF3. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one ring N atom, wherein the heterocyclic group is optionally substituted by one or more instances of F, Me and / or -CF3.

[0448] In some implementations, R 3 for: .

[0449] In some implementations, R 3 for: In some implementations, R 3for: .

[0450] In some implementations, R 3 Selected from:

[0451] , , , , , , and .

[0452] In some implementations, R 3 -(CR'R”) w -Ar 1 .

[0453] As defined herein, w is 0, 1, or 2. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2.

[0454] As defined in this article, Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted. In some embodiments, Ar 1 C is arbitrarily replaced 6-10 Aryl. In some embodiments, Ar 1 It is a 5-10 substituted heteroaryl group.

[0455] As defined in this article, Z 1 For CR Z Or N. In some implementations, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, Z 1 For CCl. In some implementations, Z 1 For CF. In some implementations, Z 1 For N. In some implementations, Z 1 It can be CH or N.

[0456] As defined in this article, Z 2 For CR Z Or N. In some implementations, Z 2 For CR Z In some implementations, Z 2 For CH. In some implementations, Z 2 For CCl. In some implementations, Z 2 For CF. In some implementations, Z2 For N. In some implementations, Z 2 It can be CH or N.

[0457] In some implementations, Z 1 For CR Z And Z 2 For CR Z In some implementations, Z 1 For CH and Z 2 For CH. In some implementations, Z 1 For CR Z And Z 2 For N. In some implementations, Z 1 For CH and Z 2 For N. In some implementations, Z 1 For N and Z 2 For CR Z In some implementations, Z 1 For N and Z 2 For CH. In some implementations, Z 1 For N and Z 2 Let N be the number of elements in the array.

[0458] As defined in this article, R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted independently.

[0459] In some implementations, R Z At least one instance is H. In some implementations, R Z Each instance is H.

[0460] In some implementations, R Z At least one instance is a halogen. In some embodiments, R Z At least one instance of R is F. In some implementations, R Z At least one instance of is Cl.

[0461] In some implementations, R Z At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R ZAt least one instance of C is 1-6 Halogenated groups. In some embodiments, R Z At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R Z At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R Z At least one instance of C is optionally replaced. 6-10 Aryl. In some embodiments, R Z At least one example is an optionally substituted 5-10 membered heteroaryl group. In some embodiments, R Z At least one instance is -CN. In some implementations, R Z At least one instance of -OR O In some implementations, R Z At least one instance is -N(R) N 2. In some implementations, R Z At least one instance of C is optionally replaced. 1-6 Acyl group.

[0462] As defined in this article, Y represents a key, -CR'R"-, -O-, or -NR. Y -

[0463] In some implementations, Y is the key.

[0464] In some implementations, Y is -CR'R"-. In some implementations, Y is -CH2-. In some implementations, Y is -CH(Me)-.

[0465] In some implementations, Y is -O-.

[0466] In some implementations, Y is -NR Y - In some implementations, Y is -NH-.

[0467] As defined in this article, R Y For H, C 1-6 Alkyl, C 3-7 A cycloalkyl or nitrogen protecting group, wherein the alkyl or cycloalkyl group is optionally substituted.

[0468] In some implementations, R Y For H.

[0469] In some implementations, R Y C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R Y C is arbitrarily replaced 3-7Cycloalkyl. In some embodiments, R Y It is a nitrogen protecting group.

[0470] In other implementations, R Y and R 3 They bond together with intercalating atoms to form 3-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted. In some embodiments, R Y and R 3 They combine with intercalated atoms to form optionally substituted 4-6 membered heterocyclic groups.

[0471] In some implementations, Y is -CR'R"- and R 3 C is arbitrarily replaced 1-8 Alkyl group. In some embodiments, Y is -CR'R"- and R 3 C is arbitrarily replaced 1-4 Alkyl group. In some embodiments, Y is -CH2- and R is... 3 For unreplaced C 1-4 Alkyl group. In some embodiments, Y is -CH2- and R is... 3 It is tert-butyl.

[0472] In some implementations, Y is -CH2- and R 3 Selected from:

[0473] , , , , , , ,

[0474] , , and .

[0475] In some implementations, Y is -CH2- and R 3 for: .

[0476] In some implementations, Y is -CH2- and R 3 Selected from:

[0477] , , , and .

[0478] As defined in this article, R 5 Each instance is independently of halogen, C 1-6Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0479] In some implementations, R 5 At least one instance is a halogen.

[0480] In some implementations, R 5 At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R 5 At least one instance is unsubstituted C 1-6 Alkyl group. In some embodiments, R 5 At least one instance of C is optionally replaced. 1-3 Alkyl group. In some embodiments, R 5 At least one instance is unsubstituted C 1-3 Alkyl group. In some embodiments, R 5 At least one instance is methyl.

[0481] In some implementations, R 5 At least one instance of C is 1-6 Halogenated groups. In some embodiments, R 5 At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R 5 At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R 5 At least one instance is -CN.

[0482] In some implementations, R 5 At least one instance of -OR O In some implementations, R 5 At least one instance is -OH.

[0483] In some implementations, R 5 At least one instance is -N(R) N 2. In some implementations, R 5 At least one instance of C is optionally replaced.1-6 Acyl group.

[0484] In some implementations, two R atoms bonded to the same carbon atom 5 It combines with intercalated atoms to form optionally substituted C 3-7 Cycloalkyl. In some embodiments, two R atoms are attached to the same carbon atom. 5 They combine with intercalated atoms to form optionally substituted 3-7 membered heterocyclic groups.

[0485] In some implementations, two R atoms bonded to the same carbon atom 5 Together they form = O.

[0486] As defined in this paper, each instance of R' is independently H, halogen, C. 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0487] In some implementations, at least one instance of R' is H.

[0488] In some embodiments, at least one instance of R' is a halogen. In some embodiments, at least one instance of R' is optionally substituted C. 1-6 Alkyl group. In some embodiments, at least one instance of R' is C. 1-6 Halogenated alkyl group. In some embodiments, at least one instance of R' is an optionally substituted C. 3-7 Cycloalkyl. In some embodiments, at least one instance of R' is an optionally substituted 3-7 membered heterocyclic group.

[0489] As defined in this paper, each instance of R is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, wherein each alkyl group is optionally substituted independently.

[0490] In some implementations, at least one instance of "R" is H.

[0491] In some embodiments, at least one instance of R” is a halogen. In some embodiments, at least one instance of R” is optionally substituted C. 1-6 Alkyl group. In some embodiments, at least one instance of "R" is -OR. O In some implementations, at least one instance of R” is -N(R) N )2.

[0492] In some implementations, R' and R'', which are attached to the same carbon atom, bond together with intercalating atoms to form C. 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted. In some embodiments, R' and R'' attached to the same carbon atom are bonded together with intercalation atoms to form optionally substituted C. 3-7 Cycloalkyl. In some embodiments, R' and R'' attached to the same carbon atom are bonded together with intercalation atoms to form optionally substituted 3-7 membered heterocyclic groups.

[0493] In some implementations, R' and R'', which are attached to the same carbon atom, together form =O.

[0494] As defined in this article, R N1 For H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 An acyl or nitrogen-protecting group, wherein the alkyl, cycloalkyl, or acyl group is optionally substituted.

[0495] In some implementations, R N1 For H.

[0496] In some implementations, R N1 C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R N1 C is arbitrarily replaced 3-7 Cycloalkyl. In some embodiments, R N1 C is arbitrarily replaced 1-6 Acyl group. In some embodiments, R N1 It is a nitrogen protecting group.

[0497] As defined in this article, each R N Independently for H and C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently.

[0498] In some implementations, R N At least one instance is H. In some implementations, R N Each instance is H.

[0499] In some implementations, R N At least one instance of C is optionally replaced. 1-6 alkyl.

[0500] In some implementations, R N At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R N At least one instance of C is optionally replaced. 1-6 Acyl group. In some embodiments, R N At least one instance is a nitrogen protecting group.

[0501] In some implementations, two R atoms bonded to the same carbon atom N They bond together with intercalating atoms to form optionally substituted 3-7 membered heterocyclic groups. In some embodiments, two R atoms are attached to the same carbon atom. N They combine with intercalated atoms to form optionally substituted 4-6 membered heterocyclic groups.

[0502] As defined in this article, R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0503] In some implementations, R O At least one instance is H. In some implementations, R O Each instance is H.

[0504] In some implementations, R O At least one instance of C is optionally replaced. 1-6 alkyl.

[0505] In some implementations, R O At least one instance of C is 1-6 Halogenated groups. In some embodiments, R O At least one instance of C is 1-3 Halogenated groups. In some embodiments, R O At least one example is a C1 haloalkyl group. In some embodiments, R O At least one instance is -CF3.

[0506] In some implementations, R O At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R O At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R O At least one instance of C is optionally replaced.1-6 Acyl group. In some embodiments, R O At least one instance is an oxygen protecting group.

[0507] As defined in this article, R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0508] In some implementations, R S At least one instance of H is H.

[0509] In some implementations, R S At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R S At least one instance is unsubstituted C 1-6 Alkyl group. In some embodiments, R S At least one instance of C is optionally replaced. 1-3 Alkyl group. In some embodiments, R S At least one instance is unsubstituted C 1-3 Alkyl group. In some embodiments, R S At least one instance is methyl.

[0510] In some implementations, R S At least one instance of C is 1-6 Halogenated groups. In some embodiments, R S At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R S At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R S At least one instance of C is optionally replaced. 1-6 Acyl group. In some embodiments, R S At least one instance is a sulfur protecting group.

[0511] As defined in this article, R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0512] In some implementations, RS1 At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R S1 At least one instance is unsubstituted C 1-6 Alkyl group. In some embodiments, R S1 At least one instance of C is optionally replaced. 1-3 Alkyl group. In some embodiments, R S1 At least one instance is unsubstituted C 1-3 Alkyl group. In some embodiments, R S1 At least one instance is methyl.

[0513] In some implementations, R S1 At least one instance of C is 1-6 Halogenated groups. In some embodiments, R S1 At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R S1 At least one instance is a substituted 3-7 membered heterocyclic group.

[0514] Pharmaceutical compositions, kits and administration

[0515] This disclosure provides pharmaceutical compositions comprising the compounds provided herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, or prodrugs thereof) and one or more pharmaceutically acceptable carriers and / or excipients. In some embodiments, the compounds described herein are provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a preventatively effective amount.

[0516] The pharmaceutical compositions described herein can be prepared by any method known in pharmacological techniques. Generally, such preparation methods involve associating the compound described herein (i.e., the “active ingredient”) with a carrier or excipient and / or one or more other auxiliary ingredients, and then, if desired and / or packaged, shaping and / or packaging the product into desired single-dose or multiple-dose units.

[0517] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. A “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is typically equal to the dose of the active ingredient to be administered to a subject and / or a convenient fraction of that dose, such as one-half or one-third of the dose.

[0518] The relative amounts of the active ingredient, pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, body type, and / or condition of the treated subject and further depending on the route of administration of the composition.

[0519] Pharmaceutically acceptable carriers / excipients used to manufacture the provided pharmaceutical compositions include inert diluents, solvents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, oils, butters and / or waxes. Excipients such as colorants, coating agents, sweeteners, flavoring agents and aromatizers may also be present in the composition.

[0520] The compounds and compositions described herein may be administered via any route, including enterically (e.g., orally), parenterally, intravenously, intramuscularly, intra-arterially, intramedullaryly, intrathecally, subcutaneously, intravenously, percutaneously, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., via powder, ointment, cream, and / or drops), mucosally, nasally, buccally, sublingually; via endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Specific routes of administration considered include oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymphatic supply, and / or direct administration to the site of influence. Generally, the most appropriate route of administration will depend on a number of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0521] Although the descriptions of pharmaceutical compositions provided herein are primarily concerned with those suitable for human administration, a skilled craftsman will understand that such compositions are generally suitable for administration to a wide variety of animals. It is well known to modify pharmaceutical compositions suitable for human administration to make them suitable for administration to a wide variety of animals, and such modifications can be designed and / or carried out by a generally skilled veterinary pharmacologist using standard experimental design and / or procedures.

[0522] The compounds described herein are typically formulated in dosage units for ease of administration and uniform dosage. However, it should be understood that the total daily dosage of the compositions described herein will be determined by a physician within the bounds of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the severity of the disease and condition being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific active ingredient used; the duration of the treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well known in the medical field.

[0523] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending on factors such as the subject's species, age and general condition, severity of side effects or illness, the identity of the specific compound, and the mode of administration. An effective dose may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, any two doses in the multiple doses comprise different or substantially the same amounts of the compound described herein.

[0524] The compounds or compositions described herein may be administered in combination with one or more additional agents (e.g., therapeutic and / or preventative active agents). The compounds or compositions may be administered in combination with additional agents that improve the activity of the compounds or compositions (e.g., activity in treating a disease in a subject of need, preventing a disease in a subject of need, or reducing the risk of a subject of need to develop a disease (e.g., potency and / or efficacy)), increase bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in the subject or cells. It should also be understood that the therapy employed may achieve the desired effect for the same condition, and / or may achieve different effects.

[0525] This disclosure also covers kits (e.g., pharmaceutical packs). The provided kits may contain the pharmaceutical compositions or compounds described herein and containers (e.g., vials, ampoules, bottles, syringes, and / or dispenser packs or other suitable containers). In some embodiments, the provided kits may optionally further include a second container containing pharmaceutical excipients for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein provided in the first and second containers are combined to form a single unit dosage form. Thus, in one aspect, a kit is provided comprising a first container containing the compounds or pharmaceutical compositions described herein. In some embodiments, the kit may be used to treat and / or prevent a disease, condition, or disorder in a subject of need.

[0526] In some embodiments, the kit described herein further includes instructions for use of the kit. The kit described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit provides instructions for treating a disease (e.g., cancer) in a subject in need. In some embodiments, the kit provides instructions for preventing a disease in a subject in need. The kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0527] Treatment methods and uses

[0528] As described in some aspects, the compounds presented herein can act as voltage-gated potassium channel synergists (e.g., Kv7.2 / Kv7.3 synergists) and are therefore used, for example, to treat diseases, symptoms and ailments.

[0529] In one aspect, this document provides a method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof. In some embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In some embodiments, the Kv7 potassium channel is Kv7.2. In some embodiments, the Kv7 potassium channel is Kv7.3. In some embodiments, the Kv7 potassium channel is Kv7.2 / Kv7.3. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2-Kv7.5 than for Kv7.1. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2 / Kv7.3 than for Kv7.1.

[0530] This article also provides the compounds disclosed herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, and pharmaceutical compositions for enhancing Kv7 potassium channels in subjects.

[0531] In another embodiment, this document provides a method for treating a disease, condition, or disorder associated with Kv7 potassium channel dysfunction in a subject of need, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof. In some embodiments, the disease, condition, or disorder is associated with dysfunction of Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In some embodiments, the disease, condition, or disorder is associated with Kv7.2 dysfunction. In some embodiments, the disease, condition, or disorder is associated with Kv7.3 dysfunction. In some embodiments, the disease, condition, or disorder is associated with Kv7.2 / Kc7.3 dysfunction.

[0532] This document also provides the compounds disclosed herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, and pharmaceutical compositions thereof, for the treatment of subjects with diseases, conditions or disorders associated with Kv7 potassium channel dysfunction.

[0533] In another respect, this article provides a method for treating seizure disorders, depression, pain, or anhedonia in subjects in need, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0534] This document also provides the compounds disclosed herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs and pharmaceutical compositions thereof, for the treatment of seizure disorders, depression, pain, or anhedonia in subjects of need.

[0535] In some implementations, the disease, condition, or disorder is referred to as a seizure symptom. "Seizure symptom" refers to seizures and conditions associated with seizures, such as partial seizures (also known as focal seizures), photosensitive epilepsy, self-induced syncope, refractory epilepsy, Angelman's syndrome, benign motor epilepsy, CDKL5 syndrome, childhood and adolescent 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), myoclonic absence epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen's syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, and Lafora progressive myoclonic epilepsy. Epilepsy, neurocutaneous syndrome, tuberous sclerosis, early-onset epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, paroxysmal dyskinesia, generalized tonic-clonic seizures or primary generalized tonic-clonic seizures or combinations thereof. In some embodiments, the epileptic seizure condition refers to generalized tonic-clonic seizures. In some embodiments, generalized tonic-clonic seizures are defined as primary generalized tonic-clonic seizures. In some embodiments, the epileptic seizure condition is primary generalized tonic-clonic seizures.

[0536] In some embodiments, the term "seizure syndrome" refers to focal paroxysmal epilepsy, also known as partial paroxysmal epilepsy. In some embodiments, seizure syndrome is photosensitive epilepsy. In some embodiments, seizure syndrome is self-induced syncope. In some embodiments, seizure syndrome is refractory epilepsy. In some embodiments, seizure syndrome is Angelman syndrome. In some embodiments, seizure syndrome is benign motor epilepsy. In some embodiments, seizure syndrome is CDKL5 syndrome. In some embodiments, seizure syndrome is childhood and adolescent absence epilepsy. In some embodiments, seizure syndrome is Dravet syndrome. In some embodiments, seizure syndrome is frontal lobe epilepsy. In some embodiments, seizure syndrome is Glut1 deficiency syndrome. In some embodiments, seizure syndrome is hypothalamic hamartoma. In some embodiments, seizure syndrome is infantile spasms / Wechsler syndrome. In some embodiments, seizure syndrome is juvenile myoclonic epilepsy. In some embodiments, seizure syndrome is Landau-Kleffner syndrome. In some embodiments, seizure syndrome is Lennox-Gastaut syndrome (LGS). In some embodiments, the epileptic seizure condition is myoclonic absence epilepsy. In some embodiments, the epileptic seizure condition is Otahara syndrome. In some embodiments, the epileptic seizure condition is Panayiotopoulos syndrome. In some embodiments, the epileptic seizure condition is PCDH19 epilepsy. In some embodiments, the epileptic seizure condition is progressive myoclonic epilepsy. In some embodiments, the epileptic seizure condition is Rasmussen syndrome. In some embodiments, the epileptic seizure condition is ring chromosome 20 syndrome. In some embodiments, the epileptic seizure condition is reflex epilepsy. In some embodiments, the epileptic seizure condition is temporal lobe epilepsy. In some embodiments, the epileptic seizure condition is Lafra progressive myoclonic epilepsy. In some embodiments, the epileptic seizure condition is neurocutaneous syndrome. In some embodiments, the epileptic seizure condition is tuberous sclerosis. In some embodiments, the epileptic seizure condition is early-onset epileptic encephalopathy. In some embodiments, the epileptic seizure condition is early-onset epileptic encephalopathy. In some embodiments, the epileptic seizure condition is generalized epilepsy. In some embodiments, the epileptic seizure condition is generalized epilepsy with febrile seizures+. In some embodiments, the epileptic seizure condition is Rett syndrome. In some embodiments, the epileptic seizure condition is multiple sclerosis. In some embodiments, the epileptic seizure condition is Alzheimer's disease. In some embodiments, the epileptic seizure condition is autism. In some embodiments, the epileptic seizure condition is ataxia. In some embodiments, the epileptic seizure condition is hypotonia. In some embodiments, the epileptic seizure condition is paroxysmal dyskinesia.In some implementations, the epileptic seizure condition is a generalized paroxysmal seizure. In some implementations, the epileptic seizure condition is a focal paroxysmal seizure (also known as a partial paroxysmal seizure).

[0537] In some implementations, the disease, symptom, or disorder is depression. "Depression" is a mood disorder characterized by depressed mood. In some implementations, depression includes major depressive disorder (MDD), schizophrenia, persistent depression, bipolar disorder, postpartum depression, premenstrual mood disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, dysregulation with depressed mood, chronic depressive response, or a combination thereof.

[0538] In some implementations, depression is major depressive disorder (MDD). In some implementations, depression is schizoaffective disorder. In some implementations, depression is persistent depression. In some implementations, depression is bipolar disorder. In some implementations, depression is postpartum depression. In some implementations, depression is premenstrual mood disorder (PMDD). In some implementations, depression is seasonal affective disorder (SAD). In some implementations, depression is atypical depression. In some implementations, depression is treatment-resistant depression (TRD). In some implementations, depression is depression associated with agitation or anxiety. In some implementations, depression is a regulation disorder with depressive mood. In some implementations, depression is a chronic depressive reaction.

[0539] This disclosure also covers the treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, social phobia, agoraphobia, agoraphobia with panic disorder, hypochondriasis, post-traumatic stress disorder (PTSD), treatment-resistant bipolar disorder, generalized anxiety disorder, attention deficit / hyperactivity disorder (ADHD), type I bipolar disorder, type II bipolar disorder, mania, cyclothymic mood disorder and unspecified bipolar disorder, mild depression, unspecified depression, mild depression, recurrent transient depression, depressive psychosis, impulse control disorder, schizophrenia, schizophrenia-like disorder, schizoaffective disorder, Parkinson's disease, dementia, Alzheimer's disease, Huntington's disease, Tourette's syndrome, aggression and substance use and / or abuse or combinations thereof.

[0540] In some implementations, disease, symptom, or disorder is pain. As used herein, “pain” means all categories of pain and includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgia, orofacial pain, burn pain, burning mouth syndrome, somatic pain, visceral pain, myofibril pain, toothache, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, labor pain, reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder disorder, acute pain (e.g., musculoskeletal and postoperative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, familial hemiplegic migraine, headache-related disorders, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, thalamic lesions, radiculopathy, HIV pain, postherpetic neuralgia, noncardiac chest pain, irritable bowel syndrome, and pain associated with intestinal disorders and indigestion, and combinations thereof.

[0541] In some implementations, the illness, symptom, or disorder is anhedonia. As used herein, "anhedonia" refers to a significant reduction in interest or pleasure in all or almost all activities. Mild anhedonia is sometimes referred to as hypohedonia. Social anhedonia is a type of anhedonia. As used herein, "social anhedonia" refers to a lack of interest in social contact and a lack of pleasure in social situations. Social anhedonia is characterized by social withdrawal and is often manifested as indifference to social interactions with others. This trait is considered a core feature and predictor of schizophrenia spectrum disorders.

[0542] In another embodiment, this document provides the compounds disclosed herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, which are used as pharmaceuticals. In some embodiments, the pharmaceuticals are used to treat a subject for a disease, condition, or disorder associated with dysfunction of the Kv7 potassium channel (e.g., dysfunction of Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5, such as Kv7.2 / Kc7.3 dysfunction). In some embodiments, the pharmaceuticals are used to treat a subject for a seizure disorder, depression, pain, or anhedonia.

[0543] This document also provides a method for enhancing Kv7 potassium channels in in vitro cells, comprising contacting said cells with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or pharmaceutical composition thereof. In some embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In some embodiments, the Kv7 potassium channel is Kv7.2. In some embodiments, the Kv7 potassium channel is Kv7.3. In some embodiments, the Kv7 potassium channel is Kv7.2 / Kv7.3. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2-Kv7.5 than for Kv7.1. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2 / Kv7.3 than for Kv7.1.

[0544] This document provides a method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in subjects or in vitro cells. In some embodiments, the activity of Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% relative to a control. In some embodiments, the activity of Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) is increased by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, or at least 1000-fold relative to a control.

[0545] Additional implementation plan

[0546] Additional implementation plans are provided according to the following numbered implementation plans:

[0547] Implementation Scheme 1. A compound of formula (I):

[0548] (I),

[0549] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein:

[0550] X 1 It can be C or N;

[0551] Z 3 Z 4 and Z 6 Each independently for CR 4 , N, NR NS or O;

[0552] Z 5 For key, CR 4 , N, NR N S or O;

[0553] The condition is Z 3 Z 4 Z 5 and Z 6 At least one of them is N, NR N S or O, and Z 3 Z 4 Z 5 and Z 6 No more than one of them is S or O;

[0554] R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0555] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0556] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0557] R Y For H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0558] Z 1 and Z 2 Each independently for CR Z Or N;

[0559] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0560] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0561] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0562] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0563] m is 1 or 2;

[0564] n is 0, 1, or 2;

[0565] Each instance of R' is independently H, halogen, C1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O;

[0566] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently;

[0567] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0568] R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and

[0569] R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0570] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (I'):

[0571] (I'),

[0572] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0573] Implementation Scheme 3. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (I''):

[0574] (I′′),

[0575] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0576] Implementation Scheme 4. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia):

[0577] (Ia),

[0578] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0579] Implementation Scheme 5. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-1):

[0580] (Ia-1),

[0581] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0582] Implementation Scheme 6. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-2):

[0583] (Ia-2),

[0584] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0585] Implementation Scheme 7. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′):

[0586] (Ia′),

[0587] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0588] Implementation Scheme 8. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-1):

[0589] (Ia′-1),

[0590] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0591] Implementation Scheme 9. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-2):

[0592] (Ia′-2),

[0593] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0594] Implementation Scheme 10. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (I′′′):

[0595] (I′′′),

[0596] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0597] Implementation Scheme 11. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ib):

[0598] (Ib),

[0599] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0600] Implementation Scheme 12. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ib-1):

[0601] (Ib-1),

[0602] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0603] Implementation Scheme 13. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ib-2):

[0604] (Ib-2),

[0605] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0606] Implementation Scheme 14. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ic):

[0607] (Ic),

[0608] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0609] Implementation Scheme 15. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ic-1):

[0610] (Ic-1),

[0611] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0612] Implementation Scheme 16. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ic-2):

[0613] (Ic-2),

[0614] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0615] Implementation Scheme 17. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Id):

[0616] (Id),

[0617] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0618] Implementation Scheme 18. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Id-1):

[0619] (Id-1),

[0620] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0621] Implementation Scheme 19. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (1d-2):

[0622] (Id-2),

[0623] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0624] Implementation Scheme 20. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

[0625] Implementation Scheme 21. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

[0626] Implementation Scheme 22. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 2.

[0627] Implementation Scheme 23. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

[0628] Implementation Scheme 24. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C is arbitrarily replaced 1-6 alkyl.

[0629] Implementation Scheme 25. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For unreplaced C 1-3 alkyl.

[0630] Implementation Scheme 26. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 It is a methyl group.

[0631] Implementation Scheme 27. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 Halogen, C 1-6 Halogenated or -OR O .

[0632] Implementation Scheme 28. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 It can be F, Cl, -CF3 or -OMe.

[0633] Implementation Scheme 29. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted.

[0634] Implementation Scheme 30. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-5 Cycloalkyl or 3-5 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups are substituted.

[0635] Implementation Scheme 31. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for:

[0636] or .

[0637] Implementation Scheme 32. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For H.

[0638] Implementation Scheme 33. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

[0639] Implementation Scheme 34. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

[0640] Implementation Scheme 35. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

[0641] Implementation Scheme 36. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a halogen.

[0642] Implementation Scheme 37. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It can be F or Cl.

[0643] Implementation Scheme 38. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0644] Implementation Scheme 39. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0645] Implementation Scheme 40. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH(Me)-.

[0646] Implementation Scheme 41. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

[0647] Implementation Scheme 42. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 For unreplaced C 1-4 alkyl.

[0648] Implementation Scheme 43. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

[0649] Implementation Scheme 44. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0650] Implementation Scheme 45. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-8 Cycloalkyl.

[0651] Implementation Scheme 46. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl.

[0652] Implementation Scheme 47. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Selected from:

[0653] , , , , , , ,

[0654] , , and .

[0655] Implementation Scheme 48. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Optionally substituted 3-7 membered heterocyclic groups.

[0656] Implementation Scheme 49. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

[0657] Implementation Scheme 50. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 A C having one or two ring N atoms and optionally substituted with one or more halogens and / or unsubstituted C atoms. 1-6 Alkyl-substituted 3-6 membered heterocyclic groups.

[0658] Implementation Scheme 51. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for:

[0659] .

[0660] Implementation Scheme 52. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

[0661] Implementation Scheme 53. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

[0662] Implementation Scheme 54. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 Let N be the number of elements in the array.

[0663] Implementation Scheme 55. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2 For CR Z .

[0664] Implementation Scheme 56. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

[0665] Implementation Scheme 57. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CF.

[0666] Implementation Scheme 58. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 Let N be the number of elements in the array.

[0667] Implementation Scheme 59. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-6 Halogenated groups.

[0668] Implementation Scheme 60. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-3 Halogenated groups.

[0669] Implementation Scheme 61. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is a C1 haloalkyl group.

[0670] Implementation Scheme 62. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is -CF3.

[0671] Implementation Scheme 63. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4At least one instance is halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, or optionally substituted phenyl.

[0672] Implementation Scheme 64. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 Cycloalkyl, or unsubstituted phenyl.

[0673] Implementation Scheme 65. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is methyl, tert-butyl, Cl, cyclopropyl or phenyl.

[0674] Implementation Scheme 66. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

[0675] Implementation Scheme 67. The compound as described in Implementation Scheme 1, wherein the compound is selected from those in Tables 1A-1C, and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs.

[0676] Implementation Scheme 68. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof.

[0677] Implementation Scheme 69. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0678] Implementation Scheme 70. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0679] Implementation Scheme 71. A method for treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0680] Implementation Scheme 72. The method described in Implementation Scheme 70 or 71, wherein the method enhances the opening of Kv7 potassium channels.

[0681] Implementation Scheme 73. The method of any one of Implementation Schemes 70 to 72, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0682] Implementation Scheme 74. The method of any one of Implementation Schemes 70 to 73, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0683] Implementation Scheme 75. A method for treating a subject in need of epileptic seizures, depression, pain, or anhedonia, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0684] Implementation Scheme 76. The method of any one of Implementation Schemes 70 to 75, wherein the subject is a human being.

[0685] Implementation Scheme 77. The compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for enhancing Kv7 potassium channels in a subject.

[0686] Implementation Scheme 78. A compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

[0687] Implementation Scheme 79. The compound for use as described in Implementation Scheme 77 or 78, wherein the compound enhances the opening of Kv7 potassium channels.

[0688] Implementation Scheme 80. The compound for use as described in any one of Implementation Schemes 77 to 79, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0689] Implementation Scheme 81. The compound for use as described in any one of Implementation Schemes 77 to 80, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0690] Implementation Scheme 82. The compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with seizure disorders, depression, pain or anhedonia.

[0691] Implementation Scheme 83. The compound for use as described in any one of Implementation Schemes 77 to 82, wherein the subject is a human being.

[0692] Implementation Scheme 84. A compound as described in any one of Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a medicament.

[0693] Additional implementation schemes are provided according to the following numbered schemes.

[0694] Implementation Scheme 1. A compound of formula (I′′):

[0695] (I''),

[0696] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein:

[0697] Z 3 For N and Z 6 For S, or Z 3 For S and Z 6 Let N be the number of people in the group.

[0698] R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2RS1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0699] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0700] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0701] R Y For H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0702] Z 1 and Z 2 Each independently for CR Z Or N;

[0703] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0704] R 4 H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0705] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0706] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0707] m is 1 or 2;

[0708] n is 0, 1, or 2;

[0709] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or R' and R" attached to the same carbon atom together to form =O, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently;

[0710] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently;

[0711] R O Each instance is independently H, C 1-6 Alkyl, C1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0712] R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and

[0713] R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0714] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia):

[0715] (Ia),

[0716] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0717] Implementation Scheme 3. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-1):

[0718] (Ia-1),

[0719] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0720] Implementation Scheme 4. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-2):

[0721] (Ia-2),

[0722] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0723] Implementation Scheme 5. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-3):

[0724] (Ia-3),

[0725] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0726] Implementation Scheme 6. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-4):

[0727] (Ia-4),

[0728] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0729] Implementation Scheme 7. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′):

[0730] (Ia′),

[0731] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0732] Implementation Scheme 8. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-1):

[0733] (Ia′-1),

[0734] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0735] Implementation Scheme 9. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-2):

[0736] (Ia′-2),

[0737] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0738] Implementation Scheme 10. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-3):

[0739] (Ia′-3),

[0740] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0741] Implementation Scheme 11. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-4):

[0742] (Ia′-4),

[0743] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0744] Implementation Scheme 12. A compound of formula (Ib):

[0745] (Ib),

[0746] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein:

[0747] R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0748] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0749] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0750] R Y For H, C 1-6 Alkyl, C3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0751] Z 1 and Z 2 Each independently for CR Z Or N;

[0752] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0753] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0754] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0755] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0756] m is 1 or 2;

[0757] n is 0, 1, or 2;

[0758] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or R' and R" attached to the same carbon atom together to form =O, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently;

[0759] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently;

[0760] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0761] R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and

[0762] R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0763] Implementation Scheme 13. The compound as described in Implementation Scheme 12, wherein the compound is a compound of formula (Ib-1):

[0764] (Ib-1),

[0765] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0766] Implementation Scheme 14. The compound as described in Implementation Scheme 12, wherein the compound is a compound of formula (Ib-2):

[0767] (Ib-2),

[0768] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0769] Implementation Scheme 15. The compound as described in Implementation Scheme 12, wherein the compound is a compound of formula (Ib-3):

[0770] (Ib-3),

[0771] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0772] Implementation Scheme 16. The compound as described in Implementation Scheme 12, wherein the compound is a compound of formula (Ib-4):

[0773] (Ib-4),

[0774] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0775] Implementation Scheme 17. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

[0776] Implementation Scheme 18. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

[0777] Implementation Scheme 19. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1 and n is 1.

[0778] Implementation Scheme 20. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 2.

[0779] Implementation Scheme 21. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1 and n is 2.

[0780] Implementation Scheme 22. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

[0781] Implementation Scheme 23. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1, n is 1, and R N1 For H.

[0782] Implementation Scheme 24. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C is arbitrarily replaced 1-6 alkyl.

[0783] Implementation Scheme 25. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For unreplaced C 1-3 alkyl.

[0784] Implementation Scheme 26. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 It is a methyl group.

[0785] Implementation Scheme 27. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1Halogen, C 1-6 Halogenated or -OR O .

[0786] Implementation Scheme 28. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 It can be F, Cl, -CF3 or -OMe.

[0787] Implementation Scheme 29. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted.

[0788] Implementation Scheme 30. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-5 Cycloalkyl or 3-5 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups are substituted.

[0789] Implementation Scheme 31. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for:

[0790] or .

[0791] Implementation Scheme 32. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For H.

[0792] Implementation Scheme 33. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

[0793] Implementation Scheme 34. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

[0794] Implementation Scheme 35. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

[0795] Implementation Scheme 36. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a halogen.

[0796] Implementation Scheme 37. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It can be F or Cl.

[0797] Implementation Scheme 38. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0798] Implementation Scheme 39. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0799] Implementation Scheme 40. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH(Me)-.

[0800] Implementation Scheme 41. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

[0801] Implementation Scheme 42. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3For unreplaced C 1-4 alkyl.

[0802] Implementation Scheme 43. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

[0803] Implementation Scheme 44. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0804] Implementation Scheme 45. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-8 Cycloalkyl.

[0805] Implementation Scheme 46. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl.

[0806] Implementation Scheme 47. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Selected from:

[0807] , , , , , , ,

[0808] , , and .

[0809] Implementation Scheme 48. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3Optionally substituted 3-7 membered heterocyclic groups.

[0810] Implementation Scheme 49. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

[0811] Implementation Scheme 50. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 A C having one or two ring N atoms and optionally substituted with one or more halogens and / or unsubstituted C atoms. 1-6 Alkyl-substituted 3-6 membered heterocyclic groups.

[0812] Implementation Scheme 51. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for:

[0813] or .

[0814] Implementation Scheme 52. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

[0815] Implementation Scheme 53. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

[0816] Implementation Scheme 54. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 Let N be the number of elements in the array.

[0817] Implementation Scheme 55. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CR Z .

[0818] Implementation Scheme 56. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

[0819] Implementation Scheme 57. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CF.

[0820] Implementation Scheme 58. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 Let N be the number of elements in the array.

[0821] Implementation Scheme 59. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-6 Halogenated groups.

[0822] Implementation Scheme 60. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-3 Halogenated groups.

[0823] Implementation Scheme 61. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is a C1 haloalkyl group.

[0824] Implementation Scheme 62. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is -CF3.

[0825] Implementation Scheme 63. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-7Cycloalkyl or optionally substituted phenyl groups.

[0826] Implementation Scheme 64. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 Cycloalkyl or unsubstituted phenyl groups.

[0827] Implementation Scheme 65. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is methyl, tert-butyl, Cl, cyclopropyl or phenyl.

[0828] Implementation Scheme 66. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

[0829] Implementation Scheme 67. A compound selected from those compounds in Tables 1A-1C, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof.

[0830] Implementation Scheme 68. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof.

[0831] Implementation Scheme 69. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0832] Implementation Scheme 70. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0833] Implementation Scheme 71. A method for treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0834] Implementation Scheme 72. The method as described in Implementation Scheme 70 or 71, wherein the method enhances the opening of Kv7 potassium channels.

[0835] Implementation Scheme 73. The method of any one of Implementation Schemes 70 to 72, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0836] Implementation Scheme 74. The method of any one of Implementation Schemes 70 to 73, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0837] Implementation Scheme 75. A method for treating a subject in need of epileptic seizures, depression, pain, or anhedonia, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0838] Implementation Scheme 76. The method of any one of Implementation Schemes 70 to 75, wherein the subject is a human being.

[0839] Implementation Scheme 77. The compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for enhancing Kv7 potassium channels in a subject.

[0840] Implementation Scheme 78. A compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

[0841] Implementation Scheme 79. The compound for use as described in Implementation Scheme 77 or 78, wherein the compound enhances the opening of Kv7 potassium channels.

[0842] Implementation Scheme 80. The compound for use as described in any one of Implementation Schemes 77 to 79, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0843] Implementation Scheme 81. The compound for use as described in any one of Implementation Schemes 77 to 80, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0844] Implementation Scheme 82. The compound of any one of Implementation Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with seizure disorders, depression, pain or anhedonia.

[0845] Implementation Scheme 83. The compound for use as described in any one of Implementation Schemes 77 to 82, wherein the subject is a human being.

[0846] Implementation Scheme 84. A compound as described in any one of Schemes 1 to 68, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a medicament.

[0847] Additional implementation schemes are provided according to the following numbered schemes.

[0848] Implementation Scheme 1. A compound of formula (I′′):

[0849] (I''),

[0850] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein:

[0851] Z 3 For N and Z 6 For S,

[0852] Z 3 For S and Z 6 Let N be the number of people in the group.

[0853] Z 3 For N and Z 6 For O, or

[0854] Z 3 For O and Z 6 Let N be the number of people in the group.

[0855] R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0856] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0857] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0858] R Y For H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0859] Z 1 and Z 2 Each independently for CR Z Or N;

[0860] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0861] R 4 H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0862] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0863] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0864] m is 1 or 2;

[0865] n is 0, 1, or 2;

[0866] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same nitrogen atom bond together with intercalation atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or R' and R” attached to the same nitrogen atom together to form =O, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently;

[0867] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently;

[0868] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0869] R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and

[0870] R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0871] Implementation Scheme 2. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 3 For N and Z 6 For S, or Z 3 For S and Z 6 Let N be the number of elements in the array.

[0872] Implementation Scheme 3. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia):

[0873] (Ia),

[0874] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0875] Implementation Scheme 4. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-1):

[0876] (Ia-1),

[0877] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0878] Implementation Scheme 5. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-2):

[0879] (Ia-2),

[0880] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0881] Implementation Scheme 6. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-3):

[0882] (Ia-3),

[0883] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0884] Implementation Scheme 7. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia-4):

[0885] (Ia-4),

[0886] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0887] Implementation Scheme 8. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′):

[0888] (Ia′),

[0889] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0890] Implementation Scheme 9. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-1):

[0891] (Ia′-1),

[0892] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0893] Implementation Scheme 10. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-2):

[0894] (Ia′-2),

[0895] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0896] Implementation Scheme 11. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-3):

[0897] (Ia′-3),

[0898] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0899] Implementation Scheme 12. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia′-4):

[0900] (Ia′-4),

[0901] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0902] Implementation Scheme 13. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (If):

[0903] (If),

[0904] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0905] Implementation Scheme 14. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (If-1):

[0906] (If-1),

[0907] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0908] Implementation Scheme 15. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (If-2):

[0909] (If-2),

[0910] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0911] Implementation Scheme 16. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (If-3):

[0912] (If-3),

[0913] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0914] Implementation Scheme 17. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (If-4):

[0915] (If-4),

[0916] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0917] Implementation Scheme 18. A compound of formula (Ib):

[0918] (Ib),

[0919] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein:

[0920] R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0921] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0922] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0923] R YFor H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0924] Z 1 and Z 2 Each independently for CR Z Or N;

[0925] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0926] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0927] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0928] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0929] m is 1 or 2;

[0930] n is 0, 1, or 2;

[0931] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or R' and R" attached to the same carbon atom together to form =O, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently;

[0932] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently;

[0933] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0934] R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and

[0935] R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0936] Implementation Scheme 19. The compound as described in Implementation Scheme 18, wherein the compound is a compound of formula (Ib-1):

[0937] (Ib-1),

[0938] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0939] Implementation Scheme 20. The compound as described in Implementation Scheme 18, wherein the compound is a compound of formula (Ib-2):

[0940] (Ib-2),

[0941] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0942] Implementation Scheme 21. The compound as described in Implementation Scheme 18, wherein the compound is a compound of formula (Ib-3):

[0943] (Ib-3),

[0944] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0945] Implementation Scheme 22. The compound as described in Implementation Scheme 18, wherein the compound is a compound of formula (Ib-4):

[0946] (Ib-4),

[0947] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0948] Implementation Scheme 23. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

[0949] Implementation Scheme 24. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

[0950] Implementation Scheme 25. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1 and n is 1.

[0951] Implementation Scheme 26. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 2.

[0952] Implementation Scheme 27. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1 and n is 2.

[0953] Implementation Scheme 28. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

[0954] Implementation Scheme 29. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1, n is 1, and R N1 For H.

[0955] Implementation Scheme 30. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C is arbitrarily replaced 1-6 alkyl.

[0956] Implementation Scheme 31. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For unreplaced C 1-3 alkyl.

[0957] Implementation Scheme 32. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 It is a methyl group.

[0958] Implementation Scheme 33. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1Halogen, C 1-6 Halogenated groups, -OR O -CN, -SR S or -S(=O)2R S1 .

[0959] Implementation Scheme 34. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For F, Cl, -CF3, -OMe, -OCF3, -CN, -SMe or -S(=O)2Me.

[0960] Implementation Scheme 35. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted.

[0961] Implementation Scheme 36. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-5 Cycloalkyl or 3-5 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups are substituted.

[0962] Implementation Scheme 37. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for:

[0963] , or .

[0964] Implementation Scheme 38. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For H.

[0965] Implementation Scheme 39. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

[0966] Implementation Scheme 40. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

[0967] Implementation Scheme 41. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

[0968] Implementation Scheme 42. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 Halogen or -OR O .

[0969] Implementation Scheme 43. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It can be F, Cl, or -OMe.

[0970] Implementation Scheme 44. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0971] Implementation Scheme 45. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0972] Implementation Scheme 46. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH(Me)-.

[0973] Implementation Scheme 47. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

[0974] Implementation Scheme 48. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 For unreplaced C 1-4 alkyl.

[0975] Implementation Scheme 49. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

[0976] Implementation Scheme 50. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0977] Implementation Scheme 51. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-8 Cycloalkyl.

[0978] Implementation Scheme 52. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl.

[0979] Implementation Scheme 53. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Selected from:

[0980] , , , , , , ,

[0981] , , , and .

[0982] Implementation Scheme 54. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Optionally substituted 3-7 membered heterocyclic groups.

[0983] Implementation Scheme 55. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

[0984] Implementation Scheme 56. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 A C having one or two ring N atoms and optionally substituted with one or more halogens and / or unsubstituted C atoms. 1-6 Alkyl-substituted 3-6 membered heterocyclic groups.

[0985] Implementation Scheme 57. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for:

[0986] or .

[0987] Implementation Scheme 58. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 6-10 Aryl.

[0988] Implementation Scheme 59. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 The phenyl group is optionally substituted.

[0989] Implementation Scheme 60. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with phenyl groups.

[0990] Implementation Scheme 61. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Selected from:

[0991] , , , and .

[0992] Implementation Scheme 62. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

[0993] Implementation Scheme 63. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

[0994] Implementation Scheme 64. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 It is CCl.

[0995] Implementation Scheme 65. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 Let N be the number of elements in the array.

[0996] Implementation Scheme 66. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CR Z .

[0997] Implementation Scheme 67. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

[0998] Implementation Scheme 68. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z2 For CF.

[0999] Implementation Scheme 69. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 Let N be the number of elements in the array.

[1000] Implementation Scheme 70. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-6 Halogenated groups.

[1001] Implementation Scheme 71. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-3 Halogenated groups.

[1002] Implementation Scheme 72. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is a C1 haloalkyl group.

[1003] Implementation Scheme 73. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is -CF3.

[1004] Implementation Scheme 74. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is -CF2H.

[1005] Implementation Scheme 75. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl or optionally substituted phenyl groups.

[1006] Implementation Scheme 76. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 Cycloalkyl or unsubstituted phenyl groups.

[1007] Implementation Scheme 77. The compound as described in any of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is methyl, tert-butyl, Cl, cyclopropyl or phenyl.

[1008] Implementation Scheme 78. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of H is H.

[1009] Implementation Scheme 79. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

[1010] Implementation Scheme 80. A compound selected from Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof.

[1011] Implementation Scheme 81. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof.

[1012] Implementation Scheme 82. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[1013] Implementation Scheme 83. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[1014] Implementation Scheme 84. A method for treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[1015] Implementation Scheme 85. The method as described in Implementation Scheme 83 or 84, wherein the method enhances the opening of Kv7 potassium channels.

[1016] Implementation Scheme 86. The method of any one of Implementation Schemes 83 to 85, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[1017] Implementation Scheme 87. The method of any one of Implementation Schemes 83 to 86, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[1018] Implementation Scheme 88. A method for treating a subject with epileptic seizure disorder, depression, pain, or anhedonia, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[1019] Implementation Scheme 89. The method of any one of Implementation Schemes 83 to 88, wherein the subject is a human being.

[1020] Implementation Scheme 90. The compound of any one of Implementation Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for enhancing Kv7 potassium channels in a subject.

[1021] Implementation Scheme 91. The compound of any one of Implementation Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

[1022] Implementation Scheme 92. The compound for use as described in Implementation Scheme 90 or 91, wherein the compound enhances the opening of Kv7 potassium channels.

[1023] Implementation Scheme 93. The compound for use as described in any one of Implementation Schemes 90 to 92, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[1024] Implementation Scheme 94. The compound for use as described in any one of Implementation Schemes 90 to 93, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[1025] Implementation Scheme 95. The compound of any one of Implementation Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with seizure disorders, depression, pain or anhedonia.

[1026] Implementation Scheme 96. The compound for use as described in any one of Implementation Schemes 90 to 95, wherein the subject is a human being.

[1027] Implementation Scheme 97. A compound as described in any one of Schemes 1 to 81, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a medicament.

[1028] Example

[1029] To provide a fuller understanding of this disclosure, the following embodiments are illustrated. The synthetic and biological embodiments described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[1030] The examples provided below include procedures, intermediates, and characterization data that can be used, for example, to prepare the compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc., are included herein as aspects of this disclosure.

[1031] Compound Synthesis

[1032] Example 1. N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)phenyl)-3,3-dimethylbutyramide

[1033]

[1034] Step 1. Preparation of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide

[1035]

[1036] N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide was prepared according to the procedure described on page 52 of WO 2008 / 024398.

[1037] Step 2. Preparation of tert-butyl 3-(4-(3,3-dimethylbutyrylamino)-3,5-dimethylphenyl)azacyclobutane-1-carboxylate

[1038]

[1039] To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide (0.050 g, 0.168 mmol) and 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (0.049 g, 0.201 mmol, hydrochloride) in dioxane (1 mL), potassium tert-butoxide (0.075 g, 0.671 mmol), 2-(2-di-tert-butylphosphoalkylphenyl)-N,N-dimethylaniline (0.026 g, 0.067 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.031 g, 0.034 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% B for 10 min). The desired fraction was collected and lyophilized to give 0.014 g of N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)phenyl)-3,3-dimethylbutyramide (18% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 6.75 (s, 2H), 4.61(s, 2H), 3.68 (t, J = 5.6 Hz, 2H), 2.92 (t, J = 5.2 Hz, 2H), 2.16 (s, 2H), 2.09 (s, 6H), 1.04 (s, 9H); MS (ES+) m / z 462.2 (M+1).

[1040] The following other examples were prepared similarly to Example 1 (as described above), with appropriate starting materials substituted where necessary and experimental conditions appropriately modified according to common knowledge. Purification was performed by silica gel chromatography, reversed-phase preparative HPLC, or supercritical fluid chromatography (SFC).

[1041]

[1042]

[1043] a Examples 18a and 18b are individual enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.

[1044] b Examples 19a and 19b are individual enantiomers with unknown absolute stereochemistry. The absolute stereochemistry of each has been arbitrarily defined.

[1045] Example 24. 3,3-Dimethyl-N-(4-methyl-2-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrimidin-5-yl)butyramide

[1046]

[1047] Step 1. Preparation of N-(2-chloro-4-methylpyrimidin-5-yl)-3,3-dimethylbutyramide

[1048]

[1049] Pyridine (7.44 g, 94.00 mmol) and 3,3-dimethylbutyryl chloride (4.22 g, 31.30 mmol) were added to a cold (0 °C) solution of 2-chloro-4-methylpyrimidin-5-amine (4.50 g, 31.30 mmol) in dichloromethane (50.0 mL). The mixture was stirred at 15 °C for 2 h. Water (100 mL) was added to the mixture, and the mixture was then extracted with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (100 mL), 1M hydrochloric acid (100 mL), and brine (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g SepaFlash® Silica Flash Column, 0–55% ethyl acetate / petroleum ether eluent gradient, 150 mL / min). The desired fraction was collected and concentrated under vacuum to give 4.0 g of N-(2-chloro-4-methylpyrimidin-5-yl)-3,3-dimethylbutyramide as a crude white solid, which can be used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s,1H), 8.76 (s, 1H), 2.43 (s, 3H), 2.29 (s, 2H), 1.04 (s, 9H).

[1050] Step 2. Preparation of 3,3-dimethyl-N-(4-methyl-2-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrimidin-5-yl)butyramide

[1051]

[1052] A mixture of N-(2-chloro-4-methylpyrimidin-5-yl)-3,3-dimethylbutyramide (0.030 g, 0.124 mmol), 2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.028 g, 0.124 mmol, hydrochloride), and N,N-diisopropylethylamine (0.080 g, 0.621 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 120 °C for 12 h. The reaction mixture was cooled to room temperature. The mixture was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 45%–75%, B, duration 10 min). The desired fraction was collected and lyophilized to give 0.016 g of 3,3-dimethyl-N-(4-methyl-2-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrimidin-5-yl)butyramide as a white solid (32% yield): 1 H NMR (400 MHz, CDCl3) δ 8.26(s, 1H), 6.57 (s, 1H), 6.31 (s, 1H), 4.95 (s, 2H), 4.41–4.07 (m, 4H), 2.28(s, 3H), 2.19 (s, 2H), 1.05 (s, 9H); MS (ES+) m / z 397.2 (M + 1).

[1053] Example 25. N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)-2-hydroxy-2,3,3-trimethylbutyramide

[1054]

[1055] Step 1. Preparation of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-2-oxobutyramide

[1056]

[1057] N,N-diisopropylethylamine (12.4 g, 96.1 mmol) and 2-chloro-1-methylpyridinium iodide (12.3 g, 48.0 mmol) were added to a solution of 3,3-dimethyl-2-oxobutyric acid (5.0 g, 38.4 mmol) in tetrahydrofuran (50 mL). The mixture was stirred at 25 °C for 1 h. 4-Bromo-2,6-dimethylaniline (6.41 g, 32.0 mmol) was added and the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1). The desired fraction was collected under reduced pressure to give 5.7 g of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-2-oxobutyramide (57% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s,1H), 7.34 (s, 2H), 2.14 (s, 6H), 1.28 (s, 9H).

[1058] Step 2. Preparation of (+ / -)N-(4-bromo-2,6-dimethylphenyl)-2-hydroxy-2,3,3-trimethyl-butyramide

[1059]

[1060] Thiophene-2-yl magnesium bromide (3 M in diethyl ether, 16 mL) was added to a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-2-oxobutyramide (3.00 g, 9.61 mmol) in tetrahydrofuran (30 mL) under nitrogen atmosphere and at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was quenched with saturated ammonium chloride (20 mL). Water (30 mL) was added to the mixture, and the mixture was then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (40 g SepaFlash® Silica Flash Column, 0-40% ethyl acetate / petroleum ether eluent gradient, 100 mL / min) to give 1.70 g of racemic N-(4-bromo-2,6-dimethyl-phenyl)-2-hydroxy-2,3,3-trimethyl-butyramide as a yellow solid (43% yield).1 H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.22 (s, 2H), 2.20 (s, 6H), 1.51 (s, 3H), 1.12 (s, 9H).

[1061] Step 2. Preparation of (+ / -)N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)-2-hydroxy-2,3,3-trimethylbutyramide

[1062]

[1063] A solution of racemic N-(4-bromo-2,6-dimethylphenyl)-2-hydroxy-2,3,3-trimethylbutanamide (0.050 g, 0.152 mmol) and 2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.045 g, 0.198 mmol hydrochloride) in dioxane (1 mL) was supplemented with potassium tert-butoxide (0.051 g, 0.457 mmol), 2-(2-di-tert-butylphosphoalkylphenyl)-N,N-dimethylaniline (0.012 g, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.056 g, 0.061 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 48%-78% B, duration: 10 min). The desired fraction was collected and lyophilized to give 0.015 g of racemic N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)phenyl)-2-hydroxy-2,3,3-trimethylbutyramide (49% yield) as a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ 8.05 (s, 1H), 6.71 (s, 2H), 6.37 (s, 1H), 4.41 (s, 2H), 4.37–4.30 (m, 2H), 3.72 (t, J = 5.4 Hz, 2H), 2.24 (s, 6H), 1.54 (s, 3H), 1.15 (s,9H); MS (ES+) m / z 439.2 (M+1).

[1064] Example 26. N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazo[4,5-c]pyridin-5(4H)-yl)phenyl)-3,3-dimethylbutyramide

[1065]

[1066] Step 1. Preparation of tert-butyl 2-(trifluoromethyl)-6,7-dihydrothiazo[4,5-c]pyridine-5(4H)-carboxylate

[1067]

[1068] A mixture of tert-butyl 2-bromo-6,7-dihydrothiazo[4,5-c]pyridine-5(4H)-carboxylate (0.200 g, 0.627 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.241 g, 1.25 mmol), and copper iodide (I) (0.240 g, 1.26 mmol) in dimethylformamide (6.0 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water (10 mL) was added to the mixture, and the mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (formic acid) – acetonitrile]; gradient: 54%–84% B, duration: 10 min). The desired fraction was collected and concentrated under reduced pressure to remove acetonitrile. The mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 0.086 g of tert-butyl 2-(trifluoromethyl)-6,7-dihydrothiazo[4,5-c]pyridine-5(4H)-carboxylate (45% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.75–4.65 (m, 2H), 3.85–3.75 (m, 2H), 3.00–2.90 (m, 2H), 1.50 (s, 9H).

[1069] Step 2. Preparation of 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazo[4,5-c]pyridine

[1070]

[1071] Acetyl chloride (0.109 g, 1.390 mmol) was added to a solution of 0.086 g (0.279 mmol) of 2-(trifluoromethyl)-6,7-dihydrothiazo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (2.0 mL) in methanol at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 0.065 g of 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazo[4,5-c]pyridine (95% yield, hydrochloride) as a yellow solid. 1 H NMR (400 MHz, MeOD-d4)δ 4.50–4.46 (m, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.30–3.29 (m, 2H).

[1072] Step 3. Preparation of N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazo[4,5-c]pyridin-5(4H)-yl)phenyl)-3,3-dimethylbutyramide

[1073]

[1074] Under nitrogen atmosphere, potassium tert-butoxide (0.100 g, 0.891 mmol), 2-(2-di-tert-butylphosphophenyl)-N,N-dimethylaniline (0.018 g, 0.046 mmol), and tris(dibenzylacetone)dipalladium(0) (0.021 g, 0.023 mmol) were added to a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.066 g, 0.221 mol) and 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazo[4,5-c]pyridine (0.065 g, 0.266 mmol, hydrochloride) in dioxane (4.0 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (fo...

Claims

1. A compound of formula (I′′): (I′′)， Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein: Z 3 For N and Z 6 For S, Z 3 For S and Z 6 Let N be the number of people in the group. Z 3 For N and Z 6 For O, or Z 3 For O and Z 6 Let N be the number of people in the group. R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted; Y represents a key, -CR'R"-, -O-, or -NR. Y -; R Y For H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted; Z 1 and Z 2 Each independently for CR Z Or N; R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 4 H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently; When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 1 or 2; n is 0, 1, or 2; Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or R' and R" attached to the same carbon atom together to form =O, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently; R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently; R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently; R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 3 For N and Z 6 For S, or Z 3 For S and Z 6 Let N be the number of elements in the array.

3. The compound of claim 1, wherein the compound is a compound of formula (Ia): (I-a), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

4. The compound of claim 1, wherein the compound is a compound of formula (Ia-1): (I-a-1), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

5. The compound of claim 1, wherein the compound is a compound of formula (Ia-2): (I-a-2), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

6. The compound of claim 1, wherein the compound is a compound of formula (Ia-2-i): (I-a-2-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

7. The compound of claim 1, wherein the compound is a compound of formula (Ia-2-ii): (Ia-2-ii), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

8. The compound of claim 1, wherein the compound is a compound of formula (Ia-3): (I-a-3), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

9. The compound of claim 1, wherein the compound is a compound of formula (Ia-3-i): (I-a-3-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

10. The compound of claim 1, wherein the compound is a compound of formula (Ia-4): (I-a-4), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

11. The compound of claim 1, wherein the compound is a compound of formula (Ia-4-i): (I-a-4-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

12. The compound of claim 1, wherein the compound is a compound of formula (Ia-5): (I-a-5), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

13. The compound of claim 1, wherein the compound is a compound of formula (Ia-6): (I-a-6), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

14. The compound of claim 1, wherein the compound is a compound of formula (Ia-7): (I-a-7), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

15. The compound of claim 1, wherein the compound is a compound of formula (Ia-8): (I-a-8), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

16. The compound of claim 1, wherein the compound is a compound of formula (Ia-9): (I-a-9), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

17. The compound of claim 1, wherein the compound is a compound of formula (Ia-10): (I-a-10), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

18. The compound of claim 1, wherein the compound is a compound of formula (Ia′): (I-a′), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

19. The compound of claim 1, wherein the compound is a compound of formula (Ia′-1): (I-a′-1), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

20. The compound of claim 1, wherein the compound is a compound of formula (Ia′-2): (I-a′-2), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

21. The compound of claim 1, wherein the compound is a compound of formula (Ia′-2-i): (I-a′-2-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

22. The compound of claim 1, wherein the compound is a compound of formula (Ia′-2-ii): (Ia′-2-ii), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

23. The compound of claim 1, wherein the compound is a compound of formula (Ia′-3): (I-a′-3), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

24. The compound of claim 1, wherein the compound is a compound of formula (Ia′-4): (I-a′-4), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

25. The compound of claim 1, wherein the compound is a compound of formula (If): (I-f), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

26. The compound of claim 1, wherein the compound is a compound of formula (If-1): (I-f-1), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

27. The compound of claim 1, wherein the compound is a compound of formula (If-2): (I-f-2), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

28. The compound of claim 1, wherein the compound is a compound of formula (If-2-i): (I-f-2-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

29. The compound of claim 1, wherein the compound is a compound of formula (If-2-ii): (If-2-ii), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

30. The compound of claim 1, wherein the compound is a compound of formula (If-3): (I-f-3), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

31. The compound of claim 1, wherein the compound is a compound of formula (If-3-i): (I-f-3-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

32. The compound of claim 1, wherein the compound is a compound of formula (If-4): (I-f-4), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

33. The compound of claim 1, wherein the compound is a compound of formula (If-5): (I-f-5), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

34. The compound of claim 1, wherein the compound is a compound of formula (If-6): (I-f-6), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

35. The compound of claim 1, wherein the compound is a compound of formula (Ig): (I-g), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

36. The compound of claim 1, wherein the compound is a compound of formula (Ig-1): (I-g-1), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

37. The compound of claim 1, wherein the compound is a compound of formula (Ig-2): (I-g-2), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

38. The compound of claim 1, wherein the compound is a compound of formula (Ig-2-i): (I-g-2-i), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

39. The compound of claim 1, wherein the compound is a compound of formula (Ig-2-ii): (Ig-2-ii), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

40. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

41. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

42. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1 and n is 1.

43. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 2.

44. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1 and n is 2.

45. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

46. ​​The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1, n is 1, and R N1 For H.

47. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C is arbitrarily replaced 1-6 alkyl.

48. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For unreplaced C 1-3 alkyl.

49. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 It is a methyl group.

50. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 Halogen, C 1-6 Halogenated groups, -OR O -CN, -SR S or -S(=O)2R S1 .

51. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For F, Cl, -CF3, -OMe, -OCF3, -CN, -SMe or -S(=O)2Me.

52. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted.

53. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-5 Cycloalkyl or 3-5 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups are substituted.

54. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for: , or .

55. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For H.

56. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

57. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

58. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

59. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 Halogen or -OR O .

60. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It can be F, Cl, or -OMe.

61. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

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

63. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug thereof, wherein Y is -CH(Me)-.

64. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

65. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 For unreplaced C 1-4 alkyl.

66. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

67. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C can be optionally replaced by one or more Fs 1-4 alkyl.

68. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is -CH2CF3.

69. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

70. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-8 Cycloalkyl.

71. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl.

72. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Selected from: 、 、 、 、 、 、 、 , , , and .

73. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Optionally substituted 3-7 membered heterocyclic groups.

74. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

75. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 A C having one or two ring N atoms and optionally substituted with one or more halogens and / or unsubstituted C atoms. 1-6 Alkyl-substituted 3-6 membered heterocyclic groups.

76. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for: or .

77. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 6-10 Aryl.

78. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 The phenyl group is optionally substituted.

79. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with phenyl groups.

80. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Selected from: , , , and .

81. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

82. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

83. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 It is CCl.

84. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 Let N be the number of elements in the array.

85. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CR Z .

86. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

87. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CF.

88. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 Let N be the number of elements in the array.

89. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-6 Halogenated groups.

90. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of C is 1-3 Halogenated groups.

91. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is a C1 haloalkyl group.

92. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is -CF3.

93. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is -CF2H.

94. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl or optionally substituted phenyl groups.

95. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 Cycloalkyl or unsubstituted phenyl groups.

96. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one example is methyl, tert-butyl, Cl, cyclopropyl or phenyl.

97. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of H is H.

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

99. A compound selected from Table 1B, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates and prodrugs thereof.

100. A compound of formula (I): (I)， Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein: X 1 It can be C or N; Z 3 Z 4 and Z 6 Each independently for CR 4 , N, NR N S or O; Z 5 For key, CR 4 , N, NR N S or O; The condition is Z 3 Z 4 Z 5 and Z 6 At least one of them is N, NR N S or O, and Z 3 Z 4 Z 5 and Z 6 No more than one of them is S or O; R 1 and R 2 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2、-SR S -S(=O)2R S1 Or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted; Y represents a key, -CR'R"-, -O-, or -NR. Y -; R Y For H, C 1-6 Alkyl, C 3-7 Cycloalkyl or nitrogen protecting group, or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted; Z 1 and Z 2 Each independently for CR Z Or N; R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently; When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 1 or 2; n is 0, 1, or 2; Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O; R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently; R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 Acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently; R S Each instance is independently H, C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 An acyl or thioprotective group, wherein each alkyl, cycloalkyl, heterocyclic, or acyl group is optionally substituted independently; and R S1 Each instance is independently for C 1-6 Alkyl, C 1-6 Halogenated, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

101. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

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

103. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

104. A method of treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

105. The method of claim 103 or 104, wherein the method enhances the opening of Kv7 potassium channels.

106. The method of any one of claims 103 to 105, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.

5.

107. The method of any one of claims 103 to 106, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

108. A method of treating a subject with epileptic seizure disorder, depression, pain, or anhedonia, comprising administering to the subject any of the compounds of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

109. The method of any one of claims 103 to 108, wherein the subject is a person.

110. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for enhancing Kv7 potassium channels in a subject.

111. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

112. The compound for use as claimed in claim 110 or 111, wherein the compound enhances the opening of Kv7 potassium channels.

113. The compound for use according to any one of claims 110 to 112, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.

5.

114. The compound for use according to any one of claims 110 to 113, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

115. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with epileptic seizures, depression, pain or anhedonia.

116. The compound for use as claimed in any one of claims 110 to 115, wherein the subject is a human being.

117. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a medicament.

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