Heteroarylamine compounds and their use

Abstract

Compounds comprising any of the formulas described herein (e.g., formula (I), e.g., formula (I")), as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotope-labeled derivatives, and prodrugs thereof, are provided herein. The compounds provided herein can act as enhancers of voltage-gated potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3), and are therefore useful for the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). TIFF2026528960000331.tif53165

Description

[Technical Field]

[0001] Related applications This application claims priority under U.S. Provisional Patent Application, USSN 63 / 520,171, filed 17 August 2023, and U.S.SN 63 / 567,980, filed 21 March 2024, in accordance with Section 119(e) of the U.S. Patent Act, the entire contents of each of these applications are incorporated herein by reference. [Background technology]

[0002] Voltage-gated potassium channels, including the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), are crucial for regulating neuronal excitability. Kv7.2 / Kv7.3 underlie the neuronal "M-current," originally characterized as a neuronal current that decreases in response to muscarinic / choline agonists (see Brown, DA et al., Nature (1980), 283:673-676). The M-current is a hyperpolarizing current accompanied by inactivation, known to act as a brake on neuronal hyperexcitability. Therefore, a decrease in Kv7.2-mediated M-current due to, for example, genetic loss of function, can lead to neuronal depolarization and increased membrane and neuronal excitability, which can result in action potential bursts, for example, manifesting as epileptic seizures. In contrast, an increase in Kv7.2-mediated M-current can hyperpolarize the cell membrane, thereby reducing neuronal excitability and preventing the initiation and propagation of action potential bursts and the resulting seizures. Enhancing the open state of the Kv7.2 / Kv7.3 channels in neurons promotes hyperpolarized resting states, thereby reducing rapid action potential spiking (i.e., burst firing). Such enhancement can provide a stabilizing effect to excitatory neurons, particularly hyperexcitatory neurons, and may therefore be useful in treating certain seizure disorders. This enhancement has been clinically proven effective in treating seizure disorders, such as partially originating seizures, in adults with epilepsy using the known Kv7.2 / Kv7.3 enhancer, retigabine (ezogabine).

[0003] While significant progress has been made in this field, there is still a substantial need for improved compounds and methods to enhance voltage-gated potassium channels, including the voltage-gated potassium channel Kv7.2 / Kv7.3. Such compounds and methods can be used to treat diseases, disorders, and conditions involving potassium channel dysfunction. [Overview of the project]

[0004] Compounds comprising any of the compounds of the formulas (e.g., formula (I)) described herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs are provided herein. The compounds provided herein can act as enhancers of voltage-dependent potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3), and thus are useful for the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits containing the same. Further, the present disclosure provides methods for preparing the compounds, pharmaceutical compositions, and intermediates useful therefor described herein.

[0005] In one aspect, a compound of formula (I):

Chemical Structure

[0006] In certain embodiments, the compound of formula (I) is a compound of formula (I”):

Chemical Structure

[0007] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0008] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0009] In a particular embodiment, the compound of formula (I) is the compound of formula (If): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0010] In certain embodiments, for example, the compounds disclosed herein are selected from those listed in Tables 1A to 1C (below), as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs.

[0011] In another embodiment, this specification provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, the pharmaceutical composition provided herein comprises an effective amount (e.g., a therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0012] 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 useful for the treatment and / or prevention of diseases, disorders, and conditions in subjects, including indications involving, for example, Kv7 potassium channel dysfunction.

[0013] In other embodiments, methods and uses of the compounds and pharmaceutical compositions provided herein are provided, including but not limited to: (a) A method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, to the subject. (b) A method for treating a disease, disorder, or condition in which Kv7 potassium channel (e.g., Kv7.2 / Kv7.3) dysfunction is required, comprising administering to the subject one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof. (c) A method for treating a subject in need of treatment for a paroxysmal disorder, depressive disorder, pain, or anhedonia, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, to the subject. (d) A method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in cells in vitro, comprising contacting cells with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0014] In another embodiment, this specification provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In another embodiment, this specification provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use as pharmaceuticals and / or in the preparation of pharmaceuticals.

[0015] In another embodiment, this specification provides kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof. The kits described herein may comprise a single dose or multiple doses of the compound or a pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein and optionally further include instructions for use of the kit (e.g., instructions for use of the compound or composition contained in the kit).

[0016] Furthermore, this specification also provides the compounds disclosed herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs, and methods for preparing their pharmaceutical compositions. Synthetic intermediates useful for the preparation of compounds and compositions are also provided herein.

[0017] Details of certain embodiments of this disclosure are described in the embodiments for carrying out the invention, as set forth below. Other embodiments of this disclosure will become apparent from the definitions, examples, abstract, and claims.

[0018] definition chemical definition The definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are identified according to the inside cover of Che Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts 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.

[0019] The compounds described herein may contain one or more chiral centers and therefore may exist in various 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 in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers 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 encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0020] Unless otherwise specified, the formulas and structures shown herein include compounds that do not contain isotopically enriched atoms, and also compounds that do contain isotopically enriched atoms ("isotope-labeled derivatives"). For example, replacing hydrogen with deuterium or tritium, 19 F 18 Replace with F, or carbon 13 C- or 14Compounds having the structure of the present invention, except for the substitution of 13C-enriched carbon, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. In certain embodiments, one or more hydrogen atoms of a compound are replaced with deuterium ("deuterated derivative").

[0021] The term "isotope" refers to a variant of a particular chemical element. All isotopes of a given element share the same number of protons in each atom of that element, but they differ in the number of neutrons they contain.

[0022] When a range of values ​​("range") is listed, it includes each value and subrange within that range. Unless otherwise specified, a range includes the values ​​at both ends of that range. For example, "C 1-6 "Alkyl" refers to 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 It includes alkyl groups.

[0023] The phrase "at least one example" refers to one, two, three, four, or more examples, but also includes ranges such as 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 examples (including both ends).

[0024] The term "aliphatic" refers to alkyl groups, alkenyl groups, alkynyl groups, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl groups, heteroalkenyl groups, heteroalkynyl groups, and heterocyclic groups.

[0025] The term "alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 This refers to an alkyl group having 1 to 12 carbon atoms ("C"). In some embodiments, an alkyl group has 1 to 12 carbon atoms. 1-12 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1-10 (alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1-9 (alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1-8 (alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1-7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 (alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 (alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3 Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 2-6 Alkyl). 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, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and n-dodecyl (C) 12Examples include the following. Unless otherwise specified, each example of an alkyl group is independently either unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-12 alkyl (for example, unsubstituted C) 1-6 Alkyl groups include, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), and unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), and unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is substituted C 1-12 alkyl (for example, substitution C) 1-6 Alkyl groups, such as -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn).

[0026] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodine. "Perhaloalkyl" is a subset of haloalkyl, referring to an alkyl group in which all hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodine. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C"). 1-20 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 10 carbon atoms ("C"). 1-10 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 9 carbon atoms ("C"). 1-9 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 8 carbon atoms ("C"). 1-8 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 7 carbon atoms ("C"). 1-7("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 6 carbon atoms ("C"). 1-6 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 5 carbon atoms ("C"). 1-5 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 4 carbon atoms ("C"). 1-4 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 3 carbon atoms ("C"). 1-3 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 2 carbon atoms ("C"). 1-2 (Haloalkyl). In some embodiments, all hydrogen atoms of the haloalkyl group are independently replaced with fluoro atoms to provide a "perfluoroalkyl" group. In some embodiments, all hydrogen atoms of the haloalkyl group are independently replaced with chloro atoms to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, etc.

[0027] The term "heteroalkyl" refers to an alkyl group that further includes 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) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group is an alkyl group that further includes 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) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the parent chain ("C"). 1-20("heteroalkyl"). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("C 1-12 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("C 1-11 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("C 1-10 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("C 1-9 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("C 1-8 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("C 1-7 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("C 1-6 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("C 1-5 ("heteroalkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("C 1-4 ("heteroalkyl"). In some embodiments, a 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, a heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom in the parent chain ("C 1-2"heteroalkyl"). 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 2 to 6 carbon atoms and one or two heteroatoms within the parent chain ("C 2-6 heteroalkyl"). Unless otherwise specified, each instance of the heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl").

[0028] The term "alkenyl" refers to a radical of a straight-chain or branched-chain 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"). In some embodiments, the alkenyl group has 2 to 12 carbon atoms ("C 2-12 alkenyl"). In some embodiments, the alkenyl group has 2 to 11 carbon atoms ("C 2-11 alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3"Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise specified, each example of an alkenyl group is independently either unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In alkenyl groups, the stereochemistry of a C=C double bond is not specified (e.g., -CH=CHCH3 or [ka] ) can be in (E)-configuration or (Z)-configuration.

[0029] The term "heteroalkenyl" refers to an alkenyl group that further contains 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) and / or within one or more terminal positions (plural) of the parent chain. In certain embodiments, a heteroalkenyl group refers to an alkenyl group that further contains 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) and / or within one or more terminal positions (plural) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (「C 2-20 heteroalkenyl」). In certain embodiments, a heteroalkenyl 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 heteroalkenyl」). In certain embodiments, a heteroalkenyl 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 heteroalkenyl」). In certain embodiments, a heteroalkenyl 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 heteroalkenyl」). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (「C 2-9 heteroalkenyl」). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (「C 2-8 heteroalkenyl」). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (「C 2-7("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("C"). 2-6 ("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("C"). 2-5 ("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("C"). 2-4 ("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2-3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("C"). 2-3 ("heteroalkenyl"). In some embodiments, the heteroalkenyl group has two carbon atoms, at least one double bond, and one heteroatom in the parent chain ("C2 heteroalkenyl"). In some embodiments, the heteroalkenyl group has two to six carbon atoms, at least one double bond, and one or two heteroatoms in the parent chain ("C 2-6 (Heteroalkenyl). Unless otherwise specified, each example of a heteroalkenyl group is either unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl").

[0030] The term "alkynyl" refers to a radical of a straight-chain or branched-chain 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) ("C 2-20 In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2-3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples 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 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyls include heptynyl (C7), octinyl (C8), and the like. Unless otherwise specified, each example of an alkynyl group is independently either unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl").

[0031] The term "heteroalkynyl" refers to an alkynyl group that further includes 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) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group refers to an alkynyl group that further includes 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) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group 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 ("heteroalkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("C 2-10 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("C"). 2-9 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("C"). 2-8 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("C"). 2-7 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("C"). 2-6 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("C"). 2-5("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("C"). 2-4 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has 2-3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("C"). 2-3 ("heteroalkynyl"). In some embodiments, the heteroalkynyl group has two carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("C2 heteroalkynyl"). In some embodiments, the heteroalkynyl group has two to six carbon atoms, at least one triple bond, and one or two heteroatoms in the parent chain ("C 1-6 ("heteroalkynyl"). Unless otherwise specified, each example of a heteroalkynyl group is independently either unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl").

[0032] The term "carbocyrill" or "carbocyclic" refers to a non-aromatic ring system with 3 to 14 ring carbon atoms ("C"). 3-14 This refers to a radical of a non-aromatic cyclic hydrocarbon group having a "carbocyclyl" ring carbon atom and zero heteroatoms. In some embodiments, the carbocyclyl group has 3 to 14 ring carbon atoms ("C"). 3-14 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 13 ring carbon atoms ("C"). 3-13 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 12 ring carbon atoms ("C"). 3-12 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 11 ring carbon atoms ("C"). 3-11 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 10 ring carbon atoms ("C"). 3-10 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3-8Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C"). 3-7 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C"). 4-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5-6 ring carbon atoms ("C"). 5-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 Examples of carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-8 As for the carbocyclyl group, the aforementioned C 3-6 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3-10 As for the carbocyclyl group, the aforementioned C 3-8 Carbocyclyl group and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include C. 3-8 As for the carbocyclyl group, the aforementioned C 3-10 Carbocyclyl group and cycloundecyl (C 11 ), spiro[5.5]undecanyl(C 11 ), cyclododecyl (C12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 Examples include the following. As the above examples show, in certain embodiments, the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., condensed, bridged, or spirocyclic systems, including, for example, bicyclic systems ("bicyclic carbocyclyl") or tricyclic systems ("tricyclic carbocyclyl")), and may be saturated and may contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes cyclic systems in which the carbocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the carbocyclyl ring, and in such examples, the number of carbons still refers to the number of carbons in the carbocyclic system. Unless otherwise specified, each example of a carbocyclyl group is independently either unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl contains 0, 1, or 2 C=C double bonds in its carbocyclic ring system, as long as the valence allows.

[0033] "Cycloalkyl" refers to a saturated carbocyclyl group. In some embodiments, the cycloalkyl group has 3 to 14 ring carbon atoms ("C"). 3-14 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C"). 3-10 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3-8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms ("C"). 3-7 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C"). 4-6("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C"). 5-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring 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, as mentioned earlier, C 5-6 Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include, as mentioned earlier, C 3-6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl").

[0034] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorus (“3- to 14-membered heterocyclyl”). In certain embodiments, a heterocyclyl group refers to a radical of a 3- to 14-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The bond site may be to either the ring carbon atom or the ring heteroatom of the heterocyclyl group, as long as the valence allows. For example, in a heterocyclyl group containing one or more nitrogen atoms, the bond site may be to either a carbon atom or a nitrogen atom, as long as the valence allows. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., condensed, bridging, or spirocyclic systems, for example, bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), and may be saturated and may contain one or more carbon-carbon double or triple bonds. A heterocyclyl polycyclic system may contain one or more heteroatoms in one or both rings. A "heterocyclyl" also includes a ring system in which the heterocyclyl ring defined above is fused with one or more carbocyclyl groups, and this bond is on either a carbocyclyl or heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, and this bond is on a heterocyclyl ring, in such examples the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each example of a heterocyclyl is independently either unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl is a substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, where one, two, or three atoms of the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, to the extent their valences allow.

[0035] In certain embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In certain embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In certain embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] Examples of three-membered heterocyclyl groups containing one heteroatom include azilidinyl, oxylanil, and thiranil. Examples of four-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include dioxolanil, oxathiolanil, and dithiolanil. Examples of five-membered heterocyclyl groups containing three heteroatoms include triazolinil, oxadiazolinil, and thiadiazolinil. Examples of six-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanil. An example of a six-membered heterocyclyl group containing three heteroatoms is triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include azokanyl, oxecanyl, and thiokanyl.Examples of bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydroclomenyl, octahydroisoclomenyl, decahydronaphthilidinyl, decahydro-1,8-naphthilidinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthaliumidyl, naphthaliumidyl, chromanyl, clomenyl, 1H-benzo[e][1,4]diazepinyl, 1 Examples include 4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-fl[3,2-b]pyrrolyl, 6,7-dihydro-5H-fl[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofl[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofl[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthilidinyl.

[0037] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement) that has 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 In some embodiments, the aryl group has 6 to 10 ring carbon atoms ("C"). 6-10 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten 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" (e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring defined above is fused with one or more carbocyrillic or heterocyclyl groups, and the radical or bond site is on the aryl ring, in such examples the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. Unless otherwise specified, each example of an aryl group is independently either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0038] The term “heteroaryl” refers to a radical of a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) of a 5- to 14-membered ring, having a ring carbon atom and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorus ("5- to 14-membered heteroaryl"). In certain embodiments, the heteroaryl group is a radical of a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) of a 5- to 14-membered ring, having a ring carbon atom and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The bond site may be on either the ring carbon atom or the ring heteroatom of the heteroaryl group, as long as the valence allows. For example, in a heteroaryl group containing one or more nitrogen atoms, the bond site may be on either a carbon or nitrogen atom, as long as the valence allows. A heteroaryl polycyclic ring system may contain one or more heteroatoms on one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more carbocykyl or heterocyclyl groups, and the bond site is on the heteroaryl ring; in such examples, the number of ring members still indicates the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site is on either the aryl ring or the heteroaryl ring; in such examples, the number of ring members still indicates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. The bond site of a polycyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) may be on either ring, for example, on a ring containing a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl).In certain embodiments, the heteroaryl is a substituted or unsubstituted, 5-membered or 6-membered monocyclic heteroaryl, where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted, 9-membered or 10-membered bicyclic heteroaryl, where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0039] In certain embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In certain embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In certain embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each example of the heteroaryl group is independently either unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl").

[0040] Exemplary five-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include pyridinyl. Exemplary six-membered heterocyclyl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetradinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include naphthylidinyl, pteridinyl, quinolinil, isoquinolinil, sinnolinil, quinoxalinil, phthalazinyl, and quinazolinil. Examples of tricyclic heteroaryl groups include phenanthidinyl, dibenzofuranil, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0041] The term "acyl" is derived from the general formula -C(=O)R aa , -C(=O)OR aa -C(=O)-OC(=O)R aa -C(=O)SR aa -C(=O)N(Rbb )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 ) refers to a group having 2, R aa and R bb This is defined herein. Examples of acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and urea.

[0042] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0043] The term "silyl" is -Si(R aa ) refers to 3 units, R aa This is defined herein.

[0044] Unless otherwise explicitly specified, the groups are optionally substituted. The term “optionally substituted” means that they are substituted or unsubstituted. In certain embodiments, alkyl groups, alkenyl groups, alkynyl groups, heteroalkyl groups, heteroalkenyl groups, heteroalkynyl groups, carbocyclyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are optionally substituted. “Optionally substituted” means a substituted or unsubstituted group (for example, a “substituted” or “unsubstituted” alkyl group, a “substituted” or “unsubstituted” alkenyl group, a “substituted” or “unsubstituted” alkynyl group, a “substituted” or “unsubstituted” heteroalkyl group, a “substituted” or “unsubstituted” heteroalkenyl group, a “substituted” or “unsubstituted” heteroalkynyl group, a “substituted” or “unsubstituted” carbocyclyl group, a “substituted” or “unsubstituted” heterocyclyl group, a “substituted” or “unsubstituted” aryl group, or a “substituted” or “unsubstituted” heteroaryl group). Generally, the term “substituted” means that at least one hydrogen atom present on the group is replaced by an acceptable substituent, for example, a substituent that results in a stable compound, such as a compound that does not spontaneously change through rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a “substituted” group has substituents at one or more substituteable positions on the group, and if multiple positions of any given structure are substituted, the substituents are either the same or different at each position. The term “substituted” is intended to include substitution by all acceptable substituents of an organic compound, including any substituent described herein that results in the formation of a stable compound. This disclosure intends all such combinations that result in a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have any suitable substituents that satisfy the hydrogen substituents and / or heteroatom valencies described herein and result in the formation of a stable moiety. The embodiments described herein are not limited in any way by the exemplary substituents described herein.

[0045] Exemplary substituents (e.g., carbon atom substituents) include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -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(R bb )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(Raa )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 bb P(=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 アルキル、C 1-20 ペルハロアルキル、C 2-20 アルケニル、C2-20 Alkinyl, C 1-20 Heteroalkyl, C 2-20 Heteralkenyl, C 2-20 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Examples include aryls and 5-14 membered heteroaryls, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd It is substituted with X - is the counterion; Alternatively, two geminal hydrogens on a carbon atom are =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 It is replaced by the base; Here, R aa Each example is independent of C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 2-20 Alkenil, C 2-20 Alkinyl, C 1-20 Heteroalkyl, C 2-20 Heteralkenyl, C 2-20 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R bb Each example is independently of 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 Perhaloalkyl, C 2-20 Alkenil, C 2-20 Alkinyl, C 1-20 Heteroalkyl, C 2-20 Heteralkenyl, C 2-20 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Aryl, and 5-14 member heteroaryl, or two R bb The groups bond to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R cc Each example is independent of hydrogen, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 2-20 Alkenil, C 2-20 Alkinyl, C1-20 Heteroalkyl, C 2-20 Heteralkenyl, C 2-20 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R dd Each example is independently halogen, -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 CO2R ee , -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(Rff )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 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by or two geminal R dd Substituents are bonded to form =O or =S, X - is the counterion; R ee Each example is independent of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, C 6-10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered ring heteroaryls, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 Rs. gg It is substituted with the base; R ff Each example is independent of hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups bond to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. gg It is substituted with the base; R gg Each example is independently 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)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -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), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C1-6 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)SC 1-6 Alkyl, -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 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, C 6-10 It is an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 10-membered heteroaryl; or two geminal R gg Substituents bond to form =O or =S, and each X - It is a counterion.

[0046] In certain embodiments, the molecular weight of the substituent (e.g., a carbon atom substituent) is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In certain embodiments, the substituent consists of a carbon atom, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an oxygen atom, a sulfur atom, a nitrogen atom, and / or a silicon atom. In certain embodiments, the substituent consists of a carbon atom, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an oxygen atom, a sulfur atom, and / or a nitrogen atom. In certain embodiments, the substituent consists of a carbon atom, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and / or an iodine atom. In certain embodiments, the substituent consists of a carbon atom, a hydrogen atom, a fluorine atom, and / or a chlorine atom.

[0047] In certain embodiments, exemplary substituents (e.g., carbon atom substituents) include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -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 bb C(=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, -BRaa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Examples include aryls and 5-14 member heteroaryls, X - is the counterion; Alternatively, two geminal hydrogens on a carbon atom are =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 It is replaced by the base; R aa Each example is independent of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups bond to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring; R bb Each example is independently of hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NRcc )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 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Aryl, and 5-14 member heteroaryl, or two R bb The groups are bonded to form a 3-14 membered heterocyclyl ring or a 5-14 membered heteroaryl ring; R cc Each example is independent of hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 1-10 Heteroalkyl, C 2-10 Heteralkenyl, C 2-10 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups bond to form a 3- to 14-membered heterocycline or a 5- to 14-membered heteroaryl ring.

[0048] In certain embodiments, each carbon atom substituent can be halogenated, substituted (e.g., substituted with 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 certain embodiments, each carbon atom substituent can be halogenated, substituted (e.g., substituted with one or more halogens), or unsubstituted C 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, and here, R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 If bonded to an alkyl or oxygen atom, it is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or if bonded to a sulfur atom, it is a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R is an oxygen protecting group. bb These are independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6The substituents are alkyl or nitrogen protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent can independently be halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, or -NO2. In certain embodiments, each carbon atom substituent can independently be halogen, substituted (e.g., substituted with one or more halogen moieties), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted. 1-6 If bonded to an alkyl or oxygen atom, it is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or if bonded to a sulfur atom, it is a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R is an oxygen protecting group. bb These are independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 It is an alkyl group or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0049] In certain embodiments, each nitrogen atom substituent can be independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa -C(=O)N(R bb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent can independently be halogen, substituted (e.g., substituted with one or more halogen moieties), or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, or a nitrogen protecting group, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 If bonded to an alkyl or oxygen atom, it is an oxygen protecting group, and each R bb These are independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group. In certain embodiments, each nitrogen atom substituent can be independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group.

[0050] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Examples of nitrogen protecting groups include -OH and -OR. 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 Alkenil, C 2-20Alkinyl, C 1-20 Heteroalkyl, C 2-20 Heteralkenyl, C 2-20 Heteroalkynyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Examples include aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd It is substituted with R aa , R bb , R cc and R dd The nitrogen protecting group is as defined herein. Nitrogen protecting groups are well known in the art and are incorporated herein by reference in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Includes details as described in edition, John Wiley & Sons, 1999.

[0051] For example, in a particular embodiment, at least one nitrogen protecting group is an amide group (e.g., a nitrogen protecting group (e.g., -C(=O)R) aa(The part containing the nitrogen atom to which the nitrogen protecting group is directly bonded). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is bonded, is a formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetamide, (N The following are independently selected from the group consisting of '-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazofenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0052] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a nitrogen protecting group (e.g., -C(=O)OR aa) is a portion containing a nitrogen atom to which the nitrogen protecting group is directly bonded. In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is bonded, is a methyl carbamate, ethyl carbamate, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfo)fluorenyl methyl carbamate, 9-(2,7-dibromo)fluoroenyl methyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxantyl)]methyl carbamate (D BD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl- 2,2,2-Trichloroethylcarbamate (TCBOC), 1-Methyl-1-(4-biphenylyl)ethylcarbamate (Bpoc), 1-(3,5-Di-t-butylphenyl)-1-methylethylcarbamate (t-Bumeoc), 2-(2'-and 4'-pyridyl)ethylcarbamate (Pyoc), 2-(N,N-Dicyclohexylcarboxamide)ethylcarbamate, t-butylcarbamate (BOC or Boc), 1-Adamantylcarbamate (Ad oc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate (p-nitobenzyl carbamate), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-Dichlorobenzylcarbamate, 4-Methylsulfinylbenzylcarbamate (Msz), 9-Anthrylmethylcarbamate, Diphenylmethylcarbamate, 2-Methylthioethylcarbamate, 2-Methylsulfonylethylcarbamate, 2-(p-Toluenesulfonyl)ethylcarbamate, [2-(1,3-Dithianyl)]methylcarbamate (Dmoc), 4-Methylthiophenylcarbamate (Mtpc), 2,4-Dimethylthiophenylcarbamate (Bmpc), 2-Phosphosphoethylcarbamate Peoc, 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethyl Toxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N- Dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,A molecule is independently selected from the group consisting of 5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0053] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., -S(=O)2R aa ) is a portion containing a nitrogen atom to which the nitrogen protecting group is directly bonded. In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is bonded, is a portion containing a nitrogen atom containing a nitrogen atom containing a nitrogen atom containing a nitrogen protecting group. A single compound is independently selected from the group consisting of methylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0054] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is bonded, forms a phenothiazinyl-(10)-carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl derivative, N'-phenylaminothiocarbonyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5 -Dimethylpyrrole, N-1,1,4,4-tetramethyldisilyl azacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-trizazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-trizazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl (4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocerylmethylamino (Fcm), N-2-picolylamine Mino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyllideneamine, N-(5,A compound is independently selected from the group consisting of 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboric acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramide, dibenzylphosphoramide, diphenylphosphoramide, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two examples of nitrogen protecting groups that are bonded to the nitrogen atom are N,N'-isopropylidenediamine.

[0055] In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), trifuryl (Tf), or dansyl (Ds).

[0056] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0057] In certain embodiments, each oxygen atom substituent can be independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituent can be a halogen, substituted (e.g., substituted with one or more halogen moieties), or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, or an oxygen protecting group, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 If bonded to an alkyl or oxygen atom, it is an oxygen protecting group, and each R bb These are independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group. In certain embodiments, each oxygen atom substituent can be independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or oxygen protecting group.

[0058] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Examples of 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(=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(Rcc )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 is given, and here, X - , R aa , R bb , and R cc The oxygen protecting group is as defined herein. The oxygen protecting group is well known in the art and is incorporated herein by reference in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Includes details as described in edition, John Wiley & Sons, 1999.

[0059] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is bonded, forms methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxy Methyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4 -methyl)phenyl]-4-methoxypiperidine-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-tri Loroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-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-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4”-tris(levrinoyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 4,4'-dimethoxy-3”' -[N-(imidazolylmethyl)]trityl ether (IDTr-OR), 4,4'-dimethoxy-3'''-[N-(imidazolylethyl)carbamoyl]trityl ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzoisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIP S), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethyltexylsilyl, t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-Xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), t-Butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylformate, Acetate, Chloroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate Triphenyl methoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-meth Xybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethyl Toxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenyl acetate, isobutyrate, monosuccinoate, (E)- Selected from the group consisting of 2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphodiamide, alkyl N-phenylcarbamate, borate, dimethylphosphinthiole, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0060] In certain embodiments, the oxygen protecting group is silyl. In certain embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-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), 1-ethoxyethyl (EE) These include 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), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0061] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0062] In certain embodiments, each sulfur atom substituent can be independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent can independently be halogen, substituted (e.g., substituted with one or more halogen moieties), or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, or a sulfur protecting group, where Raa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 If bonded to an alkyl or oxygen atom, it is an oxygen protecting group, and each R bb These are independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group. In certain embodiments, each sulfur atom substituent can be independently substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or sulfur protecting group.

[0063] In certain embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also referred to as "thiol protecting groups"). In some embodiments, each sulfur protecting group is -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 is selected from the group consisting of R aa , R bb , and R ccThe sulfur protecting group is as defined herein. The sulfur protecting group is well known in the art and is incorporated herein by reference in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Includes details as described in edition, John Wiley & Sons, 1999.

[0064] In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0065] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. Anionic counterions can be monovalent (e.g., containing one formal negative charge). Anionic counterions can also be polyvalent, such as divalent or trivalent (e.g., containing multiple formal negative charges). An exemplary counterion is a halide ion (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - , HCO3 - 、 HSO4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, ethane-1-sulfonic acid-2-sulfonate ion, etc.), carboxylate ions (e.g., acetate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, 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) - ) are examples of polyvalent counterions, such as CO3. 2- HPO4 2- , PO4 3- 、 B4O7 2- SO4 2- , S2O3 2- Examples include carboxylic acid anions (e.g., tartrate ion, citrate ion, fumarate ion, maleate ion, malate ion, malonate ion, gluconate ion, succinate ion, glutarate ion, adipicate ion, pimephosphate ion, suberate ion, azelaate ion, sebacate ion, salicylate ion, phthalate ion, aspartate ion, glutamate ion, etc.) and carboranes.

[0066] These and other exemplary substituents are described in more detail in the embodiments, examples, and claims for carrying out the invention. The embodiments provided herein are not limited in any way by the above exemplary enumeration of substituents.

[0067] Other definitions The following definitions are more general terms used throughout this application.

[0068] As used herein, the term “salt” refers to all salts, including pharmaceutically acceptable salts. Salts include ionic compounds resulting from the neutralization of acids and bases. Salts consist of one or more cations (positively charged ions) and one or more anions (negative ions) such that the salt is electrically neutral (has no net charge). Salts of compounds in this disclosure include salts derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobio Examples of salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N. + (C 1-4Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0069] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., within the normal range of reasonable medical judgment, and that balances 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 include salts derived from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxyethanesulfonic acid. Examples of salts include lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. Salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl)4- Examples of salts include those of sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include cations of ammonium, quaternary ammonium, and amines, which are formed, where appropriate, using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0070] Compounds that have the same molecular formula but differ in the properties or arrangement of their atomic bonds, or in the spatial arrangement of their atoms, are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers."

[0071] Stereoisomers that are not mirror images of each other are called diastereomers, while stereoisomers that are mirror images of each other but cannot be superimposed are called enantiomers. For example, when a compound has an asymmetric center, it is bonded to four different groups, and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by Cahn and Prelog's R-sequence and S-sequence rules, or by the way the molecule rotates its plane of polarization, and are indicated as dextrorotatory or levorotatory (i.e., (+) isomer or (-) isomer, respectively). Chiral compounds can exist as any individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a racemic mixture.

[0072] The term "tautomer" or "tautomer" refers to two or more interconvertible compounds resulting from the formal transfer of at least one hydrogen atom and at least one valence change (e.g., from a single bond to a double bond, from a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a tautomer pair) can be catalyzed by an acid or a base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (another enamine).

[0073] The term "solvate" usually refers to a form of compound containing a salt of a solvent, typically associated with the solvent by solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether. The compounds described herein can be prepared, for example, in crystalline form and solvated. Preferred solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain examples, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. "Solvate" encompasses both solution phases and solvable solvates. Representative solvates include, but are not limited to, hydrates, ethanolates, and methanelates.

[0074] The term "hydrate" refers to a solvate in which a compound is associated with water. Typically, the number of water molecules contained in a compound hydrate is in a constant ratio to the number of compound molecules in the hydrate. Thus, a compound hydrate 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 may form several types of hydrates, including, for example, monohydrates (where x is 1), lower hydrates (where x is a number greater than 0 and less than 1, e.g., hemihydrate (R × 0.5 H₂O)), and polyhydrates (where x is a number greater than 1, e.g., dihydrate (R × 2 H₂O) and hexahydrate (R × 6 H₂O)).

[0075] The term "prodrug" refers to a compound having a cleavable group that, upon solvolysis or under physiological conditions, becomes a pharmaceutically active compound described herein in vivo. See, for example, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985. Examples of prodrugs include acid derivatives such as esters prepared by the reaction of a hydrophilic acid with a suitable alcohol, or amides prepared by the reaction of a hydrophilic compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic group of the pendant of the compounds described herein are certain prodrugs. In some cases, it is desirable to prepare double ester-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 forms often offer advantages such as solubility, tissue compatibility, or delayed release in the target.

[0076] Throughout this disclosure, references to “the compound” and “a compound” provided herein are intended to include the compound or group of compounds, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs. Isotope-labeled derivatives are also included.

[0077] The terms "composition" and "formulation" are used interchangeably.

[0078] The “subjects” to which the administration is intended refers to humans (i.e., males or females of any age, e.g., pediatric subjects (e.g., infants, children, or adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly)), or non-human animals. In certain embodiments, non-human animals are mammals (e.g., primates (e.g., crab-eating macaques or rhesus macaques), commercially important mammals (e.g., cattle, pigs, horses, sheep, goats, cats, or dogs), or birds (e.g., commercially important birds such as chickens, ducks, geese, or turkeys)). In certain embodiments, non-human animals are fish, reptiles, or amphibians. Non-human animals can be male or female at any developmental stage. Non-human animals can be transgenic animals or genetically modified animals. The term “patient” refers to a human subject who requires treatment for a disease, disorder, or condition.

[0079] The terms “administer,” “dosing,” or “administer” refer to introducing, embedding, absorbing, ingesting, injecting, inhaling, providing, or otherwise introducing the compounds or compositions described herein into, into, or on a subject.

[0080] The terms “treatment,” “to treat,” and “to treat” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after the onset or observation of one or more signs or symptoms of the disease. In other embodiments, treatment may be administered when there are no signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., in light of a medical history of the symptoms and / or exposure to the pathogen). Treatment may also be continued after the symptoms have disappeared, for example, to delay or prevent relapse.

[0081] The terms “prevent,” “prevention,” or “prevention” refer to preventive treatment for individuals who are currently free from disease, or have not been free from disease in the past, but are at risk of developing the disease, or for individuals who have been free from disease in the past and are not currently free, but are at risk of disease recurrence. In certain embodiments, individuals are at a higher risk of developing the disease or experiencing disease recurrence than the average healthy member of the population.

[0082] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0083] The “effective dose” of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective dose of a compound described herein may vary depending on factors such as the desired biological endpoint, the severity of side effects, disease, or disorder, the identification of a specific compound, pharmacokinetics, and pharmacodynamics, the condition being treated, the method of administration, the route of administration, and the desired or required frequency of administration, the species, age, and health or overall condition of the subject. In certain embodiments, the effective dose is a therapeutic dose. In certain embodiments, the effective dose is a prophylactic treatment. In certain embodiments, the effective dose is a single dose of a compound described herein. In certain embodiments, the effective dose is the sum of multiple doses of a compound described herein. In certain embodiments, the effective dose is an amount sufficient to enhance Kv7 potassium channels (for example, in a subject or in vitro cells).

[0084] The “therapeutic dose” of a compound as described herein is an amount sufficient to produce a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. The therapeutic dose of a compound means the amount of a therapeutic agent that produces a therapeutic benefit in the treatment of a condition, either alone or in combination with other therapies. The term “therapeutic dose” may encompass an amount that improves the overall therapy, reduces or avoids the symptoms, signs, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent. In certain embodiments, the therapeutic dose is an amount sufficient to treat a disease, disorder, or condition in a subject (e.g., a disease, disorder, or condition associated with Kv7 potassium channel dysfunction). In certain embodiments, the therapeutic dose is an amount sufficient to enhance Kv7 potassium channels in a subject.

[0085] The “preventive effective dose” of a compound as described herein is an amount sufficient to prevent or prevent the recurrence of a condition or one or more symptoms associated with that condition. The preventive effective dose of a compound means the amount of a therapeutic agent that, alone or in combination with other agents, provides a preventive benefit in the prevention of a condition. The term “preventive effective dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. In certain embodiments, the preventive effective dose is an amount sufficient to prevent a disease, disorder, or condition in a subject (e.g., a disease, disorder, or condition associated with Kv7 potassium channel dysfunction). In certain embodiments, the preventive effective dose is an amount sufficient to enhance Kv7 potassium channels in a subject.

[0086] Voltage-gated potassium channels (VGKCs) are potassium-specific transmembrane channels that are sensitive to changes in the voltage of the cell membrane potential. During action potential generation, VGKCs play a crucial role in returning depolarized cells to a quiescent state. In VGKCs, the alpha subunit forms the actual conductance pore. Based on the sequence homology of the hydrophobic transmembrane core, the alpha subunits of voltage-gated potassium channels are grouped into 12 families (Kv1-12), with Kv7 being one of these families. The Kv7 family of voltage-gated potassium channels consists of five members (Kv7.1-7.5), each encoded by the KCNQ1-5 genes. Of these five, Kv7.2 / Kv7.3 is the active heterotetramer and is the major active Kv7 current (M current) in neurons. A Kv7 potassium channel may be a member selected from Kv7.1, Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5.

[0087] "Potassium channel enhancers" and "potassium channel openers" are used interchangeably and refer to agents that restore, enhance, or increase the activity of potassium channels (e.g., voltage-gated potassium channels, e.g., Kv7 potassium channels) by, for example, promoting ion permeability through potassium channels. For the purposes of this disclosure, "enhance," "enhance," etc., refer to restoring, enhancing, or increasing the activity or effect of potassium channels. [Modes for carrying out the invention]

[0088] Compounds comprising any of the compounds of the formulas described herein (e.g., formula (I)), as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotope-labeled derivatives, and prodrugs thereof, are provided herein. The compounds provided herein can act as enhancers of voltage-gated potassium channels (e.g., Kv7 potassium channels such as Kv7.2 / Kv7.3) and can therefore be used for the treatment and / or prevention of diseases, disorders, and conditions (e.g., diseases, disorders, and conditions associated with Kv7 potassium channel dysfunction). Pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same, are also provided herein. Furthermore, this disclosure provides methods for preparing the compounds and pharmaceutical compositions described herein, as well as intermediates useful therefor.

[0089] compound In this specification, compounds of formula (I): [ka] Furthermore, the following are provided: pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, in which, X 1 is C or N; Z 3 , Z 4 , and Z 6 Each of them operates independently, CR 4 , N, NR N , S, or O; Z 5 , combine, CR 4 , N, NR N , S, or O; However, Z 3 , Z 4 , Z 5 , and Z 6 At least one of them is N, NR N , S, or O, Z 3 , Z 4 , Z 5 , and Z 6 Provided that one or less of them is either S or O; R 1 and R 2 These are H, halogen, and C, each independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1 Here, alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 The aryl or 5- to 10-membered heteroaryl is optionally substituted; Y is a combination of -CR'R”-, -O-, or -NR Y -and; R Y H, C 1-6 Alkyl, C 3-7is a cycloalkyl, or a nitrogen protecting group, or R Y and R 3 together with the intervening atoms form a 3- to 7-membered heterocyclyl, where alkyl, cycloalkyl, acyl, or heterocyclyl is optionally substituted; Z 1 and Z 2 are each independently CR Z or N; R Z each instance of which is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 [[ID=2(]]cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R 4 each instance of which is independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R 5 each instance of which is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 acyl, or two R 5 bonded to the same carbon atom together with the intervening atoms form C3-7 They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The R'' is a cycloalkyl or 3- to 7-membered heterocycline, where each R'' is independently H, halogen, or C. 1-6 Alkyl, -OR O , or -N(R N )2 or R' and R'' bonded to the same carbon atom bonded together with the intervening atom C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted, or R' and R'' bonded to the same carbon atom combine to form =O; R N1 and R N Each example is independent of H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6An acyl or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S1 Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.

[0090] In a particular embodiment, the compound of formula (I) is the compound of formula (I'): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0091] In a particular embodiment, the compound of formula (I) is the compound of formula (I”): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments of formula (I"), Z 3 is N, Z 6 is S; Z 3 S is Z 6 is N; Z 3 is N, Z 6 is O; or Z 3 is O, and Z 6 is N.

[0092] In certain embodiments of formula (I”), Z 3 is N, and Z 6 is S, or Z 3 is S, and Z 6 is N. In certain embodiments of formula (I”), Z 3 is N, and Z 6 is S. In certain embodiments of formula (I”), Z 3 is S, and Z 6 is N.

[0093] In certain embodiments of formula (I”), Z 3 is N, and Z 6 is O, or Z 3 is O, and Z 6 is N. In certain embodiments of formula (I”), Z 3 is N, and Z[[ID=4)) 6 is O. In certain embodiments of formula (I”), Z 3 is O, and Z 6 is N.

[0094] In certain embodiments, the compound of formula (I) is a compound of formula (I-a):

Chemical formula

[0095] In certain embodiments, the compound of formula (I) is a compound of formula (I-a-1):

Chemical formula

[0096] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0097] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-2-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments, Z 1 CR Z In a particular embodiment, Z 1 is CH. In a particular embodiment, Z 1 is N. In a particular embodiment, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, R 1 and R 2 is methyl. In a particular embodiment, R 1 It is a halogen, and R 2 is unsubstituted C 1-3 It is alkyl. In a particular embodiment, R 1 F is R 2 is methyl. In a particular embodiment, R 2 It is a halogen, and R 1 is unsubstituted C 1-3 It is alkyl. In a particular embodiment, R 2 F is R 1 is methyl. In a particular embodiment, R 1 is unsubstituted C 3-6 It is cycloalkyl, R 2 is unsubstituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 is methyl. In a particular embodiment, Z 1 is N, and R 1 is a halogen, and R 2 is non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 is N, and R 1 F is R 2 is methyl. In a particular embodiment, Z 1 CH is, R 1 is non-substituted C 1-3 It is alkyl, R 2 is a halogen. In a particular embodiment, Z 1 CH is, R 1 is methyl, and R 2 is F. In a particular embodiment, Z 1 is N, and R 1 is non-substituted C 3-6 It is cycloalkyl, R 2 is non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 is N, and R 1 It is cyclopropyl, and R 2 It is methyl.

[0098] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-2-ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments, Z 1 CR Z In a particular embodiment, Z 1 is CH. In a particular embodiment, Z 1 is N. In a particular embodiment, R1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, R 1 and R 2 is methyl. In a particular embodiment, R 1 It is a halogen, and R 2 is unsubstituted C 1-3 It is alkyl. In a particular embodiment, R 1 F is R 2 is methyl. In a particular embodiment, R 2 It is a halogen, and R 1 is unsubstituted C 1-3 It is alkyl. In a particular embodiment, R 2 F is R 1 is methyl. In a particular embodiment, R 1 is unsubstituted C 3-6 It is cycloalkyl, R 2 is unsubstituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 is methyl. In a particular embodiment, Z 1 is N, and R 1 is a halogen, and R 2 is non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 is N, and R 1 F is R 2 is methyl. In a particular embodiment, Z 1 CH is, R 1 is non-substituted C 1-3 It is alkyl, R 2 is a halogen. In a particular embodiment, Z 1 CH is, R 1 is methyl, and R 2 is F. In a particular embodiment, Z1 is N, and R 1 is non-substituted C 3-6 It is cycloalkyl, R 2 is non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 is N, and R 1 It is cyclopropyl, and R 2 It is methyl.

[0099] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0100] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-3-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0101] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0102] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-4-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0103] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0104] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0105] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0106] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0107] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0108] In a particular embodiment, the compound of formula (I) is the compound of formula (Ia-10): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0109] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0110] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0111] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0112] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-2-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0113] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-2-ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0114] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0115] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0116] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0117] In a particular embodiment, the compound of formula (I) is the compound of formula (I-a'-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0118] In a particular embodiment, the compound of formula (I) is the compound of formula (I'''): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0119] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0120] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0121] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0122] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments, Z 1 CR ZIn a particular embodiment, Z 1 is CH. In a particular embodiment, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, R 1 and R 2 is methyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 It is methyl.

[0123] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments, Z 1 CR Z In a particular embodiment, Z 1 is CH. In a particular embodiment, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, R 1 and R 2 is methyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 It is methyl.

[0124] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0125] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0126] In a particular embodiment, the compound of formula (I) is the compound of formula (Ic): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0127] In a particular embodiment, the compound of formula (I) is the compound of formula (Ic-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0128] In a particular embodiment, the compound of formula (I) is the compound of formula (Ic-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0129] In a particular embodiment, the compound of formula (I) is the compound of formula (Id): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0130] In a particular embodiment, the compound of formula (I) is the compound of formula (Id-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0131] In a particular embodiment, the compound of formula (I) is the compound of formula (Id-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0132] In a particular embodiment, the compound of formula (I) is the compound of formula (Ie): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0133] In a particular embodiment, the compound of formula (I) is the compound of formula (Ie-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0134] In a particular embodiment, the compound of formula (I) is the compound of formula (Ie-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0135] In a particular embodiment, the compound of formula (I) is the compound of formula (If): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0136] In a particular embodiment, the compound of formula (I) is the compound of formula (If-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0137] In a particular embodiment, the compound of formula (I) is the compound of formula (If-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0138] In a particular embodiment, the compound of formula (I) is the compound of formula (If-2-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments, Z 1 CR Z In a particular embodiment, Z 1 is CH. In a particular embodiment, R 1 and R 2 Independently, non-substituted C1-3 It is alkyl. In a particular embodiment, R 1 and R 2 is methyl. In a particular embodiment, R 1 and R 2 R is, independently, a halogen. In a particular embodiment, R 1 is Cl, and R 2 is F. In a particular embodiment, Z 1 CH is, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 is methyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 In a particular embodiment, Z 1 CH is, R 1 is Cl, and R 2 It is F.

[0139] In a particular embodiment, the compound of formula (I) is the compound of formula (If-2-ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. In certain embodiments, Z 1 CR Z In a particular embodiment, Z 1 is CH. In a particular embodiment, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, R 1 and R 2 is methyl. In a particular embodiment, R 1 and R 2 R is, independently, a halogen. In a particular embodiment, R 1 is Cl, and R2 is F. In a particular embodiment, Z 1 CH is, R 1 and R 2 Independently, non-substituted C 1-3 It is alkyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 is methyl. In a particular embodiment, Z 1 CH is, R 1 and R 2 In a particular embodiment, Z 1 CH is, R 1 is Cl, and R 2 It is F.

[0140] In a particular embodiment, the compound of formula (I) is the compound of formula (If-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0141] In a particular embodiment, the compound of formula (I) is the compound of formula (If-3-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0142] In a particular embodiment, the compound of formula (I) is the compound of formula (If-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0143] In a particular embodiment, the compound of formula (I) is the compound of formula (If-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0144] In a particular embodiment, the compound of formula (I) is the compound of formula (If-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0145] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0146] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0147] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0148] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig-2-i): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0149] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig-2-ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0150] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0151] In a particular embodiment, the compound of formula (I) is the compound of formula (Ig-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0152] In certain embodiments, the compounds provided herein are the compound of formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof. In certain embodiments, the compounds provided herein are the compound of formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compounds provided herein are the compound of formula (I) or any subgenus or species thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds provided herein are the compound of formula (I) as a free base, or any subgenus or species thereof.

[0153] In certain embodiments, the compounds provided herein are isotope-labeled derivatives of the compound of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts thereof. In certain embodiments, the compounds provided herein are deuterated derivatives of the compound of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts thereof.

[0154] In the various embodiments and models disclosed herein, an explicit reference to a compound of formula (I) is understood to alternatively refer to any compound of its disclosed subgenus or species, e.g., any one of the compounds in Tables 1A-1C.

[0155] In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A, as well as their pharmaceutically acceptable salts, stereoisomers, and tautomers. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A, as well as their pharmaceutically acceptable salts. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1A (in the form of free bases). Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13

[0156] In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B, as well as their pharmaceutically acceptable salts, stereoisomers, and tautomers. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B, as well as their pharmaceutically acceptable salts. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1B (in the form of free bases). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0157] In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C, as well as their pharmaceutically acceptable salts, stereoisomers, and tautomers. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C, as well as their pharmaceutically acceptable salts. In certain embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1C (in the form of free bases). [Table 3-1] [Table 3-2]

[0158] The following definitions and embodiments apply to all general formulas (e.g., formula (I) or any sub-formula thereof) that include the relevant groups. Any enumeration of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the enumerated groups. Any enumeration of embodiments for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0159] As defined herein, X 1 is C or N. In a particular embodiment, X 1 is C. In a particular embodiment, X 1 It is N.

[0160] As defined herein, Z 3 CR 4 , N, NR N It is S, or O. In a particular embodiment, Z 3 CR 4 In a particular embodiment, Z 3is N. In a particular embodiment, Z 3 is NR N In a particular embodiment, Z 3 is S. In a particular embodiment, Z 3 It is O.

[0161] As defined herein, Z 4 CR 4 , N, NR N It is S, or O. In a particular embodiment, Z 4 CR 4 In a particular embodiment, Z 4 This is C-CF3. In a particular embodiment, Z 4 is N. In a particular embodiment, Z 4 is NR N In a particular embodiment, Z 4 is S. In a particular embodiment, Z 4 It is O.

[0162] As defined herein, Z 5 , combine, CR 4 , N, NR N It is S, or O. In a particular embodiment, Z 5 This is a combination. In a particular embodiment, Z 5 CR 4 In a particular embodiment, Z 5 is S. In a particular embodiment, Z 5 is O. In a particular embodiment, Z 5 is N. In a particular embodiment, Z 5 is NR N That is the case.

[0163] As defined herein, Z 6 CR 4 , N, NR N It is S, or O. In a particular embodiment, Z 6 CR 4 In a particular embodiment, Z 6 is N. In a particular embodiment, Z6 is NR N In a particular embodiment, Z 6 is S. In a particular embodiment, Z 6 It is O.

[0164] As described in this specification, Z 3 , Z 4 , Z 5 , and Z 6 At least one of them is N, NR N , S, or O, Z 3 , Z 4 , Z 5 , and Z 6 One or fewer of these are S or O. In a particular embodiment, Z 3 , Z 4 , Z 5 , and Z 6 At least two of them are independently N, NR N Selected from , S, and O, however, Z 3 , Z 4 , Z 5 , and Z 6 The condition is that one or less of these must be either S or O.

[0165] In a particular embodiment: Z 3 is N, Z 6 is S; Z 3 S is Z 6 is N; Z 3 is N, Z 6 is O; or Z 3 is O, Z 6 It is N.

[0166] In a particular embodiment, Z 3 is N, Z 6 Is it S or Z 3 S is Z 6 is N. In a particular embodiment, Z 3 is N, Z 6is S. In a particular embodiment, Z 3 S is Z 6 It is N.

[0167] In a particular embodiment, Z 3 is N, Z 6 Is it O, or Z 3 is O, Z 6 is N. In a particular embodiment, Z 3 is N, Z 6 is O. In a particular embodiment, Z 3 is O, Z 6 It is N.

[0168] As defined herein, R 4 Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted.

[0169] In a particular embodiment, R 4 At least one example of this is H.

[0170] In a particular embodiment, R 4 At least one example of this is a halogen. In a particular embodiment, R 4 At least one example of this is Cl. In a particular embodiment, R 4 At least one example of this is F.

[0171] In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 1-6 It is alkyl. In a particular embodiment, R4 At least one example of this is non-substituted C 1-6 It is alkyl. In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 1-4 It is alkyl. In a particular embodiment, R 4 At least one example of this is non-substituted C 1-4 It is alkyl. In a particular embodiment, R 4 At least one example of is methyl. In a particular embodiment, R 4 At least one example of this is tert-butyl.

[0172] In a particular embodiment, R 4 At least one example of this is C 1-6 It is a haloalkyl. In a particular embodiment, R 4 At least one example of this is C 1-3 It is a haloalkyl. In a particular embodiment, R 4 At least one example of this is a C1 haloalkyl. In a particular embodiment, R 4 At least one example of this is -CF2H.

[0173] In a particular embodiment, R 4 At least one example of this is -CF3.

[0174] In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 3-7 It is a cycloalkyl. In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 3-5 It is a cycloalkyl. In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 3-4 It is a cycloalkyl. In a particular embodiment, R 4 At least one example of this is non-substituted C 3-4 It is a cycloalkyl. In a particular embodiment, R 4At least one example of this is cyclopropyl.

[0175] In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 6-10 It is an arrow. In a particular embodiment, R 4 At least one example of this is an optionally substituted C6 aryl (phenyl). In a particular embodiment, R 4 At least one example of this is unsubstituted phenyl.

[0176] In a particular embodiment, R 4 At least one example of this is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R 4 At least one example of this is a 5- to 10-membered heteroaryl that is optionally substituted. In a particular embodiment, R 4 At least one example of this is -CN. In a particular embodiment, R 4 At least one example of this is -OR O In a particular embodiment, R 4 At least one example of this is -N(R N )2. In a particular embodiment, R 4 At least one example of this is C, which is replaced by choice. 1-6 It is Asil.

[0177] In other embodiments, R 4 At least one example of this is SR S In a particular embodiment, R 4 At least one example of this is -SMe.

[0178] In other embodiments, R 4 At least one example of this is -S(=O)2R S1 In a particular embodiment, R 4 At least one example of this is -S(=O)2Me.

[0179] As defined herein, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as far as the valence allows. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9. In certain embodiments, p is 10.

[0180] As defined herein, m is either 1 or 2. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0181] As defined herein, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0182] In a particular embodiment, both m and n are 1.

[0183] In a particular embodiment, m is 1 and n is 0.

[0184] In a particular embodiment, m is 1 and n is 2.

[0185] As defined herein, R 1 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6It is an acyl, where alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0186] In a particular embodiment, R 1 H is H.

[0187] In a particular embodiment, R 1 is a halogen. In a particular embodiment, R 1 is F. In a particular embodiment, R 1 It is Cl.

[0188] In a particular embodiment, R 1 This is C, which has been replaced by an optional substitution. 1-6 It is alkyl. In a particular embodiment, R 1 is unsubstituted C 1-6 It is alkyl. In a particular embodiment, R 1 This is C, which has been replaced by an optional substitution. 1-3 It is alkyl. In a particular embodiment, R 1 is unsubstituted C 1-3 It is alkyl. In certain embodiments, R 1 It is methyl.

[0189] In a particular embodiment, R 1 C 1-6 It is a haloalkyl. In a particular embodiment, R 1 C 1-3 It is a haloalkyl. In a particular embodiment, R 1 is a C1 haloalkyl. In a particular embodiment, R 1 It is -CF3.

[0190] In a particular embodiment, R 1 This is C, which has been replaced by an optional substitution. 3-7 It is a cycloalkyl. In a particular embodiment, R 1 is unsubstituted C 3-7 It is a cycloalkyl. In a particular embodiment, R 1 is halogen and / or unsubstituted C1-6 C substituted with one or more examples of alkyl 3-7 It is a cycloalkyl. In a particular embodiment, R 1 C is replaced with one or more examples of halogens. 3-7 It is a cycloalkyl. In a particular embodiment, R 1 C is replaced by one or more instances of F. 3-7 It is a cycloalkyl group.

[0191] In a particular embodiment, R 1 This is C, which has been replaced by an optional substitution. 3-5 It is a cycloalkyl. In a particular embodiment, R 1 is halogen and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-5 It is a cycloalkyl. In a particular embodiment, R 1 is halogen and / or unsubstituted C 1-6 A C4 cycloalkyl group optionally substituted with one or more examples of alkyl groups. In certain embodiments, R 1 is a C4 cycloalkyl that is optionally substituted with one or more examples of halogens. In certain embodiments, R 1 is a C4 cycloalkyl group that is optionally substituted with one or more examples of F.

[0192] In a particular embodiment, R 1 R is an unsubstituted C3 cycloalkyl (cyclopropyl). In certain embodiments, R 1 is halogen and / or unsubstituted C 1-6 It is a cyclopropyl substituted with one or more examples of alkyl. In a particular embodiment, R 1 is a cyclopropyl substituted with one or more halogen examples. In a particular embodiment, R 1 is a cyclopropyl substituted with one or more instances of F.

[0193] In a particular embodiment, R 1R is an unsubstituted C4 cycloalkyl (cyclobutyl) group. In certain embodiments, R 1 is halogen and / or unsubstituted C 1-6 Cyclobutyl substituted with one or more examples of alkyl. In certain embodiments, R 1 is cyclobutyl substituted with one or more halogen examples. In a particular embodiment, R 1 This is cyclobutyl substituted with one or more instances of F.

[0194] In a particular embodiment, R 1 is an unsubstituted C5 cycloalkyl (e.g., cyclopentyl). In certain embodiments, R 1 is halogen and / or unsubstituted C 1-6 Cyclopentyl substituted with one or more examples of alkyl. In a particular embodiment, R 1 is cyclopentyl substituted with one or more halogen examples. In a particular embodiment, R 1 is a cyclopentyl substituted with one or more instances of F.

[0195] In a particular embodiment, R 1 is an unsubstituted C6 cycloalkyl (e.g., cyclohexyl). In certain embodiments, R 1 is halogen and / or unsubstituted C 1-6 It is a cyclohexyl substituted with one or more examples of alkyl. In a particular embodiment, R 1 is a cyclohexyl substituted with one or more halogen examples. In a particular embodiment, R 1 is a cyclohexyl substituted with one or more instances of F.

[0196] In a particular embodiment, R 1 R is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R 1 R is an optionally substituted 3- to 7-membered heterocycline having one or two ring heteroatoms independently selected from O, N, and S. In certain embodiments, R1 R is a 3- to 6-membered heterocycline that has been optionally substituted. In a particular embodiment, R 1 is an optionally substituted 3- to 6-membered heterocycline having one or two ring heteroatoms independently selected from O, N, and S. In certain embodiments, R 1 R is a 3- to 5-membered heterocycline that has been optionally substituted. In a particular embodiment, R 1 R is an optionally substituted 3- to 5-membered heterocycline having one ring heteroatom selected from O, N, and S. In certain embodiments, R 1 is an optionally substituted four-membered heterocyclyl having one ring heteroatom selected from O, N, and S. In a particular embodiment, R 1 is an optionally substituted four-membered heterocycline having one ring heteroatom independently selected from O and N. In a particular embodiment, R 1 is oxetanil, which is optionally substituted. In a particular embodiment, R 1 This is an unsubstituted oxetanyl.

[0197] In a particular embodiment, R 1 This is C, which has been replaced by an optional substitution. 6-10 It is an arrow. In a particular embodiment, R 1 is an optionally substituted C6 aryl (phenyl). In certain embodiments, R 1 is halogen and / or unsubstituted C 1-6 This is a phenyl molecule optionally substituted with one or more alkyl groups.

[0198] In a particular embodiment, R 1 R is a 5- to 10-membered heteroaryl that is optionally substituted. In a particular embodiment, R 1 R is an optionally substituted 5-10 membered heteroaryl having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In certain embodiments, R 1 is a 5-6 member heteroaryl that is optionally substituted. In a particular embodiment, R1 This is an optionally substituted 5-6 membered heteroaryl having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S.

[0199] In a particular embodiment, R 1 The following can be selected: [ka]

[0200] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0201] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0202] In a particular embodiment, R 1 is -OR O That is the case.

[0203] In a particular embodiment, R 1 is -OR O And R O This is C, which has been replaced by an optional substitution. 1-6 It is alkyl. In a particular embodiment, R 1 is -OR O And R O This is C, which has been replaced by an optional substitution. 1-3 It is alkyl. In a particular embodiment, R 1 teeth, -OR O And in the formula, R O is unsubstituted C 1-3 It is alkyl. In a particular embodiment, R 1 It is -OMe.

[0204] In a particular embodiment, R 1 is -OR O And R O C 1-6 It is a haloalkyl. In a particular embodiment, R 1 teeth, -OR O And in the formula, R O C 1-3 It is a haloalkyl. In a particular embodiment, R 1 is -OR O And R O is a C1 haloalkyl. In a particular embodiment, R 1 It is -OCF3.

[0205] In a particular embodiment, R 1 is -CN. In a particular embodiment, R 1 is -N(R N )2. In a particular embodiment, R 1 This is C, which has been replaced by an optional substitution. 1-6 It is Asil.

[0206] In a particular embodiment, R 1 -SR S In a particular embodiment, R 1 It is -SMe.

[0207] In a particular embodiment, R 1 is -S(=O)2R S1 In a particular embodiment, R 1 This is -S(=O)2Me.

[0208] In a particular embodiment, R 1 is halogen, C 1-6 Haloalkyl, or -OR O In a particular embodiment, R 1 is halogen, C 1-6 Haloalkyl, -OR O -CN, -SR S , or -S(=O)2R S1 That is the case.

[0209] In a particular embodiment, R 1 is F, Cl, -CF3, or -OMe. In certain embodiments, R 1 F, Cl, -CF3, These are -OMe, -OCF3, -CN, -SMe, or -S(=O)2Me.

[0210] As defined herein, R 2 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is optionally substituted.

[0211] In a particular embodiment, R 2 H is H.

[0212] In a particular embodiment, R 2 is a halogen. In a particular embodiment, R 2 is F. In a particular embodiment, R 2 is Cl. In a particular embodiment, R 2 It is either F or Cl.

[0213] In a particular embodiment, R 2 This is C, which has been replaced by an optional substitution. 1-6 It is alkyl. In a particular embodiment, R 2 is unsubstituted C 1-6 It is alkyl. In a particular embodiment, R 2 This is C, which has been replaced by an optional substitution. 1-3 It is alkyl. In a particular embodiment, R 2 is unsubstituted C1-3 It is alkyl. In certain embodiments, R 2 It is methyl.

[0214] In a particular embodiment, R 2 C 1-6 It is a haloalkyl. In a particular embodiment, R 2 This is C, which has been replaced by an optional substitution. 3-7 It is a cycloalkyl. In a particular embodiment, R 2 R is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R 2 This is C, which has been replaced by an optional substitution. 6-10 It is an arrow. In a particular embodiment, R 2 R is a 5- to 10-membered heteroaryl that is optionally substituted. In a particular embodiment, R 2 It is -CN.

[0215] In a particular embodiment, R 2 is -OR O That is the case.

[0216] In a particular embodiment, R 2 is -OR O And R O This is C, which has been replaced by an optional substitution. 1-6 It is alkyl. In a particular embodiment, R 2 is -OR O And R O This is C, which has been replaced by an optional substitution. 1-3 It is alkyl. In a particular embodiment, R 2 teeth, -OR O And in the formula, R O is unsubstituted C 1-3 It is alkyl. In a particular embodiment, R 2 It is -OMe.

[0217] In a particular embodiment, R 2 is -OR O And R O C 1-6It is a haloalkyl. In a particular embodiment, R 2 teeth, -OR O And in the formula, R O C 1-3 It is a haloalkyl. In a particular embodiment, R 2 is -OR O And R O is a C1 haloalkyl. In a particular embodiment, R 2 It is -OCF3.

[0218] In a particular embodiment, R 2 is halogen or -OR O In a particular embodiment, R 2 is F, Cl, or -OMe.

[0219] In a particular embodiment, R 2 is -N(R N )2. In a particular embodiment, R 2 This is C, which has been replaced by an optional substitution. 1-6 It is Asil.

[0220] In a particular embodiment, R 2 -SR S In a particular embodiment, R 2 It is -SMe.

[0221] In a particular embodiment, R 2 is -S(=O)2R S1 In a particular embodiment, R 2 This is -S(=O)2Me.

[0222] As defined herein, R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1 Here, alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar1 C 6-10 The molecule is an aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted.

[0223] In a particular embodiment, R 3 This is C, which has been replaced by an optional substitution. 1-8 It is alkyl. In a particular embodiment, R 3 is unsubstituted C 1-8 It is alkyl. In a particular embodiment, R 3 This is C, which has been replaced by an optional substitution. 1-4 It is alkyl. In a particular embodiment, R 3 is unsubstituted C 1-4 It is alkyl. In a particular embodiment, R 3 It is tert-butyl.

[0224] In a particular embodiment, R 3 C is a C substituted with one or more halogens. 1-6 It is alkyl. In a particular embodiment, R 3 is a C substituted with one or more Fs. 1-6 It is alkyl. In a particular embodiment, R 3 is a C substituted with one or more Fs. 1-3 It is alkyl. In a particular embodiment, R 3 -CF3, -CH2CF3, or [ka] In a particular embodiment, R 3 It is -CH2CF3.

[0225] In a particular embodiment, R 3 This is C, which has been replaced by an optional substitution. 3-10 It is a cycloalkyl group.

[0226] In a particular embodiment, R 3 This is C, which has been replaced by an optional substitution. 3-8 It is a cycloalkyl. In a particular embodiment, R 3is halogen and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-8 It is a cycloalkyl. In a particular embodiment, R 3 is halogen and / or unsubstituted C 1-3 C is optionally substituted with one or more examples of alkyl. 3-8 It is a cycloalkyl. In a particular embodiment, R 3 C is optionally substituted with one or more instances of F and / or methyl. 3-8 It is a cycloalkyl. In a particular embodiment, R 3 C is optionally replaced by one or more instances of F. 3-8 It is a cycloalkyl. In a particular embodiment, R 3 is halogen, C 1-6 Haloalkyl and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-8 It is a cycloalkyl. In a particular embodiment, R 3 is halogen, C 1-3 Haloalkyl and / or unsubstituted C 1-3 C is optionally substituted with one or more examples of alkyl. 3-8 It is a cycloalkyl. In a particular embodiment, R 3 C is optionally substituted with one or more instances of F, -CF3, and / or methyl. 3-8 It is a cycloalkyl group.

[0227] In a particular embodiment, R 3 This is C, which has been replaced by an optional substitution. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 is halogen and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 is halogen and / or unsubstituted C 1-3 C is optionally substituted with one or more examples of alkyl. 3-5 It is a cycloalkyl. In a particular embodiment, R3 C is optionally substituted with one or more instances of F and / or methyl. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 is halogen, C 1-6 Haloalkyl and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 is halogen, C 1-3 Haloalkyl and / or unsubstituted C 1-3 C is optionally substituted with one or more examples of alkyl. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 C is optionally substituted with one or more instances of F, -CF3, and / or methyl. 3-5 It is a cycloalkyl group.

[0228] In a particular embodiment, R 3 C is optionally replaced by one or more instances of F. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 C is replaced by one or more instances of F. 3-5 It is a cycloalkyl. In a particular embodiment, R 3 This is a C4 cycloalkyl (cyclobutyl) substituted with one or more instances of F.

[0229] In a particular embodiment, R 3 The following can be selected: [ka]

[0230] In a particular embodiment, R 3 teeth, [ka] In a particular embodiment, R 3 teeth, [ka] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0231] In a particular embodiment, R 3 teeth, [ka] In a particular embodiment, R 3 teeth, [ka] Selected from.

[0232] In a particular embodiment, R 3 The following can be selected: [ka]

[0233] In a particular embodiment, R 3 This is C, which has been replaced by an optional substitution. 6-10 It is an arrow. In a particular embodiment, R 3 R is a phenyl compound that is optionally substituted. In a particular embodiment, R 3 is halogen and / or unsubstituted C 1-6 A phenyl molecule optionally substituted with one or more examples of alkyl groups. In certain embodiments, R 3 R is a phenyl compound optionally substituted with one or more examples of halogens. In a particular embodiment, R 3 is a phenyl compound that is optionally substituted with one or more instances of F.

[0234] In a particular embodiment, R 3 The following can be selected: [ka]

[0235] In a particular embodiment, R 3 The following can be selected: [ka]

[0236] In a particular embodiment, R 3 R is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R 3 is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms. In certain embodiments, R 3 It is a 3- to 6-membered heterocycline having one or two ring N atoms and optionally substituted with one or more halogens. In certain embodiments, R 3 It is a 3- to 6-membered heterocycline having one or two ring N atoms and optionally substituted with one or more F atoms. In certain embodiments, R 3 It is a 3- to 6-membered heterocycline having one or two ring N atoms and substituted with one or more F atoms. In certain embodiments, R 3 is an azetidinyl substituted with one or more Fs. In a particular embodiment, R 3 R is an optionally substituted 3- to 6-membered heterocycline having one or two ring heteroatoms independently selected from N and O. In certain embodiments, R 3 A heterocycline is a 3- to 6-membered heterocycline having one or two ring heteroatoms independently selected from N and O, where the heterocycline is halogenated, unsubstituted. C1-6 Alkyl, and / or C 1-6 It is optionally substituted with one or more examples of haloalkyl. In a particular embodiment, R 3 It is a 3-6 membered heterocycline having one ring N atom, and heterocyclines are halogens, unsubstituted C 1-6 Alkyl, and / or C 1-6 It is optionally substituted with one or more examples of haloalkyl. In a particular embodiment, R 3is a 3- to 6-membered heterocyclyl having one ring heteroatom selected from N and O, the heterocyclyl being optionally substituted with one or more examples of F, Me, and / or -CF3. In a particular embodiment, R 3 It is a 3- to 6-membered heterocycline having one ring N atom, and the heterocycline is optionally substituted with one or more instances of F, Me, and / or -CF3.

[0237] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0238] In a particular embodiment, R 3 teeth, [ka] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0239] In a particular embodiment, R 3 The following can be selected: [ka]

[0240] In a particular embodiment, R 3 is, or -(CR'R) w -Ar 1 That is the case.

[0241] As defined herein, w is 0, 1, or 2. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is 2.

[0242] As defined herein, Ar 1 C 6-10 An aryl or 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted. In a particular embodiment, Ar 1 This is C, which has been replaced by an optional substitution. 6-10 It is Ar. In a particular embodiment, Ar 1 These are 5- to 10-membered heteroaryls that have been optionally substituted.

[0243] As defined herein, Z 1 CR Z Or it is N. In a particular embodiment, Z 1 CR Z In a particular embodiment, Z 1 is CH. In a particular embodiment, Z 1 is CCl. In a particular embodiment, Z 1 is CF. In a particular embodiment, Z 1 is N. In a particular embodiment, Z 1 It is either CH or N.

[0244] As defined herein, Z 2 CR Z Or it is N. In a particular embodiment, Z 2 CR Z In a particular embodiment, Z 2 is CH. In a particular embodiment, Z 2 is CCl. In a particular embodiment, Z 2 is CF. In a particular embodiment, Z 2 is N. In a particular embodiment, Z 2 It is either CH or N.

[0245] In a particular embodiment, Z 1 CR Z And Z 2 CR Z In a particular embodiment, Z 1 CH is, Z 2is CH. In a particular embodiment, Z 1 CR Z And Z 2 is N. In a particular embodiment, Z 1 CH is, Z 2 is N. In a particular embodiment, Z 1 is N, Z 2 CR Z In a particular embodiment, Z 1 is N, Z 2 is CH. In a particular embodiment, Z 1 is N, Z 2 It is N.

[0246] As defined herein, R Z Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted.

[0247] In a particular embodiment, R Z At least one example of this is H. In a particular embodiment, R Z Each example is H.

[0248] In a particular embodiment, R Z At least one example of this is a halogen. In a particular embodiment, R Z At least one example of this is F. In a particular embodiment, R Z Each example is Cl.

[0249] In a particular embodiment, R Z At least one example of this is C, which is replaced by choice.1-6 It is alkyl. In a particular embodiment, R Z At least one example of this is C 1-6 It is a haloalkyl. In a particular embodiment, R Z At least one example of this is C, which is replaced by choice. 3-7 It is a cycloalkyl. In a particular embodiment, R Z At least one example of this is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R Z At least one example of this is C, which is replaced by choice. 6-10 It is an arrow. In a particular embodiment, R Z At least one example of this is a 5- to 10-membered heteroaryl that is optionally substituted. In a particular embodiment, R Z At least one example of this is -CN. In a particular embodiment, R Z At least one example of this is -OR O In a particular embodiment, R Z At least one example of this is -N(R N )2. In a particular embodiment, R Z At least one example of this is C, which is replaced by choice. 1-6 It is Asil.

[0250] As defined herein, Y is a combination, -CR'R”-, -O-, or -NR Y - is

[0251] In a particular embodiment, Y is a bond.

[0252] In certain embodiments, Y is -CR'R"-. In certain embodiments, Y is -CH2-. In certain embodiments, Y is -CH(Me)-.

[0253] In a particular embodiment, Y is -O-.

[0254] In a particular embodiment, Y is -NR Y-. In a particular embodiment, Y is -NH-.

[0255] As defined herein, R Y H, C 1-6 Alkyl, C 3-7 A cycloalkyl or nitrogen protecting group, where the alkyl or cycloalkyl group is optionally substituted.

[0256] In a particular embodiment, R Y H is H.

[0257] In a particular embodiment, R Y This is C, which has been replaced by an optional substitution. 1-6 It is alkyl. In a particular embodiment, R Y This is C, which has been replaced by an optional substitution. 3-7 It is a cycloalkyl. In a particular embodiment, R Y This is a nitrogen protecting group.

[0258] In other embodiments, R Y and R 3 It bonds with intervening atoms to form a 3- to 7-membered heterocycline, where the heterocycline is optionally substituted. In some embodiments, R Y and R 3 It bonds with intervening atoms to form a 4- to 6-membered heterocycline with optional substitutions.

[0259] In a particular embodiment, Y is -CR'R"- and R 3 This is C, which has been replaced by an optional substitution. 1-8 It is alkyl. In certain embodiments, Y is -CR'R"- and R 3 This is C, which has been replaced by an optional substitution. 1-4 It is alkyl. In a particular embodiment, Y is -CH2- and R 3 is unsubstituted C 1-4 It is alkyl. In a particular embodiment, Y is -CH2- and R 3 It is tert-butyl.

[0260] In a particular embodiment, Y is -CH2- and R 3 The following can be selected: [ka]

[0261] In a particular embodiment, Y is -CH2- and R 3 teeth, [ka] That is the case.

[0262] In a particular embodiment, Y is -CH2- and R 3 The following can be selected: [ka]

[0263] As defined herein, R 5 Each example is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 It is either an acyl or two R atoms bonded to the same carbon atom. 5 It bonds with the intervening atom and C 3-7 They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted.

[0264] In a particular embodiment, R 5 At least one example of this is halogens.

[0265] In a particular embodiment, R 5 At least one example of this is C, which is replaced by choice. 1-6 It is alkyl. In a particular embodiment, R 5 At least one example of this is non-substituted C 1-6 It is alkyl. In a particular embodiment, R 5 At least one example of this is C, which is replaced by choice. 1-3 It is alkyl. In a particular embodiment, R 5 At least one example of this is non-substituted C 1-3 It is alkyl. In a particular embodiment, R 5 At least one example of this is methyl.

[0266] In a particular embodiment, R 5 At least one example of this is C 1-6 It is a haloalkyl. In a particular embodiment, R 5 At least one example of this is C, which is replaced by choice. 3-7 It is a cycloalkyl. In a particular embodiment, R 5 At least one example of this is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R 5 At least one example of this is -CN.

[0267] In a particular embodiment, R 5 At least one example of this is -OR O In a particular embodiment, R 5 At least one example of this is -OH.

[0268] In a particular embodiment, R 5 At least one example of this is -N(R N )2. In a particular embodiment, R 5 At least one example of this is C, which is replaced by choice. 1-6 It is Asil.

[0269] In a particular embodiment, two R atoms bonded to the same carbon atom 5It is bonded together with the intervening atom and optionally substituted with C 3-7 Forms a cycloalkyl group. In certain embodiments, two R groups bonded to the same carbon atom 5 It bonds with intervening atoms to form optionally substituted 3- to 7-membered heterocyclines.

[0270] In a particular embodiment, two R atoms bonded to the same carbon atom 5 These two elements combine to form the O symbol.

[0271] As defined herein, each example of R' is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.

[0272] In a particular embodiment, at least one example of R' is H.

[0273] In certain embodiments, at least one example of R' is a halogen. In certain embodiments, at least one example of R' is a C which is optionally replaced. 1-6 It is alkyl. In a particular embodiment, at least one example of R' is C 1-6 It is a haloalkyl. In certain embodiments, at least one example of R' is optionally substituted with C 3-7 It is a cycloalkyl group. In certain embodiments, at least one example of R' is an optionally substituted 3- to 7-membered heterocycline.

[0274] As defined herein, each example of "R" is independently of C 1-6 Alkyl, -OR O , or -N(R N )2, where each alkyl group is independently and optionally substituted.

[0275] In a particular embodiment, at least one example of R'' is H.

[0276] In certain embodiments, at least one example of R'' is a halogen. In certain embodiments, at least one example of R'' is a C which is optionally replaced. 1-6 It is alkyl. In a particular embodiment, at least one example of R'' is -OR O In a particular embodiment, at least one example of R'' is -N(R N )2.

[0277] In a particular embodiment, R' and R'' bonded to the same carbon atom bond together with the intervening atom to C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is optionally substituted. In certain embodiments, R' and R'' bonded to the same carbon atom are bonded together with the intervening atom to optionally substituted C 3-7 A cycloalkyl group is formed. In certain embodiments, R' and R'' bonded to the same carbon atom bond together with an intervening atom to form an optionally substituted 3- to 7-membered heterocycline.

[0278] In certain embodiments, R' and R'' bonded to the same carbon atom combine to form =O.

[0279] As defined herein, R N1 H, C 1-6 Alkyl, C 3-7 A cycloalkyl or nitrogen protecting group, where alkyl, cycloalkyl, or acyl is optionally substituted.

[0280] In a particular embodiment, R N1 H is H.

[0281] In a particular embodiment, R N1 This is C, which has been replaced by an optional substitution. 1-6It is alkyl. In a particular embodiment, R N1 This is C, which has been replaced by an optional substitution. 3-7 It is a cycloalkyl. In a particular embodiment, R N1 This is C, which has been replaced by an optional substitution. 1-6 It is an acyl. In a particular embodiment, R N1 This is a nitrogen protecting group.

[0282] As defined herein, each R N H and C are independent of each other. 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted.

[0283] In a particular embodiment, R N At least one example of this is H. In a particular embodiment, R N Each example is H.

[0284] In a particular embodiment, R N At least one example of this is C, which is replaced by choice. 1-6 It is alkyl.

[0285] In a particular embodiment, R N At least one example of this is C, which is replaced by choice. 3-7 It is a cycloalkyl. In a particular embodiment, R N At least one example of this is C, which is replaced by choice. 1-6 It is an acyl. In a particular embodiment, R N At least one example of this is a nitrogen protecting group.

[0286] In a particular embodiment, two R atoms bonded to the same carbon atom NIt bonds with intervening atoms to form optionally substituted 3- to 7-membered heterocyclines. In certain embodiments, two R atoms bonded to the same carbon atom N It bonds with intervening atoms to form a 4- to 6-membered heterocycline with optional substitutions.

[0287] As defined herein, R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl, or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted.

[0288] In a particular embodiment, R O At least one example of this is H. In a particular embodiment, R O Each example is H.

[0289] In a particular embodiment, R O At least one example of this is C, which is replaced by choice. 1-6 It is alkyl.

[0290] In a particular embodiment, R O At least one example of this is C 1-6 It is a haloalkyl. In a particular embodiment, R O At least one example of this is C 1-3 It is a haloalkyl. In a particular embodiment, R O At least one example of this is a C1 haloalkyl. In a particular embodiment, R O At least one example of this is -CF3.

[0291] In a particular embodiment, R O At least one example of this is C, which is replaced by choice. 3-7 It is a cycloalkyl. In a particular embodiment, R OAt least one example of this is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R O At least one example of this is C, which is replaced by choice. 1-6 It is an acyl. In a particular embodiment, R O At least one example of this is the oxygen protecting group.

[0292] As defined herein, R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted.

[0293] In a particular embodiment, R S At least one example of this is H.

[0294] In a particular embodiment, R S At least one example of this is C, which is replaced by choice. 1-6 It is alkyl. In a particular embodiment, R S At least one example of this is non-substitution C1-6 It is alkyl. In a particular embodiment, R S At least one example of this is C, which is replaced by choice. 1-3 It is alkyl. In a particular embodiment, R S At least one example of this is non-substituted C 1-3 It is alkyl. In a particular embodiment, R S At least one example of this is methyl.

[0295] In a particular embodiment, R S At least one example of this is C 1-6 It is a haloalkyl. In a particular embodiment, R S At least one example of this is C, which is replaced by choice. 3-7It is a cycloalkyl. In a particular embodiment, R S At least one example of this is a 3- to 7-membered heterocycline that has been optionally substituted. In a particular embodiment, R S At least one example of this is C, which is replaced by choice. 1-6 It is an acyl. In a particular embodiment, R S At least one example of this is the sulfur protecting group.

[0296] As defined herein, R S Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.

[0297] In a particular embodiment, R S1 At least one example of this is C, which is replaced by choice. 1-6 It is alkyl. In a particular embodiment, R S1 At least one example of this is non-substitution C1-6 It is alkyl. In a particular embodiment, R S1 At least one example of this is C, which is replaced by choice. 1-3 It is alkyl. In a particular embodiment, R S1 At least one example of this is non-substituted C 1-3 It is alkyl. In a particular embodiment, R S1 At least one example of this is methyl.

[0298] In a particular embodiment, R S1 At least one example of this is C 1-6 It is a haloalkyl. In a particular embodiment, R S1 At least one example of this is C, which is replaced by choice. 3-7 It is a cycloalkyl. In a particular embodiment, R S1 At least one example of this is a 3- to 7-membered heterocycline that has been optionally substituted.

[0299] Pharmaceutical composition, kit, and administration This disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug) and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutic effective amount. In certain embodiments, the effective amount is a prophylactic effective amount.

[0300] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods include mixing the compounds described herein (i.e., “active ingredients”) with a carrier or excipient and / or one or more other auxiliary components, and then, if necessary and / or desirable, forming and / or packaging the product into desired single-dose or multi-dose units.

[0301] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as single unit doses and / or as multiple single unit doses. “Unit dose” is an individual amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is approximately equal to the dose of the active ingredient that would be administered to a subject, and / or a favorable proportion of such a dose, such as half or one-third of such a dose.

[0302] The relative amounts of the active ingredient, pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in the pharmaceutical compositions described herein vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route through which the composition is administered.

[0303] Pharmaceutically acceptable carriers / excipients used in the manufacture of 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, coatings, sweeteners, flavorings and fragrances may also be present in the composition.

[0304] The compounds and compositions described herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, percutaneous, intradermal, rectal, vaginal, intraperitoneal, topical (powders, ointments, creams, and / or infusions), mucosal, nasal, buccal, sublingual; intratracheal infusion, bronchial infusion, and / or inhalation; and / or oral spray, nasal spray, and / or aerosol. Specifically intended routes include oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via blood and / or lymphatic supply, and / or direct administration to the site of the disease. Generally, the most appropriate route of administration depends on various factors, including the properties of the drug (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0305] The descriptions of pharmaceutical compositions provided herein relate primarily to pharmaceutical compositions suitable for administration to humans, but those skilled in the art will understand that such compositions are generally suitable for administration to all kinds of animals. It is well understood that pharmaceutical compositions suitable for administration to humans can be modified to make them suitable for administration to various animals, and veterinary pharmacologists of ordinary art can design and / or perform such modifications using ordinary experiments.

[0306] The compounds provided herein are typically formulated in dose units for ease of administration and uniformity of dosage. However, it will be understood that the total daily dose of the compositions described herein should be determined by the attending physician within the bounds of sound medical judgment. The specific therapeutically effective dose level for a particular subject or organism depends on a variety of factors, whatever those subject or organism may be, such as the severity of the disease or disorder being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, overall health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well known in the medical field.

[0307] The exact amount of compound required to achieve an effective dose varies from subject to subject and depends, for example, on the subject's species, age, and overall health, the severity of side effects or disorders, the identity of the specific compound, and the mode of administration. The effective dose may be contained in a single dose (e.g., a single oral dose) or a multi-dose dose (e.g., a multi-oral dose). In certain embodiments, when a multi-dose dose is administered to a subject or applied to tissue or cells, any two of the multi-dose doses may contain different or substantially the same amount of the compound described herein.

[0308] The compounds or compositions described herein may be administered in combination with one or more additional pharmaceuticals (e.g., therapeutic and / or prophylactic agents). The compounds or compositions may be administered in combination with additional pharmaceuticals that improve their activity (e.g., potency and / or effectiveness) in treating a disease in a subject requiring treatment, preventing a disease in a subject requiring prevention, or reducing the risk of developing a disease in a subject requiring a reduction in the risk of developing a disease, improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be understood that the therapies used may achieve the desired effect for the same disorder, and / or may achieve different effects.

[0309] Kits (e.g., pharmaceutical packs) are also included in this disclosure. A kit provided may comprise a pharmaceutical composition or compound as described herein and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, a kit provided may optionally further comprise a second container comprising a pharmaceutical excipient for dilution or suspension of the pharmaceutical composition or compound as described herein. In some embodiments, the pharmaceutical composition or compound provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one embodiment, a kit is provided comprising a first container containing a compound or pharmaceutical composition as described herein. In certain embodiments, the kit is useful for the treatment and / or prevention of a disease, disorder, or condition in a subject requiring treatment and / or prevention of the disease, disorder, or condition.

[0310] In certain embodiments, the kit described herein further includes instructions for using the kit. The kit described herein may also include information required by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kit provides instructions for treating a disease (e.g., cancer) in a subject requiring treatment of the disease. In certain embodiments, the kit provides instructions for preventing a disease in a subject requiring prevention of the disease. The kit described herein may include one or more additional pharmaceuticals described herein as separate compositions.

[0311] Treatment methods and use As described in several embodiments, the compounds provided herein can act as voltage-gated potassium channel enhancers (e.g., Kv7.2 / Kv7.3 enhancers) and are therefore useful, for example, in the treatment of diseases, disorders, and conditions.

[0312] In one embodiment, the Specified Method provides for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof. In certain embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the Kv7 potassium channel is Kv7.2. In certain embodiments, the Kv7 potassium channel is Kv7.3. In certain embodiments, the Kv7 potassium channel is Kv7.2 / Kv7.3. In certain embodiments, the compound or composition is selective to one or more of Kv7.2 to Kv7.5 than to Kv7.1. In certain embodiments, the compound or composition is selective to one or more of Kv7.2 / Kv7.3 than to Kv7.1.

[0313] Furthermore, this specification also provides compounds disclosed herein for use in enhancing Kv7 potassium channels in subjects, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof.

[0314] In another embodiment, the Specified Public Service provides a method for treating a disease, disorder, or condition in a subject requiring treatment for a disease, disorder, or condition associated with Kv7 potassium channel dysfunction, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, to the subject. In certain embodiments, the disease, disorder, or condition is associated with dysfunction of Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the disease, disorder, or condition is associated with dysfunction of Kv7.2. In certain embodiments, the disease, disorder, or condition is associated with dysfunction of Kv7.3. In certain embodiments, the disease, disorder, or condition is associated with dysfunction of Kv7.2 / Kc7.3.

[0315] Furthermore, this specification also provides compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in the treatment of diseases, disorders, or conditions associated with dysfunction of the Kv7 potassium channel in a subject.

[0316] In another embodiment, the Specified provides a method for treating a subject requiring treatment for a paroxysmal disorder, depressive disorder, pain, or anhedonia, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, to the subject.

[0317] Furthermore, this specification also provides compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in the treatment of subjects requiring treatment for paroxysmal disorders, depressive disorders, pain, or anhedonia.

[0318] In certain embodiments, the disease, disorder, or condition is a seizure disorder. “Seizure disorder” refers to seizures and seizure-related disorders, including, for example, partial-origin seizures (also known as focal-origin seizures), photosensitive epilepsy, self-induced syncope, refractory epilepsy, Angelman syndrome, benign Rolandic epilepsy, CDKL5 deficiency, childhood and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, and Ohtahara syndrome. The group includes Panite porous syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epileptic febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, paroxysmal dyskinesia, generalized-origin seizures, or primary generalized tonic-clonic seizures, or a combination thereof. In certain embodiments, the paroxysmal disorder refers to generalized-origin seizures. In some embodiments, the generalized-origin seizure is a primary generalized tonic-clonic seizure. In some embodiments, the paroxysmal disorder is a primary generalized tonic-clonic seizure.

[0319] In certain embodiments, the term “paroxysmal disorder” refers to focal-origin epilepsy, also known as partial-origin epilepsy. In some embodiments, paroxysmal disorder is photosensitive epilepsy. In some embodiments, paroxysmal disorder is self-induced syncope. In some embodiments, paroxysmal disorder is refractory epilepsy. In some embodiments, paroxysmal disorder is Angelman syndrome. In some embodiments, paroxysmal disorder is benign Rolandic epilepsy. In some embodiments, paroxysmal disorder is CDKL5 deficiency. In some embodiments, paroxysmal disorder is childhood and juvenile absence epilepsy. In some embodiments, paroxysmal disorder is Dravet syndrome. In some embodiments, paroxysmal disorder is frontal lobe epilepsy. In some embodiments, paroxysmal disorder is Glut1 deficiency syndrome. In some embodiments, paroxysmal disorder is hypothalamic hamartoma. In some embodiments, paroxysmal disorder is infantile spasms / West syndrome. In some embodiments, paroxysmal disorder is juvenile myoclonic epilepsy. In some embodiments, the paroxysmal disorder is Landau-Klefner syndrome. In some embodiments, the paroxysmal disorder is Lennox-Gastaut syndrome (LGS). In some embodiments, the paroxysmal disorder is myoclonic absence epilepsy. In some embodiments, the paroxysmal disorder is Ohtahara syndrome. In some embodiments, the paroxysmal disorder is Panite porus syndrome. In some embodiments, the paroxysmal disorder is PCDH19 epilepsy. In some embodiments, the paroxysmal disorder is progressive myoclonic epilepsy. In some embodiments, the paroxysmal disorder is Rasmussen syndrome. In some embodiments, the paroxysmal disorder is ring chromosome 20 syndrome. In some embodiments, the paroxysmal disorder is reflex epilepsy. In some embodiments, the paroxysmal disorder is temporal lobe epilepsy. In some embodiments, the paroxysmal disorder is Lafora progressive myoclonus epilepsy. In some embodiments, the paroxysmal disorder is neurocutaneous syndrome. In some embodiments, the paroxysmal disorder is tuberous sclerosis. In some embodiments, the seizure disorder is early infantile epileptic encephalopathy.In some embodiments, the paroxysmal disorder is early-onset epileptic encephalopathy. In some embodiments, the paroxysmal disorder is generalized epilepsy. In some embodiments, the paroxysmal disorder is generalized epileptic febrile seizures plus. In some embodiments, the paroxysmal disorder is Rett syndrome. In some embodiments, the disorder is multiple sclerosis. In some embodiments, the paroxysmal disorder is Alzheimer's disease. In some embodiments, the paroxysmal disorder is autism. In some embodiments, the paroxysmal disorder is ataxia. In some embodiments, the paroxysmal disorder is hypotonia. In some embodiments, the paroxysmal disorder is paroxysmal dyskinesia. In some embodiments, the paroxysmal disorder is generalized-origin seizures. In some embodiments, the paroxysmal disorder is focal-origin seizures (also known as partial-origin seizures).

[0320] In certain embodiments, the disease, disorder, or condition is a depressive disorder. A “depressive disorder” is a mood disorder characterized by a depressed mood. In certain embodiments, a depressive disorder is major depressive disorder (MDD), severe mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.

[0321] In some embodiments, the depressive disorder is major depressive disorder (MDD). In some embodiments, the depressive disorder is severe mood dysregulation disorder. In some embodiments, the depressive disorder is persistent depressive disorder. In some embodiments, the depressive disorder is bipolar spectrum disorder. In some embodiments, the depressive disorder is postpartum depression. In some embodiments, the depressive disorder is premenstrual dysphoric disorder (PMDD). In some embodiments, the depressive disorder is seasonal affective disorder (SAD). In some embodiments, the depressive disorder is atypical depression. In some embodiments, the depressive disorder is treatment-resistant depression (TRD). In some embodiments, the depressive disorder is depression with agitation or anxiety. In some embodiments, the depressive disorder is adjustment disorder with depressed mood. In some embodiments, the depressive disorder is persistent depressive reaction.

[0322] Furthermore, this disclosure is intended to treat obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, social phobia, agoraphobia, agoraphobia with panic disorder, hypochondriasis, post-traumatic stress disorder (PTSD), treatment-resistant bipolar disorder, generalized anxiety disorder, attention deficit hyperactivity disorder (ADHD), bipolar I disorder, bipolar II disorder, mania, cyclothymic disorder and other unspecified bipolar disorders, dysthymic disorder, other unspecified depressive disorders, mild depression, relapsing brief depressive disorder, depressive psychosis, impulse control disorder, schizophrenia, schizophrenia-like disorder, schizoaffective disorder, Parkinson's disease, dementia, Alzheimer's disease, Huntington's disease, Tourette syndrome, aggression, and substance use and / or abuse, or combinations thereof.

[0323] In a particular embodiment, the disease, disorder, or condition is pain. As used herein, “pain” refers to, but is not limited to, all categories of pain, including, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgia, orofacial pain, burn pain, oral burning syndrome, somatic pain, visceral pain, myofascial pain, toothache, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, pain of childbirth, labor pains, reflex sympathetic dystrophy; brachial plexus avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and postoperative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, familial hemiplegic migraine, conditions associated with headache, sinusitis headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome, and pain associated with bowel and gastrointestinal disorders, as well as combinations thereof.

[0324] In certain embodiments, the disorder, condition, or state is anhedonia. As used herein, “anhedonia” refers to a markedly reduced interest in or pleasure from all or nearly all activities. Mild anhedonia may be referred to as hypohedonia. Social anhedonia is a type of anhedonia. As used herein, “social anhedonia” refers to indifference to social contact and a lack of pleasure in social situations. Social anhedonia is characterized by social withdrawal and typically manifests as indifference to social interaction with others. This trait is considered both a central feature and a predictor of schizophrenia spectrum disorders.

[0325] In another embodiment, this specification provides for use as a pharmaceutical product the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. In certain embodiments, the pharmaceutical product is for treating diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction (e.g., Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 dysfunction, e.g., Kv7.2 / Kc7.3 dysfunction) in a subject. In certain embodiments, the pharmaceutical product is for treating paroxysmal disorders, depressive disorders, pain, or anhedonia in a subject.

[0326] Furthermore, this specification provides a method for enhancing Kv7 potassium channels in cells in vitro, comprising contacting cells with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof. In certain embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In certain embodiments, the Kv7 potassium channel is Kv7.2. In certain embodiments, the Kv7 potassium channel is Kv7.3. In certain embodiments, the Kv7 potassium channel is Kv7.2 / Kv7.3. In certain embodiments, the compound or composition is selective to one or more of Kv7.2 to Kv7.5 than Kv7.1. In certain embodiments, the compound or composition is selective to one or more of Kv7.2 / Kv7.3 than Kv7.1.

[0327] This specification provides methods for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in vitro in a subject or cell. In certain 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% compared to a control. In certain 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 compared to a control.

[0328] Additional Embodiments Additional embodiments are provided according to the following numbered embodiments.

[0329] Embodiment 1. Compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, X 1 is C or N; Z 3 , Z 4 , and Z 6 Each of them operates independently, CR 4 , N, NR N , S, or O; Z 5 , combine, CR 4 , N, NR N , S, or O; However, Z 3 , Z 4 , Z 5, and Z 6 At least one of them is N, NR N , S, or O, Z 3 , Z 4 , Z 5 , and Z 6 Provided that one or less of them is either S or O; R 1 and R 2 These are H, halogen, and C, each independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1 Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a combination of -CR'R”-, -O-, or -NR Y -and; R Y H, C 1-6 Alkyl, C 3-7 It is a cycloalkyl group, or a nitrogen protecting group, or R Y and R 3It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z 1 and Z 2 Each of them operates independently, CR Z or N; R Z Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 4 Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 5 Each example is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 It is either an acyl or two R atoms bonded to the same carbon atom. 5 It bonds with the intervening atom and C 3-7They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The R'' is a cycloalkyl or 3- to 7-membered heterocycline, where each R'' is independently H, halogen, or C. 1-6 Alkyl, -OR O , or -N(R N )2 or R' and R'' bonded to the same carbon atom bonded together with the intervening atom C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted, or R' and R'' bonded to the same carbon atom combine to form =O; R N1 and R N Each example is independent of H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6An acyl or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S1 Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 (A cycloalkyl or 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.)

[0330] Embodiment 2. The compound described in Embodiment 1, having formula (I'): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0331] Embodiment 3. The compound described in Embodiment 1, having formula (I): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0332] Embodiment 4. The compound described in Embodiment 1, having formula (Ia): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0333] Embodiment 5. A compound according to Embodiment 1, having formula (Ia-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0334] Embodiment 6. A compound according to Embodiment 1, having formula (Ia-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0335] Embodiment 7. A compound according to Embodiment 1, having the formula (I-a'): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0336] Embodiment 8. A compound according to Embodiment 1, having the formula (I-a'-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0337] Embodiment 9. A compound according to Embodiment 1, having the formula (I-a'-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0338] Embodiment 10. A compound according to Embodiment 1, having formula (I'''): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0339] Embodiment 11. The compound described in Embodiment 1, having formula (Ib): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0340] Embodiment 12. A compound according to Embodiment 1, having the formula (Ib-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0341] Embodiment 13. A compound according to Embodiment 1, having the formula (Ib-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0342] Embodiment 14. A compound according to Embodiment 1, having formula (Ic): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0343] Embodiment 15. A compound according to Embodiment 1, having the formula (Ic-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0344] Embodiment 16. A compound according to Embodiment 1, having the formula (Ic-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0345] Embodiment 17. A compound according to Embodiment 1, having formula (Id): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0346] Embodiment 18. A compound according to Embodiment 1, having the formula (Id-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0347] Embodiment 19. A compound according to Embodiment 1, having the formula (Id-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0348] Embodiment 20. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1.

[0349] Embodiment 21. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein n is 1.

[0350] Embodiment 22. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein n is 2.

[0351] Embodiment 23. R N1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0352] Embodiment 24. R 1 However, C was replaced by an arbitrary choice. 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0353] Embodiment 25. R 1 However, non-substituted C 1-3A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0354] Embodiment 26. R 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the compound is methyl.

[0355] Embodiment 27. R 1 is halogen, C 1-6 Haloalkyl, or -OR O The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0356] Embodiment 28. R 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is F, Cl, -CF3, or -OMe.

[0357] Embodiment 29. R 1 However, C 3-7 A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the cycloalkyl or heterocycline is optionally substituted.

[0358] Embodiment 30. R 1 However, C 3-5 The cycloalkyl or 3-5 membered heterocycline is a halogen and / or unsubstituted C 1-6A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with one or more examples of alkyl groups.

[0359] Embodiment 31. R 1 but, [ka] The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0360] Embodiment 32. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0361] Embodiment 33. R 2 However, C was replaced by an arbitrary choice. 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0362] Embodiment 34. R 2 However, non-substituted C 1-3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0363] Embodiment 35. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the compound is methyl.

[0364] Embodiment 36. R 2A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is a halogen.

[0365] Embodiment 37. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is F or Cl.

[0366] Embodiment 38. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0367] Embodiment 39. A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0368] Embodiment 40. A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CH(Me)-.

[0369] Embodiment 41. R 3 However, C was replaced by an arbitrary choice. 1-8 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0370] Embodiment 42. R 3 However, non-substituted C 1-4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0371] Embodiment 43. R 3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is tert-butyl.

[0372] Embodiment 44. R 3 However, C was replaced by an arbitrary choice. 3-10 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0373] Embodiment 45. R 3 However, C was replaced by an arbitrary choice. 3-8 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0374] Embodiment 46. R 3 However, halogen and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-8 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0375] Embodiment 47. R 3 However, the following are compounds described in any one of the prior embodiments, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, or prodrugs thereof, selected from the following: [ka]

[0376] Embodiment 48. R 3The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a 3- to 7-membered heterocycline that is optionally substituted.

[0377] Embodiment 49. R 3 The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms.

[0378] Embodiment 50. R 3 However, it is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms, and this 3- to 6-membered heterocycline is one or more halogens and / or unsubstituted C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with an alkyl group.

[0379] Embodiment 51. R 3 but, [ka] The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0380] Embodiment 52. Z 1 CR Z The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0381] Embodiment 53. Z 1A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is CH.

[0382] Embodiment 54. Z 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein N is present.

[0383] Embodiment 55. Z 2 CR Z The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0384] Embodiment 56. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is CH.

[0385] Embodiment 57. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein CF is CF.

[0386] Embodiment 58. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein N is present.

[0387] Embodiment 59. R 4 At least one example of this is C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a haloalkyl compound.

[0388] Embodiment 60. R 4 At least one example of this is C 1-3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a haloalkyl compound.

[0389] Embodiment 61. R 4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is a C1-haloalkyl compound.

[0390] Embodiment 62. R 4 At least one example of is a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein -CF3 is a compound described in any one of the prior embodiments.

[0391] Embodiment 63. R 4 At least one example of this is C, which is optionally replaced by a halogen. 1-6 Alkyl, optionally substituted C 3-7 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, which is a cycloalkyl or optionally substituted phenyl.

[0392] Embodiment 64. R 4 At least one example of this is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 A compound described in any one of the prior embodiments, which is a cycloalkyl or unsubstituted phenyl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0393] Embodiment 65. R 4A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is methyl, tert-butyl, Cl, cyclopropyl, or phenyl.

[0394] Embodiment 66. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein p is 0.

[0395] Embodiment 67. The compound described in Embodiment 1, selected from those in Tables 1A to 1C, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, and prodrugs thereof.

[0396] Embodiment 68. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof.

[0397] Embodiment 69. A pharmaceutical composition comprising a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0398] Embodiment 70. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound described in any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate thereof, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0399] Embodiment 71. A method for treating a subject in need of treatment for a disease, disorder, or condition associated with Kv7 potassium channel dysfunction, the method comprising administering to the subject a compound described in any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0400] Embodiment 72. The method according to Embodiment 70 or 71, wherein the method enhances the opening of a Kv7 potassium channel.

[0401] Embodiment 73. The method according to any one of Embodiments 70 to 72, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0402] Embodiment 74. The method according to any one of Embodiments 70 to 73, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0403] Embodiment 75. A method for treating a subject in need of treatment for a paroxysmal disorder, depressive disorder, pain, or anhedonia, the method comprising administering to the subject a compound described in any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0404] Embodiment 76. The method according to any one of Embodiments 70 to 75, wherein the subject is a human.

[0405] Embodiment 77. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in enhancing Kv7 potassium channels in a subject.

[0406] Embodiment 78. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of a disease, disorder, or condition associated with dysfunction of the Kv7 potassium channel in a subject.

[0407] Embodiment 79. A compound for use in Embodiment 77 or 78, wherein the compound enhances the opening of a Kv7 potassium channel.

[0408] Embodiment 80. The compound for use according to any one of Embodiments 77 to 79, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0409] Embodiment 81. The compound for use according to any one of Embodiments 77 to 80, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0410] Embodiment 82. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of paroxysmal disorders, depressive disorders, pain, or anhedonia in a subject.

[0411] Embodiment 83. The compound for use according to any one of Embodiments 77 to 82, wherein the subject is a human.

[0412] Embodiment 84. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use as a pharmaceutical.

[0413] Further additional embodiments are provided according to the following numbered embodiments: Embodiment 1. Compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, Z 3 is N, Z6 Is it S or Z 3 S is Z 6 is N; R 1 and R 2 These are H, halogen, and C, each independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1 Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a combination of -CR'R”-, -O-, or -NR Y -and; R Y H, C 1-6 Alkyl, C 3-7 It is a cycloalkyl group, or a nitrogen protecting group, or R Y and R 3 It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z 1 and Z 2 Each of them operates independently, CR Zor N; R Z Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 4 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 5 Each example is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 It is either an acyl or two R atoms bonded to the same carbon atom. 5 It bonds with the intervening atom and C 3-7 They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The R'' is a cycloalkyl or 3- to 7-membered heterocycline, where each R'' is independently H, halogen, or C. 1-6 Alkyl, -OR O , or -N(R N )2 or R' and R'' bonded to the same carbon atom bonded together with the intervening atom C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, or R' and R'' bonded to the same carbon atom combine to form =O, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted; R N1 and R N Each example is independent of H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S1 Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 (A cycloalkyl or 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.)

[0414] Embodiment 2. The compound described in Embodiment 1, having formula (Ia): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0415] Embodiment 3. The compound described in Embodiment 1, having formula (Ia-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0416] Embodiment 4. A compound according to Embodiment 1, having formula (Ia-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0417] Embodiment 5. A compound according to Embodiment 1, having formula (Ia-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0418] Embodiment 6. A compound according to Embodiment 1, having formula (Ia-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0419] Embodiment 7. A compound according to Embodiment 1, having the formula (I-a'): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0420] Embodiment 8. A compound according to Embodiment 1, having the formula (I-a'-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0421] Embodiment 9. A compound according to Embodiment 1, having the formula (I-a'-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0422] Embodiment 10. A compound according to Embodiment 1, having the formula (I-a'-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0423] Embodiment 11. A compound according to Embodiment 1, having the formula (I-a'-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0424] Embodiment 12. Compound of formula (Ib): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, R 1 and R 2 These are H, halogen, and C, each independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a combination of -CR'R”-, -O-, or -NR Y -and; R Y H, C 1-6 Alkyl, C 3-7 It is a cycloalkyl group, or a nitrogen protecting group, or R Y and R 3 It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z 1 and Z 2 Each of them operates independently, CR Z or N; R Z Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 4 Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 5 Each example is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 It is either an acyl or two R atoms bonded to the same carbon atom. 5 It bonds with the intervening atom and C 3-7 They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The R'' is a cycloalkyl or 3- to 7-membered heterocycline, where each R'' is independently H, halogen, or C. 1-6 Alkyl, -OR O , or -N(R N )2 or R' and R'' bonded to the same carbon atom bonded together with the intervening atom C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, or R' and R'' bonded to the same carbon atom combine to form =O, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted; R N1 and R N Each example is independent of H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S1 Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 (A cycloalkyl or 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.)

[0425] Embodiment 13. A compound according to Embodiment 12, having formula (Ib-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0426] Embodiment 14. A compound according to Embodiment 12, having the formula (Ib-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0427] Embodiment 15. A compound according to Embodiment 12, having the formula (Ib-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0428] Embodiment 16. A compound according to Embodiment 12, having the formula (Ib-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0429] Embodiment 17. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1.

[0430] Embodiment 18. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein n is 1.

[0431] Embodiment 19. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1 and n is 1.

[0432] Embodiment 20. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein n is 2.

[0433] Embodiment 21. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1 and n is 2.

[0434] Embodiment 22. R N1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0435] Embodiment 23. m is 1, n is 1, and R N1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0436] Embodiment 24. R 1 However, C was replaced by an arbitrary choice. 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0437] Embodiment 25. R 1 However, non-substituted C 1-3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0438] Embodiment 26. R 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the compound is methyl.

[0439] Embodiment 27. R 1 is halogen, C 1-6 Haloalkyl, or -OR O The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0440] Embodiment 28. R 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is F, Cl, -CF3, or -OMe.

[0441] Embodiment 29. R 1 However, C 3-7 A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the cycloalkyl or heterocycline is optionally substituted.

[0442] Embodiment 30. R 1 However, C 3-5 The cycloalkyl or 3-5 membered heterocycline is a halogen and / or unsubstituted C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with one or more examples of alkyl groups.

[0443] Embodiment 31. R 1 but, [ka] The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0444] Embodiment 32. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0445] Embodiment 33. R 2 However, C was replaced by an arbitrary choice. 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0446] Embodiment 34. R 2 However, non-substituted C 1-3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0447] Embodiment 35. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the compound is methyl.

[0448] Embodiment 36. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is a halogen.

[0449] Embodiment 37. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is F or Cl.

[0450] Embodiment 38. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0451] Embodiment 39. A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0452] Embodiment 40. A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CH(Me)-.

[0453] Embodiment 41. R 3 However, C was replaced by an arbitrary choice. 1-8 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0454] Embodiment 42. R 3 However, non-substituted C 1-4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0455] Embodiment 43. R 3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is tert-butyl.

[0456] Embodiment 44. R 3 However, C was replaced by an arbitrary choice. 3-10A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0457] Embodiment 45. R 3 However, C was replaced by an arbitrary choice. 3-8 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0458] Embodiment 46. R 3 However, halogen and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-8 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0459] Embodiment 47. R 3 However, the following are compounds described in any one of the prior embodiments, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, or prodrugs thereof, selected from the following: [ka]

[0460] Embodiment 48. R 3 The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a 3- to 7-membered heterocycline that is optionally substituted.

[0461] Embodiment 49. R 3The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms.

[0462] Embodiment 50. R 3 However, it is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms, and this 3- to 6-membered heterocycline is one or more halogens and / or unsubstituted C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with an alkyl group.

[0463] Embodiment 51. R 3 but, [ka] The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0464] Embodiment 52. Z 1 CR Z The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0465] Embodiment 53. Z 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is CH.

[0466] Embodiment 54. Z 1A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein N is present.

[0467] Embodiment 55. Z 2 CR Z The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0468] Embodiment 56. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is CH.

[0469] Embodiment 57. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein CF is CF.

[0470] Embodiment 58. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein N is present.

[0471] Embodiment 59. R 4 At least one example of this is C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a haloalkyl compound.

[0472] Embodiment 60. R 4 At least one example of this is C 1-3A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a haloalkyl compound.

[0473] Embodiment 61. R 4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is a C1-haloalkyl compound.

[0474] Embodiment 62. R 4 At least one example of is a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein -CF3 is a compound described in any one of the prior embodiments.

[0475] Embodiment 63. R 4 At least one example of this is C, which is optionally replaced by a halogen. 1-6 Alkyl, optionally substituted C 3-7 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, which is a cycloalkyl or optionally substituted phenyl.

[0476] Embodiment 64. R 4 At least one example of this is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 A compound described in any one of the prior embodiments, which is a cycloalkyl or unsubstituted phenyl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0477] Embodiment 65. R 4A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is methyl, tert-butyl, Cl, cyclopropyl, or phenyl.

[0478] Embodiment 66. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein p is 0.

[0479] Embodiment 67. Compounds selected from Tables 1A to 1C, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, and prodrugs thereof.

[0480] Embodiment 68. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof.

[0481] Embodiment 69. A pharmaceutical composition comprising a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0482] Embodiment 70. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound described in any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate thereof, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0483] Embodiment 71. A method for treating a subject in need of treatment for a disease, disorder, or condition associated with Kv7 potassium channel dysfunction, the method comprising administering to the subject a compound described in any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0484] Embodiment 72. The method according to Embodiment 70 or 71, wherein the method enhances the opening of a Kv7 potassium channel.

[0485] Embodiment 73. The method according to any one of Embodiments 70 to 72, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0486] Embodiment 74. The method according to any one of Embodiments 70 to 73, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0487] Embodiment 75. A method for treating a subject in need of treatment for a paroxysmal disorder, depressive disorder, pain, or anhedonia, the method comprising administering to the subject a compound described in any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0488] Embodiment 76. The method according to any one of Embodiments 70 to 75, wherein the subject is a human.

[0489] Embodiment 77. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in enhancing Kv7 potassium channels in a subject.

[0490] Embodiment 78. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of a disease, disorder, or condition associated with dysfunction of the Kv7 potassium channel in a subject.

[0491] Embodiment 79. A compound for use in Embodiment 77 or 78, wherein the compound enhances the opening of a Kv7 potassium channel.

[0492] Embodiment 80. The compound for use according to any one of Embodiments 77 to 79, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0493] Embodiment 81. The compound for use according to any one of Embodiments 77 to 80, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0494] Embodiment 82. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of paroxysmal disorders, depressive disorders, pain, or anhedonia in a subject.

[0495] Embodiment 83. The compound for use according to any one of Embodiments 77 to 82, wherein the subject is a human.

[0496] Embodiment 84. A compound according to any one of Embodiments 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use as a pharmaceutical.

[0497] Further additional embodiments are provided according to the following numbered embodiments: Embodiment 1. Compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, Z 3 is N, Z6 is S, Z 3 S is Z 6 is N, Z 3 is N, Z 6 is O, or Z 3 is O, Z 6 is N; R 1 and R 2 These are H, halogen, and C, each independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1 Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a combination of -CR'R”-, -O-, or -NR Y -and; R Y H, C 1-6 Alkyl, C 3-7 It is a cycloalkyl group, or a nitrogen protecting group, or R Y and R 3It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z 1 and Z 2 Each of them operates independently, CR Z or N; R Z Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 4 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 5 Each example is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 It is either an acyl or two R atoms bonded to the same carbon atom. 5 It bonds with the intervening atom and C 3-7They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The R'' is a cycloalkyl or 3- to 7-membered heterocycline, where each R'' is independently H, halogen, or C. 1-6 Alkyl, -OR O , or -N(R N )2 or R' and R'' bonded to the same carbon atom bonded together with the intervening atom C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, or R' and R'' bonded to the same carbon atom combine to form =O, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted; R N1 and R N Each example is independent of H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6An acyl or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S1 Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 (A cycloalkyl or 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.)

[0498] Embodiment 2. Z 3 is N, Z 6 Is it S or Z 3 S is Z 6 The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is N.

[0499] Embodiment 3. The compound described in Embodiment 1, having formula (Ia): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0500] Embodiment 4. A compound according to Embodiment 1, having formula (Ia-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0501] Embodiment 5. A compound according to Embodiment 1, having formula (Ia-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0502] Embodiment 6. A compound according to Embodiment 1, having formula (Ia-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0503] Embodiment 7. A compound according to Embodiment 1, having formula (Ia-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0504] Embodiment 8. A compound according to Embodiment 1, having formula (I-a'): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0505] Embodiment 9. A compound according to Embodiment 1, having the formula (I-a'-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0506] Embodiment 10. A compound according to Embodiment 1, having the formula (I-a'-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0507] Embodiment 11. A compound according to Embodiment 1, having the formula (I-a'-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0508] Embodiment 12. A compound according to Embodiment 1, having the formula (I-a'-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0509] Embodiment 13. A compound according to Embodiment 1, having formula (If): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0510] Embodiment 14. A compound according to Embodiment 1, having the formula (If-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0511] Embodiment 15. A compound according to Embodiment 1, having the formula (If-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0512] Embodiment 16. A compound according to Embodiment 1, having the formula (If-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0513] Embodiment 17. A compound according to Embodiment 1, having the formula (If-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0514] Embodiment 18. Compound of formula (Ib): [ka] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, R 1 and R 2 These are H, halogen, and C, each independently. 1-6Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, -SR S -S(=O)2R S1 , or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R)”) w -Ar 1 Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a combination of -CR'R”-, -O-, or -NR Y -and; R Y H, C 1-6 Alkyl, C 3-7 It is a cycloalkyl group, or a nitrogen protecting group, or R Y and R 3 It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z 1 and Z 2 Each of them operates independently, CR Z or N; R Z Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 4 Each example independently involves H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -CN, -OR O , -N(R N )2, or C 1-6 It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R 5 Each example is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR O , -N(R N )2, or C 1-6 It is either an acyl or two R atoms bonded to the same carbon atom. 5 It bonds with the intervening atom and C 3-7 They form a cycloalkyl or a 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom. 5 These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7The R'' is a cycloalkyl or 3- to 7-membered heterocycline, where each R'' is independently H, halogen, or C. 1-6 Alkyl, -OR O , or -N(R N )2 or R' and R'' bonded to the same carbon atom bonded together with the intervening atom C 3-7 They form cycloalkyl or 3- to 7-membered heterocyclines, or R' and R'' bonded to the same carbon atom combine to form =O, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted; R N1 and R N Each example is independent of H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 It is an acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom. N It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R O Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S Each example is independent of H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R S1 Each example is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7(A cycloalkyl or 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.)

[0515] Embodiment 19. A compound described in Embodiment 18, having the formula (Ib-1): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0516] Embodiment 20. A compound described in Embodiment 18, having the formula (Ib-2): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0517] Embodiment 21. A compound according to Embodiment 18, having the formula (Ib-3): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0518] Embodiment 22. A compound according to Embodiment 18, having the formula (Ib-4): [ka] The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0519] Embodiment 23. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1.

[0520] Embodiment 24. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein n is 1.

[0521] Embodiment 25. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1 and n is 1.

[0522] Embodiment 26. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein n is 2.

[0523] Embodiment 27. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein m is 1 and n is 2.

[0524] Embodiment 28. R N1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0525] Embodiment 29. m is 1, n is 1, and R N1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0526] Embodiment 30. R 1 However, C was replaced by an arbitrary choice. 1-6A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0527] Embodiment 31. R 1 However, non-substituted C 1-3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0528] Embodiment 32. R 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the compound is methyl.

[0529] Embodiment 33. R 1 However, halogen, C 1-6 Haloalkyl, -OR O -CN, -SR S , or -S(=O)2R S1 The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0530] Embodiment 34. R 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is F, Cl, -CF3, -OMe, -OCF3, -CN, -SMe, or -S(=O)2Me.

[0531] Embodiment 35. R 1 However, C 3-7A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the cycloalkyl or heterocycline is optionally substituted.

[0532] Embodiment 36. R 1 However, C 3-5 The cycloalkyl or 3-5 membered heterocycline is a halogen and / or unsubstituted C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with one or more examples of alkyl groups.

[0533] Embodiment 37. R 1 but, [ka] The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0534] Embodiment 38. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is H.

[0535] Embodiment 39. R 2 However, C was replaced by an arbitrary choice. 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0536] Embodiment 40. R 2 However, non-substituted C 1-3A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0537] Embodiment 41. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the compound is methyl.

[0538] Embodiment 42. R 2 is halogen or -OR O The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0539] Embodiment 43. R 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is F, Cl, or -OMe.

[0540] Embodiment 44. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0541] Embodiment 45. A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0542] Embodiment 46. A compound according to any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein Y is -CH(Me)-.

[0543] Embodiment 47. R 3However, C was replaced by an arbitrary choice. 1-8 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0544] Embodiment 48. R 3 However, non-substituted C 1-4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0545] Embodiment 49. R 3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is tert-butyl.

[0546] Embodiment 50. R 3 However, C was replaced by an arbitrary choice. 3-10 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0547] Embodiment 51. R 3 However, C was replaced by an arbitrary choice. 3-8 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0548] Embodiment 52. R 3 However, halogen and / or unsubstituted C 1-6 C is optionally substituted with one or more examples of alkyl. 3-8 A cycloalkyl compound as described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0549] Embodiment 53. R 3 However, the following are compounds described in any one of the prior embodiments, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, or prodrugs thereof, selected from the following: [ka]

[0550] Embodiment 54. R 3 The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a 3- to 7-membered heterocycline that is optionally substituted.

[0551] Embodiment 55. R 3 The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms.

[0552] Embodiment 56. R 3 However, it is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms, and this 3- to 6-membered heterocycline is one or more halogens and / or unsubstituted C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with an alkyl group.

[0553] Embodiment 57. R 3 but, [ka] The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0554] Embodiment 58. R 3 However, C was replaced by an arbitrary choice. 6-10 An aryl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0555] Embodiment 59. R 3 The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein the phenyl is optionally substituted.

[0556] Embodiment 60. R 3 However, halogen and / or unsubstituted C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein the phenyl is optionally substituted with one or more examples of alkyl groups.

[0557] Embodiment 61. R 3 However, the following are compounds described in any one of the prior embodiments, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled derivatives, or prodrugs thereof, selected from the following: [ka]

[0558] Embodiment 62. Z 1 CR Z The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0559] Embodiment 63. Z 1A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is CH.

[0560] Embodiment 64. Z 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein is CCl.

[0561] Embodiment 65. Z 1 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein N is present.

[0562] Embodiment 66. Z 2 CR Z The compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0563] Embodiment 67. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein is CH.

[0564] Embodiment 68. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein CF is CF.

[0565] Embodiment 69. Z 2 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein N is present.

[0566] Embodiment 70. R4 At least one example of this is C 1-6 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a haloalkyl compound.

[0567] Embodiment 71. R 4 At least one example of this is C 1-3 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, which is a haloalkyl compound.

[0568] Embodiment 72. R 4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is a C1-haloalkyl compound.

[0569] Embodiment 73. R 4 At least one example of is a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein -CF3 is a compound described in any one of the prior embodiments.

[0570] Embodiment 74. R 4 At least one example of is -CF2H, which is a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0571] Embodiment 75. R 4 At least one example of this is C, which is optionally replaced by a halogen. 1-6 Alkyl, optionally substituted C 3-7A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, which is a cycloalkyl or optionally substituted phenyl.

[0572] Embodiment 76. R 4 At least one example of this is halogen, unsubstituted C 1-6 Alkyl, halogen, unsubstituted C 3-7 A compound described in any one of the prior embodiments, which is a cycloalkyl or unsubstituted phenyl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

[0573] Embodiment 77. R 4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is methyl, tert-butyl, Cl, cyclopropyl, or phenyl.

[0574] Embodiment 78. R 4 A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is H.

[0575] Embodiment 79. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein p is 0.

[0576] Embodiment 80. Compounds selected from those listed in Table 1, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, and prodrugs thereof.

[0577] Embodiment 81. A compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof.

[0578] Embodiment 82. A pharmaceutical composition comprising a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

[0579] Embodiment 83. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound described in any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate thereof, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0580] Embodiment 84. A method for treating a subject in need of treatment for a disease, disorder, or condition associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound described in any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0581] Embodiment 85. The method according to Embodiment 83 or 84, wherein the method enhances the opening of a Kv7 potassium channel.

[0582] Embodiment 86. The method according to any one of Embodiments 83 to 85, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0583] Embodiment 87. The method according to any one of Embodiments 83 to 86, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0584] Embodiment 88. A method for treating a subject in need of treatment for a paroxysmal disorder, depressive disorder, pain, or anhedonia, the method comprising administering to the subject a compound described in any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0585] Embodiment 89. The method according to any one of Embodiments 83 to 88, wherein the subject is a human.

[0586] Embodiment 90. A compound according to any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in enhancing Kv7 potassium channels in a subject.

[0587] Embodiment 91. A compound according to any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of a disease, disorder, or condition associated with dysfunction of the Kv7 potassium channel in a subject.

[0588] Embodiment 92. A compound for use in Embodiment 90 or 91, wherein the compound enhances the opening of a Kv7 potassium channel.

[0589] Embodiment 93. The compound for use according to any one of Embodiments 90 to 92, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[0590] Embodiment 94. The compound for use according to any one of Embodiments 90 to 93, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0591] Embodiment 95. A compound according to any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of paroxysmal disorders, depressive disorders, pain, or anhedonia in a subject.

[0592] Embodiment 96. The compound for use according to any one of Embodiments 90 to 95, wherein the subject is a human.

[0593] Embodiment 97. A compound according to any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use as a pharmaceutical. [Examples]

[0594] To better understand this disclosure, the following examples may be described. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not intended to limit their scope in any way.

[0595] The examples provided below include, for example, procedures, intermediates, and characterization data useful for the preparation of the compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc., are included herein in aspects of this disclosure.

[0596] Compound synthesis Example 1. N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide [ka]

[0597] Step 1. Preparation of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide [ka] N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide was prepared according to the procedure described on page 52 of WO2008 / 024398.

[0598] Step 2. Preparation of tert-butyl 3-(4-(3,3-dimethylbutanamide)-3,5-dimethylphenyl)azetidine-1-carboxylate [ka] To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (0.050 g, 0.168 mmol) and 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[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-butylphosphanylphenyl)-N,N-dimethylaniline (0.026 g, 0.067 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.031 g, 0.034 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 100 °C for 16 hours. 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, over 10 minutes). The desired fraction was collected and lyophilized to obtain 0.014 g of N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide (yield 18%) as a bright yellow solid: 1H 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).

[0599] The following further examples were prepared in the same manner as Example 1 (as described above), by substituting appropriate starting materials as necessary and appropriately modifying experimental conditions based on general knowledge. Purification was performed by silica gel chromatography, reverse-phase preparative HPLC, or supercritical fluid chromatography (SFC). [Table 4-1] [Table 4-2] [Table 4-3]

[0600] Example 24. 3,3-Dimethyl-N-(4-methyl-2-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)pyrimidine-5-yl)butanamide [ka]

[0601] Step 1. Preparation of N-(2-chloro-4-methylpyrimidine-5-yl)-3,3-dimethylbutanamide [ka] To a cold (0°C) solution of 2-chloro-4-methylpyrimidine-5-amine (4.50 g, 31.30 mmol) in dichloromethane (50.0 mL), pyridine (7.44 g, 94.00 mmol) and 3,3-dimethylbutanoyl chloride (4.22 g, 31.30 mmol) were added. The mixture was stirred at 15°C for 2 hours. Water (100 mL) was added to the mixture, and then the mixture was extracted with dichloromethane (3 × 100 mL). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (100 mL), 1 M hydrochloric acid (100 mL), and brine (3 × 100 mL), dried on sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g SepaFlash® silica flash column, eluate with a 0-55% ethyl acetate / petroleum ether gradient at 150 mL / min). The desired fraction was collected and concentrated in vacuum to obtain 4.0 g of N-(2-chloro-4-methylpyrimidine-5-yl)-3,3-dimethylbutanamide as a crude white solid, which was used without further purification: 1 H 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).

[0602] Step 2. Preparation of 3,3-dimethyl-N-(4-methyl-2-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)pyrimidine-5-yl)butanamide [ka] A mixture of N-(2-chloro-4-methylpyrimidine-5-yl)-3,3-dimethylbutanamide (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 hours. 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, over 10 minutes). The desired fraction was collected and freeze-dried to obtain 0.016 g of 3,3-dimethyl-N-(4-methyl-2-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)pyrimidine-5-yl)butanamide (yield 32%) as a white solid: 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).

[0603] Example 25. N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)phenyl)-2-hydroxy-2,3,3-trimethylbutanamide [ka]

[0604] Step 1. Preparation of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-2-oxobutanamide [ka] To a solution of 3,3-dimethyl-2-oxobutanoic acid (5.0 g, 38.4 mmol) in tetrahydrofuran (50 mL), N,N-diisopropylethylamine (12.4 g, 96.1 mmol) and 2-chloro-1-methylpyridinium iodide (12.3 g, 48.0 mmol) were added. The mixture was stirred at 25°C for 1 hour. 4-bromo-2,6-dimethylaniline (6.41 g, 32.0 mmol) was added, and the mixture was stirred at 25°C for 12 hours. 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 obtain 5.7 g of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-2-oxobutanamide (yield 57%) 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).

[0605] Step 2. Preparation of (+ / -)N-(4-bromo-2,6-dimethylphenyl)-2-hydroxy-2,3,3-trimethylbutanamide [ka] To a solution of N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethyl-2-oxobutanamide (3.00 g, 9.61 mmol) in tetrahydrofuran (30 mL), thiophene-2-ylmagnesium bromide (3 M in diethyl ether, 16 mL) was added under nitrogen at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction product was quenched with saturated ammonium chloride (20 mL). Water (30 mL) was added to the mixture, and then the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (40g SepaFlash® silica flash column, eluate with a 0-40% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain 1.70 g of racemic N-(4-bromo-2,6-dimethylphenyl)-2-hydroxy-2,3,3-trimethylbutanamide (43% yield) as a yellow solid: 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).

[0606] Step 2. Preparation of (+ / -)N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)phenyl)-2-hydroxy-2,3,3-trimethylbutanamide [ka] To 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), potassium tert-butoxide (0.051 g, 0.457 mmol), 2-(2-di-tert-butylphosphanylphenyl)-N,N-dimethylaniline (0.012 g, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0) (0.056 g, 0.061 mmol) were added under nitrogen. The mixture was stirred at 100°C for 16 hours. 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, over 10 minutes). The desired fraction was collected and lyophilized to obtain 0.015 g of racemic N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)phenyl)-2-hydroxy-2,3,3-trimethylbutanamide (yield 49%) as an off-white solid: 1 H NMR (400 MHz, 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).

[0607] Example 26. N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide [ka]

[0608] Step 1. Preparation of tert-butyl 2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate [ka] A mixture of tert-butyl 2-bromo-6,7-dihydrothiazolo[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(I) iodide (0.240 g, 1.26 mmol) in dimethylformamide (6.0 mL) was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature. Water (10 mL) was added to the mixture, and then the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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, over 10 minutes). 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 obtain 0.086 g of 2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (yield 45%) 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).

[0609] Step 2. Preparation of 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine [ka] To a solution of tert-butyl 2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (0.086 g, 0.279 mmol) in methanol (2.0 mL), acetyl chloride (0.109 g, 1.390 mmol) was added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.065 g of 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[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).

[0610] Step 3. Preparation of N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide [ka] 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-tetrahydrothiazolo[4,5-c]pyridine (0.065 g, 0.266 mmol, hydrochloride) in dioxane (4.0 mL), potassium tert-butoxide (0.100 g, 0.891 mmol), 2-(2-di-tert-butylphosphanylphenyl)-N,N-dimethylaniline (0.018 g, 0.046 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol) were added under nitrogen. The mixture was stirred at 100 °C for 16 hours. 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 (formic acid)-acetonitrile]; gradient: 56%~76% B, over 10 minutes). The desired fraction was collected and lyophilized to obtain 0.024 g of N-(2,6-dimethyl-4-(2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide (yield 25%) as a bright yellow solid: 1 H NMR (400 MHz, MeOD-d4) δ 6.80 (s, 2H), 4.41 (s, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.08 (t, J = 5.2 Hz, 2H), 2.30 (s, 2H), 2.20 (s, 6H), 1.13 (s, 9H); MS (ES+) m / z 426.2 (M+1).

[0611] Example 27. N-(2-(3,3-difluorocyclobutyl)-6-fluoro-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide [ka]

[0612] Step 1. Preparation of N-(2-bromo-6-fluorophenyl)-3,3-dimethylbutanamide [ka] To a cold (0°C) solution of 2-bromo-6-fluoroaniline (10.0 g, 52.6 mmol) in dichloromethane (100.0 mL), pyridine (8.3 g, 105.0 mmol) and 3,3-dimethylbutanoyl chloride (7.8 g, 57.9 mmol) were added. The mixture was stirred at 15°C for 1 hour. Water (100 mL) was added to the mixture, and the mixture was extracted with dichloromethane (3 × 100 mL). The combined organic phase was washed with saturated sodium bicarbonate (100 mL), 1 M hydrochloric acid (100 mL), and brine (3 × 100 mL), dried on sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g SepaFlash® silica flash column, eluate with a 0-22% ethyl acetate / petroleum ether gradient at 100 mL / min). The desired fraction was collected and concentrated in vacuum to obtain 13.0 g of N-(2-bromo-6-fluorophenyl)-3,3-dimethylbutanamide (86% yield) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.43-7.20 (m, 2H), 2.23 (s, 2H), 1.06 (s, 9H).

[0613] Step 2. Preparation of N-(2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3-dimethylbutanamide [ka] The reaction was carried out in three batches, each using a 0.300g scale. N-(2-bromo-6-fluorophenyl)-3,3-dimethylbutanamide (0.300 g, 1.040 mmol), 3-bromo-1,1-difluorocyclobutane (0.267 g, 1.560 mmol), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2-bipyridyl]iridium hexafluorophosphate (0.012 g, 0.011 mmol), tris(trimethylsilyl)silane (0.259 g, 1.040 mmol), [4-4-bis(1,1-dimethylethyl)-2,2-bipyridine]nickel(II) dichloride (0.013 g, 0.033 mmol), sodium carbonate (0.221 g, 0.209 mmol), and acetonitrile (12.0 mL) were added to a vial equipped with a stirring bar. The vial was sealed and placed under nitrogen. The reaction mixture was stirred and irradiated with a 34W blue LED lamp (7 cm away), and the reaction temperature was maintained at 25°C for 14 hours using a cooling fan. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g SepaFlash® silica flash column, eluate with a 0-12% ethyl acetate / petroleum ether gradient at 100 mL / min). The desired fraction was collected and concentrated under vacuum to obtain 0.410 g of N-(2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3-dimethylbutanamide (yield 44%) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.28-7.18 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 8.8 Hz, 1H), 3.45-3.31 (m, 1H), 2.91-2.76 (m, 2H), 2.63-2.46 (m, 2H), 2.14 (s, 2H), 0.96 (s, 9H).

[0614] Step 3. Preparation of N-(4-bromo-2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3-dimethylbutanamide [ka] To a cold (0°C) solution of N-(2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3-dimethylbutanamide (0.500 g, 1.67 mmol) in acetonitrile (5.0 mL), 1-bromopyrrolidine-2,5-dione (2.38 g, 13.4 mmol) was added. The mixture was stirred at 50°C for 72 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna 150 mm × 25 mm × 10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 54%~74% B, over 2 minutes). The desired fraction was collected and freeze-dried to obtain 0.28 g of N-(4-bromo-2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3-dimethylbutanamide (44% yield) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.52 (J = 2.0, 9.2 Hz, 1H), 7.43 (s, 1H), 3.52-3.39 (m, 1H), 3.01-2.83 (m, 2H), 2.80-2.61 (m, 2H), 2.23 (s, 2H), 1.04 (s, 9H).

[0615] Step 4. Preparation of N-(2-(3,3-difluorocyclobutyl)-6-fluoro-4-(2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)phenyl)-3,3-dimethylbutanamide [ka] To a solution of N-(4-bromo-2-(3,3-difluorocyclobutyl)-6-fluorophenyl)-3,3-dimethylbutanamide (0.050 g, 0.132 mmol), 2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.030 g, 0.132 mmol, hydrochloride), and potassium tert-butoxide (0.059 g, 0.5...

Claims

1. Compound of formula (I''): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, Z ３ is N, Z ６ is S, Z ３ S is Z ６ is N, Z ３ is N, Z ６ is O, or Z ３ is O, Z ６ is N; R １ and R ２ each independently is H, halogen, C １－６ alkyl, C １－６ haloalkyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , -SR Ｓ , -S(=O) ２ R Ｓ１ , or C １－６ acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently optionally substituted; R ３ C １－８ Alkyl, C ３－１０ Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R'') ｗ -Ar １ Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar １ C ６－１０ An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a bond, -CR'R"-, -O-, or -NR Ｙ - and; R Ｙ H, C １－６ Alkyl, C ３－７ It is a cycloalkyl group, or a nitrogen protecting group, or R Ｙ and R ３ It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z １ and Z ２ Each of them operates independently, CR Ｚ or N; R Ｚ Each example is independent of H, halogen, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , or C １－６ It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R ４ H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , or C １－６ It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R ５ Each example is independent of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , or C １－６ It is either an acyl or two Rs bonded to the same carbon atom. ５ It bonds with the intervening atom and C ３－７ Forming a cycloalkyl or 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom ５ These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each R'' is independently H, halogen, or C. １－６ Alkyl, -OR Ｏ , or -N(R Ｎ ) ２ Either R' and R'' bonded to the same carbon atom are bonded together with the intervening atom to C ３－７ They form cycloalkyl or 3- to 7-membered heterocyclines, or R' and R'' bonded to the same carbon atom together form =O, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted; R Ｎ１ and R Ｎ Each example is independent of H, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ An acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom Ｎ It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R Ｏ Each example is independent of H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C １－６ An acyl, or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R Ｓ Each example of １－６ H, C １－６ alkyl, C ３－７ haloalkyl, C １－６ cycloalkyl, 3- to 7-membered heterocyclyl, C Ｓ１ acyl, or a sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently optionally substituted; R Ｓ１ Each example is independent of C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.

2. Z ３ is N, and Z ６ is S, or Z ３ is S, and Z ６ is N, the compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

3. A compound according to claim 1, having formula (I-a): 【Chemistry 2】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

4. A compound according to claim 1, having the formula (I-a-1): 【Transformation 3】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

5. A compound according to claim 1, having the formula (I-a-2): 【Chemistry 4】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

6. A compound according to claim 1, having the formula (I-a-2-i): 【Transformation 5】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

7. A compound according to claim 1, having the formula (I-a-2-ii): 【Transformation 6】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

8. A compound according to claim 1, having the formula (I-a-3): 【Transformation 7】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

9. A compound according to claim 1, having the formula (I-a-3-i): 【Transformation 8】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

10. A compound according to claim 1, having the formula (I-a-4): 【Chemistry 9】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

11. A compound according to claim 1, having the formula (I-a-4-i): 【Chemistry 10】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

12. A compound according to claim 1, having the formula (I-a-5): 【Chemistry 11】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

13. A compound according to claim 1, having the formula (I-a-6): 【Chemistry 12】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

14. A compound according to claim 1, having the formula (I-a-7): 【Chemistry 13】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

15. A compound according to claim 1, having the formula (I-a-8): 【Chemistry 14】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

16. A compound according to claim 1, having the formula (I-a-9): 【Chemistry 15】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

17. A compound according to claim 1, having the formula (I-a-10): 【Chemistry 16】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

18. A compound according to claim 1, having the formula (I-a'): 【Chemistry 17】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

19. A compound according to claim 1, having the formula (I-a'-1): 【Chemistry 18】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

20. A compound according to claim 1, having the formula (I-a'-2): 【Chemistry 19】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

21. A compound according to claim 1, having the formula (I-a'-2-i): 【Chemistry 20】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

22. A compound according to claim 1, having the formula (I-a'-2-ii): 【Chemistry 21】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

23. A compound according to claim 1, having the formula (I-a'-3): 【Chemistry 22】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

24. A compound according to claim 1, having the formula (I-a'-4): 【Chemistry 23】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

25. A compound according to claim 1, having formula (I-f): 【Chemistry 24】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

26. A compound according to claim 1, having the formula (I-f-1): 【Chemistry 25】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

27. A compound according to claim 1, having the formula (I-f-2): 【Chemistry 26】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

28. A compound according to claim 1, having the formula (I-f-2-i): 【Chemistry 27】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

29. A compound according to claim 1, having the formula (I-f-2-ii): 【Chemistry 28】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

30. A compound according to claim 1, having the formula (I-f-3): 【Chemistry 29】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

31. A compound according to claim 1, having the formula (I-f-3-i): 【Transformation 30】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

32. A compound according to claim 1, having the formula (I-f-4): 【Chemistry 31】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

33. A compound according to claim 1, having the formula (I-f-5): 【Chemistry 32】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

34. A compound according to claim 1, having the formula (I-f-6): 【Transformation 33】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

35. A compound according to claim 1, having the formula (I-g): 【Transformation 34】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

36. A compound according to claim 1, having the formula (I-g-1): 【Chemistry 35】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

37. A compound according to claim 1, having the formula (I-g-2): 【Transformation 36】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

38. A compound according to claim 1, having the formula (I-g-2-i): 【Chemistry 37】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

39. A compound according to claim 1, having the formula (I-g-2-ii): 【Chemistry 38】 The compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

40. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein m is 1.

41. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein n is 1.

42. A compound according to any one of claims 1 to 41, wherein m is 1 and n is 1, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

43. A compound according to any one of claims 1 to 42, wherein n is 2, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

44. A compound according to any one of claims 1 to 43, wherein m is 1 and n is 2, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

45. R Ｎ１ A compound according to any one of claims 1 to 44, wherein is H, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

46. m is 1, n is 1, and R Ｎ１ A compound according to any one of claims 1 to 45, wherein is H, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

47. R １ However, C was replaced by an arbitrary choice. １－６ A compound according to any one of claims 1 to 46, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

48. R １ However, non-substituted C １－３ A compound according to any one of claims 1 to 47, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

49. R １ A compound according to any one of claims 1 to 48, wherein is methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

50. R １ However, halogen, C １－６ Haloalkyl, -OR Ｏ -CN, -SR Ｓ , or -S (=O) ２ R Ｓ１ The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

51. R １ F, Cl, -CF ３ , -OMe, -OCF ３ -CN, -SMe, or -S (=O) ２ A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

52. R １ However, C ３－７ A compound according to any one of claims 1 to 51, wherein the compound is a cycloalkyl or a 3- to 7-membered heterocycline, wherein the cycloalkyl or heterocycline is optionally substituted, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

53. R １ However, C ３－５ The cycloalkyl or 3- to 5-membered heterocycline is a halogen and / or unsubstituted C １－６ A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, which is optionally substituted with one or more examples of alkyl groups.

54. R １ However, the following: 【Chemistry 39】 The compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

55. R ２ A compound according to any one of claims 1 to 54, wherein is H, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

56. R ２ However, C was replaced by an arbitrary choice. １－６ A compound according to any one of claims 1 to 55, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

57. R ２ However, non-substituted C １－３ A compound according to any one of claims 1 to 56, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

58. R ２ A compound according to any one of claims 1 to 57, wherein is methyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

59. R ２ is halogen or -OR Ｏ The compound according to any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

60. R ２ A compound according to any one of claims 1 to 59, wherein is F, Cl, or -OMe, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

61. A compound according to any one of claims 1 to 60, wherein Y is -CR'R'', or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

62. Y is -CH ２ - The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

63. A compound according to any one of claims 1 to 62, wherein Y is -CH(Me)-, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

64. R ３ However, C was replaced by an arbitrary choice. １－８ A compound according to any one of claims 1 to 63, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

65. R ３ However, non-substituted C １－４ A compound according to any one of claims 1 to 66, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

66. R ３ A compound according to any one of claims 1 to 67, wherein is tert-butyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

67. R ３ However, C is replaced by one or more F at will. １－４ A compound according to any one of claims 1 to 66, which is alkyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

68. R ３ However, -CH ２ CF ３ The compound according to any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

69. R ３ However, C was replaced by an arbitrary choice. ３－１０ A cycloalkyl compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

70. R ３ However, C was replaced by an arbitrary choice. ３－８ A cycloalkyl compound according to any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

71. R ３ However, halogen and / or unsubstituted C １－６ C is optionally substituted with one or more examples of alkyl groups. ３－８ A cycloalkyl compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

72. R ３ However, the compound described in any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, selected from the following: 【Chemistry 40】

73. R ３ The compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein the compound is a 3 to 7 member heterocycline that is optionally substituted.

74. R ３ The compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein the compound is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms.

75. R ３ However, it is an optionally substituted 3- to 6-membered heterocycline having one or two ring N atoms, and this 3- to 6-membered heterocycline is one or more halogens and / or unsubstituted C １－６ A compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, optionally substituted with an alkyl group.

76. R ３ However, the following: 【Chemistry 41】 The compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

77. R ３ However, C was replaced by an arbitrary choice. ６－１０ A compound according to any one of claims 1 to 76, which is an aryl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

78. R ３ The compound according to any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein the phenyl is optionally substituted.

79. R ３ However, halogen and / or unsubstituted C １－６ A compound according to any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof, wherein the phenyl is optionally substituted with one or more examples of alkyl groups.

80. R ３ However, the compound described in any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, selected from the following: 【Chemistry 42】

81. Z １ CR Ｚ The compound according to any one of claims 1 to 80, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

82. Z １ A compound according to any one of claims 1 to 81, wherein is CH, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

83. Z １ A compound according to any one of claims 1 to 82, wherein is CCl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

84. Z １ A compound according to any one of claims 1 to 83, wherein N is present, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

85. Z ２ CR Ｚ The compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

86. Z ２ A compound according to any one of claims 1 to 85, wherein is CH, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

87. Z ２ A compound according to any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein CF is CF.

88. Z ２ A compound according to any one of claims 1 to 87, wherein N is present, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

89. R ４ At least one example of this is C １－６ A compound according to any one of claims 1 to 88, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

90. R ４ At least one example of this is C １－３ A compound according to any one of claims 1 to 89, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

91. R ４ At least one example of this is C １ A compound according to any one of claims 1 to 90, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

92. R ４ At least one example of this is -CF ３ The compound according to any one of claims 1 to 91, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

93. R ４ At least one example of this is -CF ２ A compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

94. R ４ At least one example of this is C, which is optionally replaced by a halogen. １－６ Alkyl, optionally substituted C ３－７ A compound according to any one of claims 1 to 93, which is a cycloalkyl or optionally substituted phenyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof.

95. R ４ At least one example of this is halogen, unsubstituted C １－６ Alkyl, halogen, and unsubstituted C ３－７ A compound according to any one of claims 1 to 94, which is a cycloalkyl or unsubstituted phenyl, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

96. R ４ A compound according to any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is methyl, tert-butyl, Cl, cyclopropyl, or phenyl.

97. R ４ A compound according to any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein at least one example of is H.

98. A compound according to any one of claims 1 to 97, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, wherein p is 0.

99. Compounds selected from those listed in Table 1B, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, and prodrugs.

100. Compound of formula (I): 【Chemistry 43】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug thereof. (In the formula, X １ is C or N; Z ３ Z ４ , and Z ６ Each of them operates independently, CR ４ , N, NR Ｎ , S, or O; Z ５ is bond, CR ４ , N, NR Ｎ , S, or O; However, Z ３ Z ４ Z ５ , and Z ６ At least one of them is N, NR Ｎ , S, or O, Z ３ Z ４ Z ５ , and Z ６ Provided that one or less of them is either S or O; R １ and R ２ These are H, halogen, and C, each independently. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -CN, -OR Ｏ , -N(R Ｎ ) ２ ,-SR Ｓ , -S (=O) ２ R Ｓ１ , or C １－６ It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R ３ C １－８ Alkyl, C ３－１０ Cycloalkyl, 3- to 7-membered heterocyclyl, or -(CR'R'') ｗ -Ar １ Herein, the alkyl, cycloalkyl, or heterocyclyl is optionally substituted; w is 0, 1, or 2; Ar １ C ６－１０ An aryl or a 5- to 10-membered heteroaryl, where the aryl or heteroaryl is optionally substituted; Y is a bond, -CR'R"-, -O-, or -NR Ｙ - and; R Ｙ H, C １－６ Alkyl, C ３－７ It is a cycloalkyl group, or a nitrogen protecting group, or R Ｙ and R ３ It bonds with an intervening atom to form a 3- to 7-membered heterocycline, where the alkyl, cycloalkyl, acyl, or heterocycline is optionally substituted; Z １ and Z ２ Each of them operates independently, CR Ｚ or N; R Ｚ Each example is independent of H, halogen, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , or C １－６ It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R ４ Each example is independent of H, halogen, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , or C １－６ It is an acyl, where each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or acyl is independently and optionally substituted; R ５ Each example is independent of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, -CN, -OR Ｏ , -N(R Ｎ ) ２ , or C １－６ It is either an acyl or two Rs bonded to the same carbon atom. ５ It bonds with the intervening atom and C ３－７ Forming a cycloalkyl or 3- to 7-membered heterocycline, or two R atoms bonded to the same carbon atom ５ These combine to form =O, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as long as its valence allows; m is either 1 or 2; n is 0, 1, or 2; Each example of R' is independent of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each R'' is independently H, halogen, or C. １－６ Alkyl, -OR Ｏ , or -N(R Ｎ ) ２ Either R' and R'' bonded to the same carbon atom are bonded together with the intervening atom to C ３－７ They form cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted, or R' and R'' bonded to the same carbon atom combine to form =O; R Ｎ１ and R Ｎ Each example is independent of H, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ An acyl or nitrogen protecting group, or two R groups bonded to the same nitrogen atom Ｎ It bonds with the intervening atom to form a 3- to 7-membered heterocycline, where each alkyl, cycloalkyl, acyl, or heterocycline is independently and optionally substituted; R Ｏ Each example is independent of H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C １－６ An acyl, or oxygen protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R Ｓ Each example is independent of H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C １－６ An acyl or sulfur protecting group, where each alkyl, cycloalkyl, heterocyclyl, or acyl is independently and optionally substituted; R Ｓ１ Each example is independent of C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ The elements are cycloalkyl or 3- to 7-membered heterocyclines, where each alkyl, cycloalkyl, or heterocycline is independently and optionally substituted.

101. A compound according to any one of claims 1 to 100, or a pharmaceutically acceptable salt thereof.

102. A pharmaceutical composition comprising a compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug.

103. A method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate thereof, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

104. A method for treating a subject in need of treatment for a disease, disorder, or condition associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

105. The method according to claim 103 or 104, wherein the method enhances the opening of a Kv7 potassium channel.

106. The method according to 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 according to any one of claims 103 to 106, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

108. A method for treating a subject in need of treatment for a paroxysmal disorder, depressive disorder, pain, or anhedonia, the method comprising administering to the subject a compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof.

109. The method according to any one of claims 103 to 108, wherein the subject is a human.

110. A compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in enhancing Kv7 potassium channels in a subject.

111. A compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of a disease, disorder, or condition associated with dysfunction of the Kv7 potassium channel in a subject.

112. A compound for use in claim 110 or 111, wherein the compound enhances the opening of a Kv7 potassium channel.

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. A compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use in the treatment of paroxysmal disorders, depressive disorders, pain, or anhedonia in a subject.

116. The method according to any one of claims 110 to 115, wherein the subject is a human.

117. A compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, isotope-labeled derivative, or prodrug, or a pharmaceutical composition thereof, for use as a pharmaceutical.

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