Arylamine compound and use thereof

Abstract

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

Description

[0001] Related applications

[0002] This application is based on 35 USC 119(e) claims priority to U.S. Provisional Patent Application No. 63 / 520,164, filed August 17, 2023, and U.S. Provisional Patent Application No. 63 / 570,014, filed March 26, 2024, the full contents of which are incorporated herein by reference. Background Technology

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

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

[0005] This document provides compounds comprising any of the formulas described herein (e.g., formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. The compounds provided herein can act as potentiators of voltage-gated potassium channels (e.g., Kv7 potassium channels, such as Kv7.2 / Kv7.3) and are therefore suitable for the treatment and / or prevention of diseases, conditions, and disorders (e.g., diseases, conditions, and disorders associated with Kv7 potassium channel dysfunction). This document also provides pharmaceutical compositions comprising the compounds provided herein, and kits comprising said pharmaceutical compositions. Additionally, this disclosure provides methods for preparing the compounds and pharmaceutical compositions described herein, as well as intermediates useful thereto.

[0006] In one respect, this article provides compounds of formula (I):

[0007] (I),

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

[0009] In some embodiments, for example, the compound of formula (I) is selected from those compounds listed in Table 1 (hereinafter), and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs.

[0010] On the other hand, this document provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In some embodiments, the pharmaceutical compositions provided herein comprise an effective amount (e.g., a therapeutically effective amount) of a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0011] As described herein, the compounds and pharmaceutical compositions provided herein can enhance voltage-gated potassium channels (e.g., Kv7.2 / Kv7.3 potassium channels) and are therefore suitable for the treatment and / or prevention of diseases, conditions and disorders in subjects, including, for example, indications involving Kv7 potassium channel dysfunction.

[0012] In other respects, this document provides methods and uses for the compounds and pharmaceutical compositions provided herein, including but not limited to the following:

[0013] (a) A method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0014] (b) A method of treating a subject in need of a disease, condition or disorder associated with dysfunction of a Kv7 potassium channel (e.g., Kv7.2 / Kv7.3), comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0015] (c) A method of treating a subject with seizure disorder, depression, pain or anhedonia, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0016] (d) A method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in in vitro cells, comprising administering to said cells a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0017] In another aspect, this document provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof, for use in any of the methods provided herein. In another aspect, this document provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof, for use as pharmaceutical agents and / or for the preparation of pharmaceutical agents.

[0018] On the other hand, this document provides kits comprising the compounds disclosed herein, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives or prodrugs thereof, or pharmaceutical compositions thereof. The kits described herein may comprise single-dose or multiple-dose compounds or pharmaceutical compositions thereof. The kits described herein may be used in any of the methods or uses provided herein and optionally further include instructions for using the kit (e.g., instructions for using the compounds or compositions included in the kit).

[0019] This document also provides methods for preparing the compounds disclosed herein, their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, and pharmaceutical compositions thereof. Synthetic intermediates that can be used to prepare the compounds and compositions are also provided herein.

[0020] As described below, details of certain embodiments of this disclosure are set forth in the specific embodiments. Other embodiments of this disclosure will become apparent from the definitions, implementation details, abstract, and claims.

[0021] definition

[0022] Chemical definition

[0023] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner pages, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; and Michael B. Smith, March's Advanced Organic Chemistry, 7th edition. , John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive OrganicTransformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed. , Cambridge University Press, Cambridge, 1987.

[0024] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEliel ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further covers compounds that are substantially free of other isomers and, alternatively, mixtures of various isomers.

[0025] Unless otherwise provided, the formulas and structures described herein include compounds that do not contain isotopically enriched atoms, and also include compounds that do contain isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the structures of the present invention (hydrogen replaced by deuterium or tritium, ...) 19 F was 18 F replacement or carbonization 13 C or 14 (Except for carbon substitution enriched with C) This disclosure applies. Such compounds can be used as analytical tools or probes, for example, in bioassays. The term "isotope" refers to a variant of a particular chemical element such that, although all isotopes of a given element have the same number of protons per atom of the element, those isotopes differ in the number of neutrons.

[0026] When a range of values ​​is listed (“range”), it encompasses every value within the range and its subranges. Unless otherwise specified, a range includes the values ​​at both ends of the range. For example, “C” 1-6 "Alkyl" encompasses C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5-6 alkyl.

[0027] The phrase “at least one instance” is used to refer to one, two, three, four or more instances, but also includes, for example, one to four, one to three, one to two, two to four, two to three or three to four instances, including endpoints.

[0028] The term "aliphatic" refers to alkyl, alkenyl, ynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic group" refers to heteroalkyl, heteroalkenyl, heteroynyl, and heterocyclic groups.

[0029] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C16”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and n-dodecyl (C9). 12 ), etc. Unless otherwise stated, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C 1-12 Alkyl groups (such as unsubstituted C4) 1-6 Alkyl groups, such as -CH3 (Me), unsubstituted ethyl groups (Et), unsubstituted propyl groups (Pr, such as unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), and unsubstituted butyl groups (Bu, such as 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 some embodiments, the alkyl group is a substituted C. 1-12 Alkyl groups (such as substituted C4 groups) 1-6 Alkyl groups, such as –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3 or benzyl (Bn)).

[0030] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen (e.g., fluorine, bromine, chlorine, or iodine). "Hyperhaloalkyl" is a subset of haloalkyl groups and refers to an alkyl group in which all hydrogen atoms are independently replaced by a halogen (e.g., fluorine, bromine, chlorine, or iodine). In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C"). 1-20 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C10”). 1-10 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1”). 1-9 (“haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C”). 1-8 (“halogenated alkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C”). 1-7(Halogenated alkyl group). In some embodiments, the halogenated alkyl group has 1 to 6 carbon atoms (“C6”). 1-6 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1”). 1-5 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1”). 1-4 Haloalkyl group”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1”). 1-3 (Halogenated alkyl group). In some embodiments, the halogenated alkyl group has 1 to 2 carbon atoms (“C2”). 1-2 (Haloalkyl). In some embodiments, all hydrogen atoms of the haloalkyl group are independently replaced by fluorine to provide a "perfluoroalkyl". In some embodiments, all hydrogen atoms of the haloalkyl group are independently replaced by chlorine to provide a "perchloroalkyl". Examples of haloalkyl groups include –CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, etc.

[0031] The term "heteroalkyl" refers to an alkyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroalkyl group is an alkyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, and sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroalkyl group refers to a saturated group ("C") having 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain. 1-20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms within the parent chain (“C…”). 1-12 (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–11 (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–10 (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–9 (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–8(“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–7 (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C”). 1–6 (Heteroalkyl). In some embodiments, the heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C…”). 1–5 (Heteroalkyl). In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C…”). 1–4 (Heteroalkyl). In some embodiments, the heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain (“C…”). 1–3 (Heteroalkyl). In some embodiments, the heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain (“C…”). 1–2 In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“C1 heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms within the parent chain (“C1 heteroalkyl”). 2-6 (Heteroalkyl). Unless otherwise stated, each instance of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”).

[0032] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, the alkenyl group has 2 to 20 carbon atoms ("C..."). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 12 carbon atoms (“C”). 2–12 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 11 carbon atoms (“C”). 2–11 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2–10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2–9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2–8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2–5Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2–3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. One or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenes include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenes include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl is independently unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In alkenes, the stereochemical C=C double bond is not specified (e.g., -CH=CHCH3 or ...). It can be in (E)- or (Z)- configuration.

[0033] The term "heteroalkenyl" refers to an alkenyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more end positions of the parent chain. In some embodiments, a heteroalkenyl is an alkenyl group that further comprises at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more end positions of the parent chain. In some embodiments, a heteroalkenyl refers to a group ("C") having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain. 2-20 (“heterenyl”). In some embodiments, a heteroene group refers to a group having 2 to 12 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“C”). 2-12 "Heteroalkenyl"). In some embodiments, heteroalkenyl 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 (“heterene”). In some embodiments, a heteroene group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“C”). 2-10 (“heterene”). In some embodiments, the heteroene group has 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2-9(“heterene”). In some embodiments, the heteroene group has 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2–8 (“heterene”). In some embodiments, the heteroene group has 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2–7 (“heterene”). In some embodiments, the heteroene group has 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms (“C”) within the parent chain. 2–6 (“heterene”). In some embodiments, the heteroene group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–5 (“heterene”). In some embodiments, the heteroene group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–4 (“heterene”). In some embodiments, the heteroene group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“C”) within the parent chain. 2–3 In some embodiments, the heteroalkenyl group has two carbon atoms, at least one double bond, and one heteroatom (“C2 heteroalkenyl”) within the parent chain. In some embodiments, the heteroalkenyl group has two to six carbon atoms, at least one double bond, and one or two heteroatoms (“C2 heteroalkenyl”) within the parent chain. 2–6 (“heterenyl”). Unless otherwise stated, each instance of a heteroalkenyl is independently unsubstituted (“unsubstituted heteroalkenyl”) or substituted by one or more substituents (“substituted heteroalkenyl”).

[0034] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 2-20 The alkynyl group (“acetylation”) has 2 to 10 carbon atoms in some embodiments. 2-10 The alkynyl group (“Alynyl”) has 2 to 9 carbon atoms in some embodiments. 2-9 The alkynyl group (“acetylation”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“acetylation”) has 2 to 6 carbon atoms in some embodiments. 2-6 The alkynyl group (“H”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C”). 2-5 The alkynyl group (“H”) has 2 to 4 carbon atoms in some embodiments. 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4 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 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Additional examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of the alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (“substituted alkynyl”).

[0035] The term "heteroyne" refers to an alkynyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more terminal positions in the parent chain. In some embodiments, a heteroyne is an alkynyl group that further comprises at least one heteroatom selected from oxygen, nitrogen, and sulfur (e.g., 1, 2, 3, or 4 heteroatoms) within the parent chain (e.g., inserted between adjacent carbon atoms in the parent chain) and / or at one or more terminal positions in the parent chain. In some embodiments, a heteroyne refers to a group having 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("C"). 2–20 (“C-Hydynyl”). In some embodiments, a C-Hydynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain. 2–10 (“heteroyne group”). In some embodiments, the heteroyne group has 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms (“C…”) within the parent chain. 2–9 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms (“C”) within the parent chain. 2–8 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms (“C”) within the parent chain. 2–7 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms (“C”) within the parent chain. 2–6 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C”) within the parent chain. 2–5 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“C”) within the parent chain.2–4 (“Xyrynyl”). In some embodiments, the xyrynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“C”) within the parent chain. 2–3 In some embodiments, the heteroyne group has two carbon atoms, at least one triple bond, and one heteroatom within the parent chain (“C2 heteroyne group”). In some embodiments, the heteroyne group has two to six carbon atoms, at least one triple bond, and one or two heteroatoms within the parent chain (“C2 heteroyne group”). 1–6 (“Zyneyl”). Unless otherwise stated, each instance of a zyneyl group is independently unsubstituted (“unsubstituted zyneyl”) or substituted by one or more substituents (“substituted zyneyl”).

[0036] The term "carbocyclic" or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C"). 3-14 A group consisting of a carbocyclic group (“C”) and a non-aromatic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 14 cyclic carbon atoms (“C”). 3-14 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 13 cyclic carbon atoms (“C”). 3-13 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 12 cyclic carbon atoms (“C”). 3-12 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 11 cyclic carbon atoms (“C”). 3-11 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 10 cyclic carbon atoms (“C”). 3-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 4 to 6 cyclic carbon atoms (“C”). 4-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 6 cyclic carbon atoms (“C”). 5-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6 Carbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-6Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 ), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-10 Carbocyclic and cycloundecyl (C 11 ), spiro[5.5]undecyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or polycyclic (e.g., containing fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”) or tricyclic systems (“tricyclic carbocyclic”)) and may be saturated or may contain one or more carbon-carbon double or triple bonds. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the carbon number continues to specify the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group includes 0, 1, or 2 C=C double bonds in the carbocyclic system, where the valence allows.

[0037] "Cycloalkyl" refers to a saturated carbocyclic group. In some embodiments, the cycloalkyl group has 3 to 14 cyclic carbon atoms ("C"). 3-14 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”).4-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”).

[0038] The term "heterocyclic group" or "heterocycle" refers to a group having a 3- to 14-membered non-aromatic ring system with a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorus ("3-14-membered heterocyclic group"). In some embodiments, the heterocyclic group is a group having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Where the valence allows, the linking point may be attached to the cyclic carbon atom or the cyclic heteroatom of the heterocyclic group. For example, in a heterocyclic group containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, where the valence allows. The heterocyclic group may be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and may be saturated or may contain one or more carbon-carbon double or triple bonds. A heterocyclic polycyclic system may contain one or more heteroatoms in one or two rings. "Hypercyclic group" also includes ring systems in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or ring systems in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring. In such cases, the number of ring members continues to specify the number of ring members in the heterocyclic ring system. Unless otherwise stated, each instance of a heterocyclic group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclic group, wherein one, two, or three atoms in the heterocyclic system are independently oxygen, nitrogen, or sulfur, where the valence allows.

[0039] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0040] Exemplary 3-membered heterocyclic groups containing one heteroatom include azirropropyl, ethylene oxide, and thiopyrropropyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include azirrobutyl, oxetanebutyl, and thiopyranebutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include dioxetanepentyl, oxetanethiopentyl, and dithiopyranepentyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include piperazine, morpholino, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include triazine. Exemplary 7-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromanyl, octahydroisochromanyl, decahydronaphthidyl, decahydro-1,8-naphthidyl, octahydropyrrolo[3,2-b]pyrrole, indololinyl, phthalimide, naphthimide, chromanyl, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyrano[3,2-b]pyrrole, and chromenyl. [4-b]pyrrolithyl, 5,6-dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-dihydrofurano[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthidyl, etc.

[0041] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a ring array) that provides 6-14 ring carbon atoms and zero heteroatoms ("C") in the aromatic ring system. 6-14 Aryl group (“Aryl”). In some embodiments, the aryl group has 6-10 cyclic carbon atoms (“C”). 6-10Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein a linking group or dot is located on the aryl ring, and in such cases, the number of ring members continues to specify the number of ring atoms in the aryl ring system. Unless otherwise stated, each instance of an aryl is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0042] The term "heteroaryl" refers to a group comprising a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the ring array), providing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorus ("5-14 membered heteroaryl"). In some embodiments, the heteroaryl is a group comprising a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the ring array), providing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Where the valence allows, the linker may be attached to the cyclic carbon atom or the cyclic heteroatom of the heteroaryl. For example, in a heteroaryl containing one or more nitrogen atoms, the linker may be a carbon or nitrogen atom, where the valence allows. A heteroaryl polycyclic system may contain one or more heteroatoms in one or two rings. "Hyperaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, wherein the connection point is on the heteroaryl ring, and in such cases, the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in such cases, the number of ring members specifies the number of ring members in the fused polycyclic (aryl / heteraryl) ring system. A polycyclic heteroaryl, in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazoyl, etc.), may have a connection point on either ring, such as a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, the heteroaryl group is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0043] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each instance of a heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”).

[0044] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azirrolyl, oxoheptanyl, and thioheptanyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenidyl, dibenzofuranyl, carbazoleyl, acridineyl, phenothiazinyl, phenoxazinyl, and phenidyl.

[0045] The term "acyl" refers to an acyl group having the general formula -C(=O)R aa -C(=O)OR aa -C(=O)-OC(=O)R aa -C(=O)SR aa -C(=O)N(R)bb )2、-C(=S)R aa -C(=S)N(R) bb )2、-C(=S)S(R aa -C(=NR) bb )R aa -C(=NR) bb OR aa -C(=NR) bb )SR aa and -C(=NR) bb )N(R bb )2 groups, wherein R aa and R bb As defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0046] The term “halogen” or “halogen” refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (bromo, -Br) or iodine (iodinated, -I).

[0047] The term "silyl group" refers to the group -Si(R) aa )3, where R aa As defined in this article.

[0048] Unless otherwise expressly specified, groups are optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" means substituted or unsubstituted groups (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" ynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substitution" means that at least one hydrogen atom present on a group is replaced by a permissible substituent (e.g., a substituent that, upon substitution, produces a stable compound, such as a substituent that does not spontaneously undergo transformation through rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a "substitution" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. The term "substitution" is contemplated to include substitution by all permissible substituents of an organic compound and includes any of the substituents described herein that result in the formation of a stable compound. This disclosure covers any and all such combinations to achieve a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The embodiments described herein are not in any way limited to the exemplary substituents described herein.

[0049] Exemplary substituents (e.g., carbon substituents) include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(Rbb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3 -C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bbP(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc 2. -P(OR) cc )2、-P(R cc )3 + X - -P(OR) cc )3 + X - -P(R) cc 4. -P(OR) cc 4. -OP(R) cc )2、-OP(R cc )3 + X - -OP(OR) cc 2. -OP(OR) cc )3 + X - -OP(R) cc 4. -OP(OR) cc )4、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20 Heterene, C 2–20 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and where X - These are balanced ions;

[0050] Or the two twin hydrogens on the carbon atom are replaced by the following groups: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa=NR bb or = NOR cc ;

[0051] in:

[0052] R aa Each instance is independently selected from C 1-20 Alkyl, C 1-20 All-halogenated alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 1-20 Heteroalkyl, C 2-20 Heterene, C 2-20 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa The groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0053] R bb Each instance is independently selected from hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)(N(R cc )2)2、C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20Heterene, C 2–20 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb The groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0054] R cc Each instance is independently selected from hydrogen, C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20 Heterene, C 2–20 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc The groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0055] R dd Each instance is independently selected from halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2Ree -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)(OR) ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 heteroyne group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two twins dd Substituents bond to form =O or =S, and where X - These are balanced ions;

[0056] Ree Each instance is independently selected from C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 heteroyne group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0057] R ff Each instance is independently selected from hydrogen, C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 heteroyne group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff The groups are joined to form a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0058] R gg Each instance is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1–6 Alkyl, -ON(C) 1–6 Alkyl)2, -N(C 1–6 Alkyl)2, -N(C 1–6 Alkyl)3 + X - -NH(C 1–6 Alkyl)2 + X - -NH2(C 1–6 alkyl) + X - -NH3 + X - -N(OC) 1–6 Alkyl)(C 1–6 Alkyl), -N(OH)(C1–6 Alkyl groups, -NH(OH), -SH, -SC 1–6 Alkyl, -SS(C 1–6 Alkyl), -C(=O)(C 1–6 Alkyl group, -CO2H, -CO2(C 1–6 Alkyl), -OC (=O)(C 1–6 Alkyl), -OCO2(C 1–6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1–6 Alkyl)2、-OC(=O)NH(C 1–6 Alkyl), -NHC(=O)(C 1–6 alkyl), -N(C) 1–6 Alkyl)C(=O)(C 1–6 alkyl), -NHCO2(C 1–6 Alkyl), -NHC(=O)N(C 1–6 alkyl)2、-NHC(=O)NH(C 1–6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1–6 Alkyl group), -OC (=NH)(C 1–6 Alkyl group), -OC (=NH)OC 1–6 Alkyl group, -C(=NH)N(C 1–6 Alkyl)2、-C(=NH)NH(C 1–6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1–6 Alkyl)2、-OC(NH)NH(C 1–6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1–6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1–6 alkyl), -SO2N(C 1–6 alkyl)2、-SO2NH(C 1–6 Alkyl groups, -SO2NH2, -SO2C 1–6 Alkyl, -SO2OC 1–6 Alkyl, -OSO2C 1–6 Alkyl, -SOC 1–6 Alkyl, -Si(C) 1–6 Alkyl)3、-OSi(C 1–6 Alkyl)3-C(=S)N(C 1–6 Alkyl)2、C(=S)NH(C 1–6 Alkyl), C(=S)NH2, -C(=O)S(C 1–6 Alkyl), -C(=S)SC 1–6 Alkyl, -SC(=S)SC1–6 Alkyl, -P(=O)(OC) 1–6 Alkyl)2、-P(=O)(C 1–6 Alkyl)2、-OP(=O)(C 1–6 Alkyl)2、-OP(=O)(OC 1–6 Alkyl)2, C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 1–10 Heteroalkyl, C 2–10 Heterene, C 2–10 heteroyne group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic or 5-10 heteroaryl; or two twins gg Substituents can join to form =O or =S; and each X - These are balanced ions.

[0059] In some embodiments, the substituent (e.g., a carbon atom substituent) has a molecular weight of less than 250, less than 200, less than 150, less than 100, or less than 50 g / mol. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0060] In some embodiments, exemplary substituents (e.g., carbon atom substituents) include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa -N(R) bb )2、-N(R bb )3 + X - -SH, -SR aa -C(=O)R aa -CO2H, -CHO, -CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bbC(=O)N(R bb )2、-NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 membered heteroaryl, of which X - These are balanced ions;

[0061] Or the two twin hydrogens on the carbon atom are replaced by the following groups: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc ;

[0062] R aa Each instance is independently selected from C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa Groups combine to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings;

[0063] R bb Each instance is independently selected from hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb Groups combine to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings; and

[0064] R cc Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Heteroalkyl, C 2-10 Heterene, C 2-10 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc Groups combine to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings.

[0065] In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 1-6 Alkyl, -OR aa -SR aa -N(R) bb )2、–CN、–NO2、-C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-OC(=O)R aa -OCO2R aa -OC(=O)N(R) bb )2、-NR bb C(=O)R aa -NR bb CO2R aa or -NR bb C(=O)N(R bb 2. In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C atom. 1–10 Alkyl, -OR aa -SR aa -N(R) bb )2、–CN、–NO2、-C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-OC(=O)R aa -OCO2R aa -OC(=O)N(R) bb )2、-NR bb C(=O)R aa -NR bb CO2R aa or -NR bb C(=O)N(R bb )2, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6Alkyl, oxygen-protecting group (when attached to an oxygen atom) (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) or sulfur-protecting group (when attached to a sulfur atom) (e.g., acetaminomethyl, t-Bu, 3-nitro-2-pyridinylthioyl, 2-pyridinylthioyl, or triphenylmethyl); and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or nitrogen-protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In some embodiments, each carbon atom substituent is independently halogenated, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl, -OR aa -SR aa -N(R) bb 2. -CN or -NO2. In some embodiments, each carbon atom substituent is independently a halogenated, substituted (e.g., substituted by one or more halogen moieties), or unsubstituted C. 1–6 Alkyl, -OR aa -SR aa -N(R) bb 2. –CN, –SCN, or –NO2, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–6 Alkyl, oxygen-protecting group (when attached to an oxygen atom) (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) or sulfur-protecting group (when attached to a sulfur atom) (e.g., acetaminomethyl, t-Bu, 3-nitro-2-pyridinylthioyl, 2-pyridinylthioyl, or triphenylmethyl); and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–10 Alkyl or nitrogen protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0066] In some embodiments, each nitrogen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb)2 or nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or nitrogen protecting group, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or oxygen protecting group (when attached to an oxygen atom); and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or nitrogen protecting group.

[0067] In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen protecting groups include -OH, -OR... aa -N(R) cc )2、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc C 1–10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2–20 alkenyl, C 2–20 alkynyl group, C 1–20 Heteroalkyl, C 2–20 Heterene, C 2–20 heteroyne group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aralkyl, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and include Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition. The references described in detail in John Wiley & Sons, 1999, are incorporated herein by reference.

[0068] For example, in some embodiments, at least one nitrogen protecting group is an amide (e.g., including a nitrogen protecting group (e.g., -C(=O)R) aa (The part directly connected to the nitrogen atom). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridinecarboxamide, 3-pyridylcarboxamide, N-benzoylphenylpropanamide derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0069] For example, in some embodiments, at least one nitrogen protecting group is a carbamate group (e.g., including nitrogen protecting groups (e.g., -C(=O)OR)). aa(The portion directly connected to the nitrogen atom). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: methyl carbamate, ethyl carbamate, 9-enyl methyl carbamate (Fmoc), 9-(2-sulfonyl)enyl methyl carbamate, 9-(2,7-dibromo)fluoroenyl methyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl methyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trichloroethyl carbamate, etc. Methyl silyl ethyl ester (Teoc), 2-phenyl ethyl carbamate (hZ), 1-(1-adamantyl)-1-methyl ethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methyl ethyl carbamate (t-Bumeoc), 2-(2- and 4-pyridyl)ethyl carbamate (Pyoc) ), 2-(N,N-dicyclohexylformamido) ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-- Bromobenzyl ester, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinyl benzyl carbamate (Msz), 9-anthrayl methyl carbamate, diphenyl carbamate, 2-methylthioethyl carbamate, 2-methanesulfonyl ethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiaalkyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphoethyl carbamate (Peoc), 2-triphenylphosphoisopropyl carbamate (Ppoc), 1-carbamate1-Dimethyl-2-cyanoethyl ester, m-chloro-p-acyloxybenzyl ester of carbamate, p-(dihydroxyboryl)benzyl ester of carbamate, 5-benzisoxazolyl methyl ester of carbamate, 2-(trifluoromethyl)-6-chromone methyl ester of carbamate (Tcroc), m-nitrophenyl ester of carbamate, 3,5-dimethoxybenzyl ester of carbamate, o-nitrobenzyl ester of carbamate, 3,4-dimethoxy-6-nitrobenzyl ester of carbamate, phenyl(o-nitrophenyl)methyl ester of carbamate, tert-amyl ester of carbamate, S-benzyl ester of thiocarbamate, p-cyanoethyl ester of carbamate Benzyl ester, Cyclobutyl carbamate, Cyclohexyl carbamate, Cyclopentyl carbamate, Cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylvinyl carbamate, o-(N,N-dimethylformamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamide)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate (carbamate), isobutyl carbamate, isonicocyanate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0070] In some embodiments, at least one nitrogen protecting group is a sulfonamide (e.g., including a nitrogen protecting group (e.g., -S(=O)2R)). aa(The portion directly connected to the nitrogen atom). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide... Amines (Mbs), 2,4,6-trimethylbenzenesulfonamides (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamides (iMds), 2,2,5,7,8-pentamethylchromane-6-sulfonamides (Pmc), methanesulfonamides (Ms), β-trimethylsilyl ethyl sulfonamides (SES), 9-anthracitesulfonamides, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamides (DNMBS), benzylsulfonamides, trifluoromethylsulfonamides, and benzyl sulfonamides.

[0071] In some embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of: phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylpropanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazine adduct (STABASE), 5- Substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptanamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N -9-Phenylenylamine (PhF), N-2,7-dichloro-9-pyrenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N-p-nitrobenzylamine, N-salinomylamine, N-5-chlorosalinomylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexylamine) Alkenylamines, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amines, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphamides (Dpp), dimethylthiophosphamides (Mpt), diphenylthiophosphamides (Ppt), dialkyl aminophosphates, dibenzyl aminophosphates, diphenyl aminophosphates, benzyl sulfenamides, o-nitro-o-phenylsulfenamides (Nps), 2,4-dinitrophenylsulfenamides, pentachlorophenylsulfenamides, 2-nitro-4-methoxyphenylsulfenamides, triphenylmethylsulfenamides, and 3-nitropyridinesulfenamides (Npys). In some embodiments, two examples of the nitrogen protecting group together with the nitrogen atom to which the nitrogen protecting group is attached are N,N'-isopropylidene diamines.

[0072] In some embodiments, the nitrogen protecting group is benzyl (Bn), tert-butoxycarbonyl (BOC), carboxybenzyloxy (Cbz), 9-enylamethoxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (Tr), toluenesulfonyl (Ts), p-bromobenzenesulfonyl (Bs), nitrobenzenesulfonyl (Ns), methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), or dansyl (Ds).

[0073] In some embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0074] In some embodiments, each oxygen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or oxygen protecting group. In some embodiments, each oxygen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2 or oxygen protecting group, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or oxygen protecting group (when attached to an oxygen atom); and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-6 Alkyl or nitrogen protecting group. In some embodiments, each oxygen atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or oxygen protecting group.

[0075] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa -N(R) bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NRbb )R aa -C(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa -SO2R aa 、-Si(R aa 3. -P(R) cc )2、-P(R cc )3 + X - -P(OR) cc 2. -P(OR) cc )3 + X - -P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - R aa R bb and R cc As defined herein, oxygen protecting groups are well known in the art and include Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition. The references described in detail in John Wiley & Sons, 1999, are incorporated herein by reference.

[0076] In some embodiments, each oxygen protecting group, together with the oxygen atom to which it is attached, is selected from the group consisting of: methoxy, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl) )Ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-Bromotetrahydropyranyl, Tetrahydrothiaranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl (MTHP), 4-Methoxytetrahydrothiaranyl, 4-Methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-bridged methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxy Ethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl, N-oxide, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenyl Methyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthaliminophenyl)methyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 4,4'-dimethoxy-3"'-[N-(imidazolylmethyl)]triphenylmethyl ether (IDTr-OR), 4,4'-dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]tribenzyl ether (IETr-OR), 1,1-Bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)oxanthracene, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiacyclopentan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl Diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxovalerate (acetylpropionate), 4,4-(ethylidene dithio)valerate (acetylpropionyl dithioacetal), tertylvalerate, adamantyl ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-monomethyl carbonate ( Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-epoxybenzyl ester Nitrobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, dichlorophenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate, alkyl N,N,N',N'-Tetramethyldiaminophosphate, alkyl N-phenylcarbamate, borate, dimethylphosphonothioyl, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (methanesulfonate), benzyl sulfonate, and toluenesulfonate (Ts).

[0077] In some embodiments, the oxygen protecting group is silyl. In some embodiments, the oxygen protecting group is tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), or 1-ethoxyethyl. (EE), 2-methoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytriphenylmethyl (MMT), dimethoxytriphenylmethyl (DMT), allyl, p-methoxybenzyl (PMB), tert-butyl, benzyl (Bn), allyl or pivaloyl (Piv).

[0078] In some embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

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

[0080] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). In some embodiments, each sulfur protecting group is selected from the group consisting of: -R aa -N(R) bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa -SO2R aa 、-Si(R aa 3. -P(R) cc )2、-P(R cc )3 + X - -P(OR) cc 2. -P(OR) cc )3 + X - -P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where R aa R bb and R cc As defined herein, sulfur protecting groups are well known in the art and include Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition. The references described in detail in John Wiley & Sons, 1999, are incorporated herein by reference.

[0081] In some embodiments, the sulfur protecting group is acetaminomethyl, t-Bu, 3-nitro-2-pyridinethioyl, 2-pyridine-thioyl or triphenylmethyl.

[0082] A "balanced ion" or "anionic balance ion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic balance ions can be monovalent (e.g., including one form of negative charge). Anionic balance ions can also be polyvalent (e.g., including more than one form of negative charge), such as divalent or trivalent. Exemplary balance ions include halide ions (e.g., F). – Cl – ,Br – I – NO3 – ClO4 – OH – H2PO4 – HCO3 – HSO4 – Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 – PF4 – PF6 – AsF6 – SbF6 – B[3,5-(CF3)2C6H3]4] – B(C6F5)4 – BPh4 – Al(OC(CF3)3)4 – and carborane anions (e.g., CB) 11 H 12 – or (HCB) 11 Me5Br6) – Exemplary balanced ions that may be multivalent include CO3. 2- HPO4 2- PO4 3- B4O7 2- SO4 2- S2O3 2- Carboxylate anions (such as tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipic acid, pimelic acid, succinate, azelaic acid, sebacic acid, salicylic acid, phthalate, aspartate, glutamate, etc.) and carborane.

[0083] These and other exemplary substituents are described in more detail in the detailed descriptions, embodiments, and claims. The embodiments provided herein are not in any way limited to the exemplary list of substituents described above.

[0084] Other definitions

[0085] The following are more general terms used throughout this application.

[0086] As used herein, the term "salt" means any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds produced by the neutralization reaction of acids and bases. A salt consists of one or more cations (positively charged ions) and one or more anions (negative ions), such that the salt is electrically neutral (without net charge). Salts of the compounds disclosed herein include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts formed by reacting amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactose, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl 4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other salts include ammonium, quaternary ammonium, and amine cations formed using balancing ions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0087] The term "pharmaceutically acceptable salt" refers to those salts that, to the extent of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by reacting amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 – Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0088] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers."

[0089] Stereoisomers that are not mirror images of each other are called diastereomers, and those stereoisomers that are non-overlapping mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described and specified as dextrorotatory or levorotatory by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarization (i.e., as (+)- or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a racemic mixture.

[0090] The term "tautomer" or "tautomer" refers to two or more interconvertible compounds resulting from at least one formal migration of hydrogen atoms and at least one change in valence (e.g., from single to double, triple to single, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerizations include ketone to enol, amide to imide, lactam to lactimide, enamine to imide, and enamine to (different enamines) tautomerization.

[0091] The term "solvent" refers to a compound (including its salts) that typically associates with a solvent via a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, solvates will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0092] The term "hydrate" refers to a solvate in which a compound is associated with water. Typically, the number of water molecules in a compound hydrate is in a definite ratio to the number of compound molecules in the hydrate. Therefore, 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 can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R×0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R×2H₂O) and hexahydrates (R×6H₂O)).

[0093] The term "prodrug" refers to a compound having a cleavable group and being converted into the compound described herein by solvent decomposition or under physiological conditions, which has pharmaceutical activity in vivo. See, for example, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985. Prodrugs include acid derivatives, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the acidic groups side-attached to the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Other derivatives of the compounds described herein are active in both their acidic and acid derivative forms, but the acid-sensitive form often provides advantages in subjects such as solubility, tissue compatibility, or delayed release.

[0094] Throughout this disclosure, references to “the compound” and “a compound” are intended to encompass the compound or group of compounds, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof. Isotopically labeled derivatives are also included.

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

[0096] The term "subject" intended for administration refers to a human being (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird, such as a chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any developmental stage. The non-human animal can be a transgenic or genetically engineered animal. The term "patient" refers to a human subject who requires treatment for a disease, symptom, or illness.

[0097] The terms “administer,” “administering,” or “administration” mean the implantation, absorption, ingestion, injection, inhalation, provision, or other introduction of a compound or combination thereof described herein into, into, or onto a subject.

[0098] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have been acquired or observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen). Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0099] The terms "prevent," "preventing," or "prevention" refer to preventive treatment of a subject who does not have or has had the disease but is at risk of developing it, or who has the disease, or who does not have the disease but is at risk of disease relapse. In some implementations, the subject has a higher risk of developing the disease or a higher risk of disease relapse compared to the average healthy member of the population.

[0100] The terms “illness,” “disease,” and “symptom” are used interchangeably.

[0101] The “effective amount” of the compounds described herein refers to an amount sufficient to elicit the desired biological response. The effective amount of the compounds described herein may vary depending on factors such as: the desired biological endpoint, the severity of side effects, the disease or condition, the identity of the specific compound, pharmacokinetics and pharmacodynamics, the disease being treated, the mode of administration, route of administration and desired or required frequency, the species, age, and health or general condition of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is for prophylactic treatment. In some embodiments, the effective amount is the amount of the compound described herein in a single dose. In some embodiments, the effective amount is the combined amount of the compound described herein in multiple doses. In some embodiments, the effective amount is an amount sufficient to enhance Kv7 potassium channels (e.g., in a subject or in in vitro cells).

[0102] The "therapeuticly effective amount" of the compounds described herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease or to delay or minimize one or more symptoms associated with said disease. Therapeuticly effective amount of a compound means an amount in which a therapeutic agent, alone or in combination with other therapies, provides therapeutic benefit in the treatment of a disease. The term "therapeuticly effective amount" may encompass amounts that improve overall therapy, reduce or avoid symptoms, signs, or causes of a disease, and / or enhance the therapeutic efficacy of another therapeutic agent. In some embodiments, the therapeutically effective amount is an amount sufficient to treat a subject's disease, condition, or disorder (e.g., a disease, condition, or disorder associated with Kv7 potassium channel dysfunction). In some embodiments, the therapeutically effective amount is an amount sufficient to enhance Kv7 potassium channels in a subject.

[0103] The “preventive effective amount” of the compounds described herein is an amount sufficient to prevent a disease, or one or more symptoms associated with said disease, or to prevent its recurrence. The preventive effective amount of a compound means the amount by which a therapeutic agent, alone or in combination with other agents, provides a preventive benefit in preventing a disease. The term “preventive effective amount” may also encompass an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. In some embodiments, the preventive effective amount is an amount sufficient to prevent a subject’s disease, condition, or disorder (e.g., a disease, condition, or disorder associated with Kv7 potassium channel dysfunction). In some embodiments, the preventive effective amount is an amount sufficient to enhance Kv7 potassium channels in a subject.

[0104] Voltage-gated potassium channels (VGKCs) are transmembrane channels that are specific to potassium and sensitive to voltage changes in cell membrane potential. They play a crucial role in returning depolarized cells to a resting state during action potentials. In VGKCs, the α subunit forms the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane core, the α subunits of voltage-gated potassium channels are divided into 12 families (Kv1-12), with Kv7 being one family. The Kv7 family of voltage-gated potassium channels consists of five members (Kv7.1-7.5) encoded by the KCNQ1-5 genes. Of these five members, Kv7.2 / Kv7.3 is an active heterotetramer, which is the major active Kv7 current (M-current) in neurons. Kv7 potassium channels can be members selected from Kv7.1, Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5.

[0105] "Potassium channel enhancer" and "potassium channel opener" are used interchangeably and refer to an agent that restores, enhances, or increases the activity of a potassium channel (e.g., a voltage-gated potassium channel, such as the Kv7 potassium channel), for example, by promoting ion transport across the potassium channel. For the purposes of this disclosure, "potentiating," "potentiation," etc., refer to restoring, enhancing, or increasing the activity or effect of a potassium channel. Detailed Implementation

[0106] This document provides compounds comprising any of the formulas described herein (e.g., formula (I)), and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, isotopically labeled derivatives, and prodrugs thereof. The compounds provided herein can act as potentiators of voltage-gated potassium channels (e.g., Kv7 potassium channels, such as Kv7.2 / Kv7.3) and are therefore suitable for the treatment and / or prevention of diseases, conditions, and disorders (e.g., diseases, conditions, and disorders associated with Kv7 potassium channel dysfunction). This document also provides pharmaceutical compositions comprising the compounds provided herein, and kits comprising said pharmaceutical compositions. Additionally, this disclosure provides methods for preparing the compounds and pharmaceutical compositions described herein, as well as intermediates useful thereto.

[0107] compound

[0108] This article provides compounds of formula (I):

[0109] (I),

[0110] and its pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs, wherein:

[0111] R 1 C 4-8 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted;

[0112] R 2 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted;

[0113] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0114] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0115] R Y For H, C 1-6 Alkyl, C 3-7 cycloalkyl or nitrogen protecting group - , or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0116] Z 1 and Z 2 Each independently for CR Z Or N;

[0117] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group is optionally substituted independently;

[0118] Z 3 Z 4 Z 5 and Z 6 Each independently for CR 4 ;

[0119] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0120] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6- Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0121] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0122] m is 0 or 1;

[0123] n is 0, 1, 2, or 3;

[0124] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O;

[0125] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They bond with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl, or heterocyclic group is independently and optionally substituted; and

[0126] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6- An acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0127] In some embodiments, the compound of formula (I) is the compound of formula (Ia):

[0128] (Ia),

[0129] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0130] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0131] (Ib),

[0132] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0133] In some embodiments, the compound of formula (I) is the compound of formula (Ib-1):

[0134] (Ib-1),

[0135] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0136] In some embodiments, the compound of formula (I) is the compound of formula (Ic):

[0137] (Ic),

[0138] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0139] In some embodiments, the compound of formula (I) is the compound of formula (Ic-1):

[0140] (Ic-1),

[0141] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0142] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0143] (Id),

[0144] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0145] In some embodiments, the compound of formula (I) is the compound of formula (Id-1):

[0146] (Id-1),

[0147] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0148] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0149] (Ie),

[0150] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0151] In some embodiments, the compound of formula (I) is a compound of formula (Ie-5):

[0152] (Ie-5),

[0153] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0154] In some embodiments, the compound of formula (I) is a compound of formula (Ie-1) or (Ie-2):

[0155] (Ie-1),

[0156] (Ie-2),

[0157] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0158] In some embodiments, the compound of formula (I) is a compound of formula (Ie-3) or (Ie-4):

[0159] (Ie-3),

[0160] (Ie-4),

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

[0162] In some embodiments, the compound of formula (I) is the compound of formula (If):

[0163] (If),

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

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

[0166] (If-2),

[0167] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0168] In some embodiments, the compound of formula (I) is the compound of formula (If-1):

[0169] (If-1),

[0170] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

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

[0172] (If-3),

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

[0174] In some embodiments, the compounds provided herein are compounds of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts, stereoisomers, tautomers, or solvates thereof. In some embodiments, the compounds provided herein are compounds of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof. In some embodiments, the compounds provided herein are compounds of formula (I) or any subgenus or species thereof, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds provided herein are compounds of formula (I) in free base form, or any subgenus or species thereof.

[0175] In each aspect and embodiment disclosed herein, explicit reference to a compound of formula (I) should be understood to alternatively refer to any compound of its subgenus or species disclosed, such as the compounds in Table 1.

[0176] In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1, and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1, and their pharmaceutically acceptable salts, stereoisomers, and tautomers. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1, and their pharmaceutically acceptable salts. In some embodiments, the compounds disclosed herein are selected from the compounds listed in Table 1 (in free base form).

[0177] Table 1

[0178]

[0179]

[0180] The following definitions and embodiments apply to all general formulas containing the relevant groups provided herein (e.g., formula (I) or any of its sub-formulas). Any description of a list of chemical groups in any definition of a variable herein includes defining the variable as any single group or combination of the listed groups. Descriptions of embodiments of a variable herein include the embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0181] As defined in this article, R 1 C 4-8 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted.

[0182] In some implementations, R 1 C is arbitrarily replaced 4-8 Alkyl group. In some embodiments, R 1 For unreplaced C 4-8 Alkyl group. In some embodiments, R 1 C is arbitrarily replaced 5-8 Alkyl group. In some embodiments, R 1 For unreplaced C 5-8 Alkyl group. In some embodiments, R 1 C is arbitrarily replaced 6-8 Alkyl group. In some embodiments, R 1 For unreplaced C 6-8 alkyl.

[0183] In some implementations, R 1 For optional replacement of branch C 4-8Alkyl group. In some embodiments, R 1 For unreplaced branch C 4-8 Alkyl group. In some embodiments, R 1 For optional replacement of branch C 5-8 Alkyl group. In some embodiments, R 1 For unreplaced branch C 5-8 Alkyl group. In some embodiments, R 1 For optional replacement of branch C 6-8 Alkyl group. In some embodiments, R 1 For unreplaced branch C 6-8 alkyl.

[0184] In some implementations, R 1 C 3-8 Cycloalkyl, 3-8 membered heterocyclic or C 6-10 Aryl group, wherein cycloalkyl, heterocyclic or aryl groups are optionally substituted.

[0185] In some implementations, R 1 C is arbitrarily replaced 3-8 Cycloalkyl. In some embodiments, R 1 For unreplaced C 3-8 Cycloalkyl. In some embodiments, R 1 C is arbitrarily replaced 3-7 Cycloalkyl. In some embodiments, R 1 For unreplaced C 3-7 Cycloalkyl. In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with C 3-7 Cycloalkyl. In some embodiments, R 1 C is replaced by one or more instances of halogen. 3-7 Cycloalkyl. In some embodiments, R 1 C is replaced by one or more instances of F. 3-7 Cycloalkyl.

[0186] In some implementations, R 1 It is an unsubstituted C3 cycloalkyl (cyclopropyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with cyclopropyl groups. In some embodiments, R 1 The cyclopropyl group is substituted with one or more instances of halogen. In some embodiments, R 1 The cyclopropyl group is replaced by one or more instances of F.

[0187] In some implementations, R 1 It is an unsubstituted C4 cycloalkyl (cyclobutyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl-substituted cyclobutyl groups. In some embodiments, R 1 The cyclobutyl group is substituted with one or more instances of halogen. In some embodiments, R 1 is a cyclobutyl group that is replaced by one or more instances of F.

[0188] In some implementations, R 1 It is an unsubstituted C5 cycloalkyl group (e.g., cyclopentyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with cyclopentyl groups. In some embodiments, R 1 The cyclopentyl group is substituted with one or more instances of halogen. In some embodiments, R 1 , which is a cyclopentyl group substituted by one or more instances of F.

[0189] In some implementations, R 1 It is an unsubstituted C6 cycloalkyl group (e.g., cyclohexyl). In some embodiments, R 1 For halogenated and / or unsubstituted C 1-6 One or more instances of alkyl-substituted cyclohexyl groups. In some embodiments, R 1 A cyclohexyl group substituted with one or more instances of halogen. In some embodiments, R 1 For cyclohexyl groups that are replaced by one or more instances of F.

[0190] In some implementations, R 1 Optionally substituted 3-8 membered heterocyclic groups. In some embodiments, R 1 It is a 3- to 8-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1 Optionally substituted 3-6 membered heterocyclic groups. In some embodiments, R 1 It is a 3- to 6-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1 Optionally substituted 3-5 membered heterocyclic groups. In some embodiments, R 1 It is a 3- to 5-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1It is an optionally substituted 4-membered heterocyclic group having one independently selected cyclic heteroatom chosen from O, N, and S. In some embodiments, R 1 It is a optionally substituted 4-membered heterocyclic group having one independently selected cyclic heteroatom chosen from O and N. In some embodiments, R 1 It is an optionally substituted oxocyclic butyl group. In some embodiments, R 1 It is an unsubstituted oxocyclic butyl group.

[0191] In some implementations, R 1 C is arbitrarily replaced 6-10 Aryl. In some embodiments, R 1 It is an optionally substituted C6 aryl (phenyl). In some embodiments, R 1 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with phenyl groups.

[0192] In some implementations, R 1 Optionally substituted 5-10 membered heteroaryl groups. In some embodiments, R 1 It is a 5-10 membered heteroaryl group having one, two, or three independently substituted cyclic heteroatoms selected from O, N, and S. In some embodiments, R 1 Optionally substituted 5-6 membered heteroaryl groups. In some embodiments, R 1 It is a 5-6 membered heteroaryl group having 1, 2 or 3 independently selected cyclic heteroatoms chosen from O, N and S, which are optionally substituted.

[0193] In some implementations, R 1 for: In some implementations, R 1 for: In some implementations, R 1 for: In some implementations, R 1 for: In some implementations, R 1 for: In some implementations, R 1 for: In some implementations, R 1 for: .

[0194] As defined in this article, R 2 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted.

[0195] In some implementations, R 2 For H.

[0196] In some implementations, R 2 It is a halogen. In some embodiments, R 2 For F. In some implementations, R 2 It is Cl.

[0197] In some implementations, R 2 C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R 2 For unreplaced C 1-6 Alkyl group. In some embodiments, R 2 C is arbitrarily replaced 1-3 Alkyl group. In some embodiments, R 2 For unreplaced C 1-3 Alkyl group. In some embodiments, R 2 It is a methyl group.

[0198] In some implementations, R 2 C 1-6 Halogenated alkyl groups. In some embodiments, R 2 C is arbitrarily replaced 3-8 Cycloalkyl. In some embodiments, R 2 Optionally substituted 3-8 membered heterocyclic groups. In some embodiments, R 2 C is arbitrarily replaced 6-10 Aryl. In some embodiments, R 2 Optionally substituted 5-10 membered heteroaryl groups. In some embodiments, R 2 For -CN.

[0199] In some implementations, R 2 For -OR O .

[0200] In some implementations, R 2 For -OR O , where R O C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R 2 For -OR O , where R OC is arbitrarily replaced 1-3 Alkyl group. In some embodiments, R 2 For -OR O , where R O For unreplaced C 1-3 Alkyl group. In some embodiments, R 2 For -OMe.

[0201] In some implementations, R 2 For -OR O , where R O C 1-6 Halogenated alkyl groups. In some embodiments, R 2 For -OR O , where R O C 1-3 Halogenated alkyl groups. In some embodiments, R 2 For -OR O , where R O It is a C1 haloalkyl group. In some embodiments, R 2 It is -OCF3.

[0202] In some implementations, R 2 -N(R) N 2. In some implementations, R 2 C is arbitrarily replaced 1-6 Acyl group.

[0203] In other implementations, R 2 For -SR S In some implementations, R 2 For -SMe.

[0204] In other implementations, R 2 is -S(=O)2R S1 In some implementations, R 2 It is -S(=O)2Me.

[0205] As defined in this article, R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; and Ar 1 C 6-10 Aryl or 5-10 heteroaryl, wherein the aryl or heteroaryl group is optionally substituted.

[0206] In some implementations, R 3C is arbitrarily replaced 1-8 Alkyl group. In some embodiments, R 3 For unreplaced C 1-8 Alkyl group. In some embodiments, R 3 C is arbitrarily replaced 1-4 Alkyl group. In some embodiments, R 3 For unreplaced C 1-4 Alkyl group. In some embodiments, R 3 It is tert-butyl.

[0207] In some implementations, R 3 C substituted by one or more halogens 1-6 Alkyl group. In some embodiments, R 3 C replaced by one or more F 1-6 Alkyl group. In some embodiments, R 3 C replaced by one or more F 1-3 Alkyl group. In some embodiments, R 3 Is it -CF3, -CH2CF3 or In some implementations, R 3 It is -CH2CF3.

[0208] In some implementations, R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0209] In some implementations, R 3 C is arbitrarily replaced 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-3 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F and / or methyl. 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally replaced by one or more instances of F. 3-8 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-6 Halogenated alkyl groups and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R3 For optional halogen, C 1-3 Halogenated alkyl groups and / or unsubstituted C 1-3 One or more instances of alkyl groups substituted with C 3-8 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F, -CF3, and / or methyl. 3-8 Cycloalkyl.

[0210] In some implementations, R 3 C is arbitrarily replaced 3-6 Cycloalkyl. In some embodiments, R 3 C that is optionally substituted with one or more halogens 3-6 Cycloalkyl. In some embodiments, R 3 C can be optionally replaced by one or more Fs 3-6 Cycloalkyl. In some embodiments, R 3 C replaced by one or more F 3-6 Cycloalkyl. In some embodiments, R 3 It is a C4 cycloalkyl group substituted with one or more F.

[0211] In some implementations, R 3 C is arbitrarily replaced 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally halogenated and / or unsubstituted. 1-3 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F and / or methyl. 3-5 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-6 Halogenated alkyl groups and / or unsubstituted C 1-6 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 For optional halogen, C 1-3 Halogenated alkyl groups and / or unsubstituted C 1-3 One or more instances of alkyl groups substituted with C 3-5 Cycloalkyl. In some embodiments, R 3 C is optionally substituted with one or more instances of F, -CF3, and / or methyl. 3-5Cycloalkyl.

[0212] In some implementations, R 3 C is optionally replaced by one or more instances of F. 3-5 Cycloalkyl. In some embodiments, R 3 C is replaced by one or more instances of F. 3-5 Cycloalkyl. In some embodiments, R 3 C4 cycloalkyl (cyclobutyl) substituted by one or more instances of F.

[0213] In some implementations, R 3 for: .

[0214] In some implementations, R 3 Selected from:

[0215] , , , , , , , , , , , , and .

[0216] In some implementations, R 3 for: In some implementations, R 3 Selected from: and .

[0217] In some implementations, R 3 C is arbitrarily replaced 6-10 Aryl. In some embodiments, R 3 The phenyl group is optionally substituted. In some embodiments, R... 3 C is optionally halogenated and / or unsubstituted. 1-6 One or more instances of alkyl groups substituted with phenyl groups. In some embodiments, R 3 The phenyl group is optionally substituted with one or more instances of halogen. In some embodiments, R 3 A phenyl group that is optionally substituted with one or more instances of F.

[0218] In some implementations, R 3 Selected from:

[0219] , , , and .

[0220] In some implementations, R 3 Optionally substituted 3-7 membered heterocyclic groups. In some embodiments, R 3 It is an optionally substituted 3-6 membered heterocyclic group having one or two ring N atoms. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and optionally substituted with one or more halogens. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and optionally substituted with one or more F atoms. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and being substituted by one or more F atoms. In some embodiments, R 3 It is an nitrogen-containing heterocyclic butyl group substituted with one or more F atoms. In some embodiments, R... 3 It is a 3- to 6-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from N and O. In some embodiments, R 3 A 3-6 membered heterocyclic group having one or two independent cyclic heteroatoms selected from N and O, wherein the heterocyclic group is optionally substituted with one or more instances of a halogen, an unsubstituted C1-6 alkyl group, and / or a C1-6 haloalkyl group. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one ring N atom, wherein the heterocyclic group is optionally converted by halogen, unsubstituted C 1-6 Alkyl and / or C 1-6 One or more instances of haloalkyl substitution. In some embodiments, R 3 A 3-6 membered heterocyclic group having one cyclic heteroatom selected from N and O, wherein the heterocyclic group is optionally substituted with one or more instances of F, Me, and / or -CF3. In some embodiments, R 3 It is a 3-6 membered heterocyclic group having one ring N atom, wherein the heterocyclic group is optionally substituted by one or more instances of F, Me and / or -CF3.

[0221] In some implementations, R 3 for: .

[0222] In some implementations, R 3 Selected from:

[0223] , , , , , , and .

[0224] In some implementations, R 3 -(CR'R”) w -Ar 1 .

[0225] As defined herein, w is 0, 1, or 2. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2.

[0226] As defined in this article, Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted. In some embodiments, Ar 1 C is arbitrarily replaced 6-10 Aryl. In some embodiments, Ar 1 It is a 5-10 substituted heteroaryl group.

[0227] As defined in this article, Y represents a key, -CR'R"-, -O-, or -NR. Y -

[0228] In some implementations, Y is the key.

[0229] In some implementations, Y is -CR'R"-. In some implementations, Y is -CH2-.

[0230] In some implementations, Y is -O-.

[0231] In some implementations, Y is -NR Y - In some implementations, Y is -NH-.

[0232] As defined in this article, R Y For H, C 1-6 Alkyl, C 3-7 A cycloalkyl or nitrogen protecting group, wherein the alkyl or cycloalkyl group is optionally substituted.

[0233] In some implementations, R Y For H.

[0234] In some implementations, R Y C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R Y C is arbitrarily replaced 3-7 Cycloalkyl. In some embodiments, R Y It is a nitrogen-protecting group.

[0235] In other implementations, R Y and R 3 They bond together with intercalating atoms to form 3-7 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted. In some embodiments, R Y and R 3 They combine with intercalated atoms to form optionally substituted 4-6 membered heterocyclic groups.

[0236] In some implementations, Y is -CR'R"- and R 3 C is arbitrarily replaced 1-8 Alkyl group. In some embodiments, Y is -CR'R"- and R 3 C is arbitrarily replaced 1-4 Alkyl group. In some embodiments, Y is -CH2- and R is... 3 For unreplaced C 1-4 Alkyl group. In some embodiments, Y is -CH2- and R is... 3 It is tert-butyl.

[0237] In some implementations, Y is -CH2- and R 3 for: .

[0238] As defined in this article, Z 1 For CR Z Or N. In some implementations, Z 1 For CR Z In some implementations, Z 1 For CH. In some implementations, Z 1 For CCl. In some implementations, Z 1 For CF. In some implementations, Z 1 Let N be the number of elements in the array.

[0239] As defined in this article, Z 2 For CR Z Or N. In some implementations, Z 2 For CR Z In some implementations, Z 2 For CH. In some implementations, Z 2 For CCl. In some implementations, Z 2 For CF. In some implementations, Z 2 Let N be the number of elements in the array.

[0240] In some implementations, Z 1 For CR Z And Z 2 For CR ZIn some implementations, Z 1 For CH and Z 2 For CH. In some implementations, Z 1 For CR Z And Z 2 For N. In some implementations, Z 1 For CH and Z 2 For N. In some implementations, Z 1 For N and Z 2 For CR Z In some implementations, Z 1 For N and Z 2 For CH. In some implementations, Z 1 For N and Z 2 Let N be the number of elements in the array.

[0241] As defined in this article, R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group may be independently and optionally substituted.

[0242] In some implementations, R Z At least one instance is H. In some implementations, R Z Each instance is H.

[0243] In some implementations, R Z At least one instance is a halogen. In some embodiments, R Z At least one instance of R is F. In some implementations, R Z At least one instance of is Cl.

[0244] In some implementations, R Z At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R Z At least one instance of C is 1-6 Halogenated alkyl groups. In some embodiments, R Z At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R Z At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, RZ At least one instance of C is optionally replaced. 6-10 Aryl. In some embodiments, R Z At least one example is an optionally substituted 5-10 membered heteroaryl group. In some embodiments, R Z At least one instance is -CN. In some implementations, R Z At least one instance of -OR O In some implementations, R Z At least one instance is -N(R) N 2. In some implementations, R Z At least one instance of C is optionally replaced. 1-6 Acyl group.

[0245] As defined in this article, Z 3 For CR 4 In some implementations, Z 3 For CH.

[0246] As defined in this article, Z 4 For CR 4 In some implementations, Z 4 For CH. In some implementations, Z 4 For CF.

[0247] As defined in this article, Z 5 For CR 4 In some implementations, Z 5 For CH.

[0248] As defined in this article, Z 6 For CR 4 In some implementations, Z 6 For CH.

[0249] As defined in this article, R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group may be independently and optionally substituted.

[0250] In some implementations, R 4 Each instance is independently H, halogen, or optionally substituted C. 1-6 Alkyl or C1-6 Halogenated alkyl groups. In some embodiments, R 4 Each instance is independently H, halogen, unsubstituted C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups. In some embodiments, R 4 Each instance is independently H, halogen, or unsubstituted C. 1-6 Alkyl group. In some embodiments, R 4 Each instance is independently H or halogen. In some implementations, R 4 Each instance is independently either H or F.

[0251] In some implementations, R 4 At least one instance of H is H.

[0252] In some implementations, R 4 At least one instance is a halogen. In some embodiments, R 4 At least one instance of F is F.

[0253] In some implementations, R 4 At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R 4 At least one instance of C is 1-6 Halogenated alkyl groups. In some embodiments, R 4 At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R 4 At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R 4 At least one instance of C is optionally replaced. 6-10 Aryl. In some embodiments, R 4 At least one example is an optionally substituted 5-10 membered heteroaryl group. In some embodiments, R 4 At least one instance is -CN. In some implementations, R 4 At least one instance of -OR O In some implementations, R 4 At least one instance is -N(R) N 2. In some implementations, R 4 At least one instance of C is optionally replaced. 1-6 Acyl group.

[0254] As defined in this article, R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6- Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0255] In some implementations, R 5 At least one instance is a halogen. In some embodiments, R 5 At least one instance of C is optionally replaced. 1-6 Alkyl group. In some embodiments, R 5 At least one instance of C is 1-6 Halogenated alkyl groups. In some embodiments, R 5 At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R 5 At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, R 5 At least one instance is -CN.

[0256] In some implementations, R 5 At least one instance of -OR O In some implementations, R 5 At least one instance is -OH.

[0257] In some implementations, R 5 At least one instance is -N(R) N 2. In some implementations, R 5 At least one instance of C is optionally replaced. 1-6 Acyl group.

[0258] In some implementations, two R atoms bonded to the same carbon atom 5 It combines with intercalated atoms to form optionally substituted C 3-7 Cycloalkyl. In some embodiments, two R atoms are attached to the same carbon atom. 5 They combine with intercalated atoms to form optionally substituted 3-7 membered heterocyclic groups.

[0259] In some implementations, two R atoms bonded to the same carbon atom 5 Together they form = O.

[0260] As defined in this paper, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, where valence is permissible.

[0261] In some implementations, p is 0.

[0262] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0263] As defined herein, m is 0 or 1. In some implementations, m is 0. In some implementations, m is 1.

[0264] As defined herein, n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0265] In some implementations, both m and n are 1.

[0266] As defined in this paper, each instance of R' is independently H, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is optionally substituted independently.

[0267] In some implementations, at least one instance of R' is H.

[0268] In some embodiments, at least one instance of R' is a halogen. In some embodiments, at least one instance of R' is optionally substituted C. 1-6 Alkyl group. In some embodiments, at least one instance of R' is C. 1-6 Halogenated alkyl group. In some embodiments, at least one instance of R' is an optionally substituted C. 3-7 Cycloalkyl. In some embodiments, at least one instance of R' is an optionally substituted 3-7 membered heterocyclic group.

[0269] As defined in this paper, each instance of R is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, wherein each alkyl group is optionally substituted independently.

[0270] In some implementations, at least one instance of "R" is H.

[0271] In some embodiments, at least one instance of R” is a halogen. In some embodiments, at least one instance of R” is optionally substituted C. 1-6 Alkyl group. In some embodiments, at least one instance of "R" is -OR. O In some implementations, at least one instance of R” is -N(R) N )2.

[0272] In some implementations, R' and R'', which are attached to the same carbon atom, bond together with intercalating atoms to form C. 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally substituted. In some embodiments, R' and R'' attached to the same carbon atom are bonded together with intercalation atoms to form optionally substituted C. 3-7 Cycloalkyl. In some embodiments, R' and R'' attached to the same carbon atom are bonded together with intercalation atoms to form optionally substituted 3-7 membered heterocyclic groups.

[0273] In some implementations, R' and R'', which are attached to the same carbon atom, together form =O.

[0274] As defined in this article, R N1 For H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 An acyl or nitrogen-protecting group, wherein the alkyl, cycloalkyl, or acyl group is optionally substituted.

[0275] In some implementations, R N1 For H.

[0276] In some implementations, R N1 C is arbitrarily replaced 1-6 Alkyl group. In some embodiments, R N1 C is arbitrarily replaced 3-7 Cycloalkyl. In some embodiments, R N1 C is arbitrarily replaced 1-6 Acyl group. In some embodiments, R N1 It is a nitrogen-protecting group.

[0277] As defined in this article, R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They combine with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted independently.

[0278] In some implementations, R N At least one instance is H. In some implementations, R N Each instance is H.

[0279] In some implementations, R N At least one instance of C is optionally replaced. 1-6 alkyl.

[0280] In some implementations, R N At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R N At least one instance of C is optionally replaced. 1-6 Acyl group. In some embodiments, R N At least one instance is a nitrogen protecting group.

[0281] In some implementations, two R atoms bonded to the same carbon atom N They bond together with intercalating atoms to form optionally substituted 3-7 membered heterocyclic groups. In some embodiments, two R atoms are attached to the same carbon atom. N They combine with intercalated atoms to form optionally substituted 4-6 membered heterocyclic groups.

[0282] As defined in this article, R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6- An acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0283] In some implementations, R O At least one instance is H. In some implementations, R O Each instance is H.

[0284] In some implementations, R O At least one instance of C is optionally replaced. 1-6 alkyl.

[0285] In some implementations, R O At least one instance of C is 1-6 Halogenated alkyl groups. In some embodiments, R O At least one instance of C is optionally replaced. 3-7 Cycloalkyl. In some embodiments, R O At least one example is an optionally substituted 3-7 membered heterocyclic group. In some embodiments, RO At least one instance of C is optionally replaced. 1-6- Acyl group. In some embodiments, R O At least one instance is an oxygen protecting group.

[0286] Pharmaceutical compositions, kits and administration

[0287] This disclosure provides pharmaceutical compositions comprising the compounds provided herein (e.g., compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, or prodrugs thereof) and one or more pharmaceutically acceptable carriers and / or excipients. In some embodiments, the compounds described herein are provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a preventatively effective amount.

[0288] The pharmaceutical compositions described herein can be prepared by any method known in pharmacological techniques. Generally, such preparation methods involve associating the compound described herein (i.e., the “active ingredient”) with a carrier or excipient and / or one or more other auxiliary ingredients, and then, if desired and / or packaged, shaping and / or packaging the product into desired single-dose or multiple-dose units.

[0289] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and / or a convenient fraction of that dose, such as one-half or one-third of the dose.

[0290] The relative amounts of the active ingredient, pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, body type, and / or condition of the treated subject and further depending on the route of administration of the composition.

[0291] Pharmaceutically acceptable carriers / excipients used to manufacture the provided pharmaceutical compositions include inert diluents, solvents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, oils, butters and / or waxes. Excipients such as colorants, coating agents, sweeteners, flavoring agents and aromatizers may also be present in the composition.

[0292] The compounds and compositions described herein may be administered via any route, including enterically (e.g., orally), parenterally, intravenously, intramuscularly, intra-arterially, intramedullaryly, intrathecally, subcutaneously, intravenously, percutaneously, intradermally, rectally, intravaginally, intraperitoneally, topically (e.g., via powder, ointment, cream, and / or drops), mucosally, nasally, buccally, sublingually; via endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Specific routes of administration considered include oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymphatic supply, and / or direct administration to the site of influence. Generally, the most appropriate route of administration will depend on a number of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0293] Although the description of pharmaceutical compositions provided herein is primarily directed toward those suitable for human administration, a skilled craftsman will understand that such compositions are generally suitable for administration to a wide variety of animals. It is well known to modify pharmaceutical compositions suitable for human administration to make them suitable for administration to a wide variety of animals, and such modifications can be designed and / or carried out by a generally skilled veterinary physicist using common experimental techniques.

[0294] The compounds described herein are typically formulated in dosage units for ease of administration and uniform dosage. However, it should be understood that the total daily dosage of the compositions described herein will be determined by a physician within the bounds of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the severity of the disease and condition being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific active ingredient used; the duration of the treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well known in medical technology.

[0295] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending on factors such as the subject's species, age and general condition, severity of side effects or illness, the identity of the specific compound, and the mode of administration. An effective dose may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to tissues or cells, any two doses in the multiple doses comprise different or substantially the same amounts of the compound described herein.

[0296] The compounds or compositions described herein may be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutic and / or preventative active agents). The compounds or compositions may be administered in combination with additional pharmaceutical agents that improve the activity of the compounds or compositions (e.g., activity in treating a disease in a subject of need, preventing a disease in a subject of need, or reducing the risk of a subject of need to develop a disease (e.g., potency and / or efficacy)), increase bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in the subject or cells. It should also be understood that the therapy employed may achieve the desired effect for the same condition, and / or may achieve different effects.

[0297] This disclosure also covers kits (e.g., pharmaceutical packs). The provided kits may include the pharmaceutical compositions or compounds described herein and containers (e.g., vials, ampoules, bottles, syringes, and / or dispenser packs or other suitable containers). In some embodiments, the provided kits may optionally further include a second container containing pharmaceutical excipients for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein provided in the first and second containers are combined to form a single unit dosage form. Thus, in one aspect, a kit is provided comprising a first container containing the compounds or pharmaceutical compositions described herein. In some embodiments, the kit may be used to treat and / or prevent a disease, condition, or disorder in a subject of need.

[0298] In some embodiments, the kit described herein further includes instructions for use of the kit. The kit described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit provides instructions for use in treating a condition in a subject in need (e.g., a condition associated with Kv7 potassium channel dysfunction). In some embodiments, the kit provides instructions for use in preventing a condition in a subject in need. The kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0299] Treatment methods and uses

[0300] As described in some aspects, the compounds presented herein can act as voltage-gated potassium channel synergists (e.g., Kv7.2 / Kv7.3 synergists) and are therefore used, for example, to treat diseases, symptoms and ailments.

[0301] In one aspect, this document provides a method for enhancing Kv7 potassium channels in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof. In some embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In some embodiments, the Kv7 potassium channel is Kv7.2. In some embodiments, the Kv7 potassium channel is Kv7.3. In some embodiments, the Kv7 potassium channel is Kv7.2 / Kv7.3. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2-Kv7.5 than for Kv7.1. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2 / Kv7.3 than for Kv7.1.

[0302] This article also provides the compounds disclosed herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, and pharmaceutical compositions for enhancing Kv7 potassium channels in subjects.

[0303] On the other hand, this document provides a method for treating a disease, condition, or disorder associated with Kv7 potassium channel dysfunction in a subject of need, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof. In some embodiments, the disease, condition, or disorder is associated with dysfunction of Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In some embodiments, the disease, condition, or disorder is associated with Kv7.2 dysfunction. In some embodiments, the disease, condition, or disorder is associated with Kv7.3 dysfunction. In some embodiments, the disease, condition, or disorder is associated with Kv7.2 / Kc7.3 dysfunction.

[0304] This document also provides the compounds disclosed herein, as well as pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs, and pharmaceutical compositions thereof, for the treatment of subjects with diseases, conditions or disorders associated with Kv7 potassium channel dysfunction.

[0305] On the other hand, this article provides methods for treating seizure disorders, depression, pain, or anhedonia in subjects in need, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0306] This document also provides the compounds disclosed herein, as well as their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs and pharmaceutical compositions thereof, for the treatment of seizure disorders, depression, pain, or anhedonia in subjects of need.

[0307] In some implementations, the disease, symptom, or disorder is epileptic seizure symptom. "Epileptic seizure disorders" refers to epileptic seizures and related disorders, such as partial seizures (also known as focal seizures), photosensitive epilepsy, self-induced syncope, refractory epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 syndrome, childhood and adolescent absence epilepsy, Dravet syndrome, frontal lobe epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West's syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen's syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, and Lafora progressive myoclonic epilepsy. Myoclonus epilepsy), neurocutaneous syndrome, tuberous sclerosis complex, early-onset epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, paroxysmal dyskinesia, generalized tonic-clonic seizures or primary generalized tonic-clonic seizures or combinations thereof. In some embodiments, the epileptic seizure condition refers to generalized tonic-clonic seizures. In some embodiments, generalized tonic-clonic seizures are defined as primary generalized tonic-clonic seizures. In some embodiments, the epileptic seizure condition is primary generalized tonic-clonic seizures.

[0308] In some embodiments, the term "seizure syndrome" refers to focal paroxysmal epilepsy, also known as partial paroxysmal epilepsy. In some embodiments, seizure syndrome is photosensitive epilepsy. In some embodiments, seizure syndrome is self-induced syncope. In some embodiments, seizure syndrome is refractory epilepsy. In some embodiments, seizure syndrome is Angelman syndrome. In some embodiments, seizure syndrome is benign motor epilepsy. In some embodiments, seizure syndrome is CDKL5 syndrome. In some embodiments, seizure syndrome is childhood and adolescent absence epilepsy. In some embodiments, seizure syndrome is Dravet syndrome. In some embodiments, seizure syndrome is frontal lobe epilepsy. In some embodiments, seizure syndrome is Glut1 deficiency syndrome. In some embodiments, seizure syndrome is hypothalamic hamartoma. In some embodiments, seizure syndrome is infantile spasms / Wechsler syndrome. In some embodiments, seizure syndrome is juvenile myoclonic epilepsy. In some embodiments, seizure syndrome is Landau-Kleffner syndrome. In some embodiments, seizure syndrome is Lennox-Gastaut syndrome (LGS). In some embodiments, the epileptic seizure condition is myoclonic absence epilepsy. In some embodiments, the epileptic seizure condition is Ōtahara syndrome. In some embodiments, the epileptic seizure condition is Panayiotopoulos syndrome. In some embodiments, the epileptic seizure condition is PCDH19 epilepsy. In some embodiments, the epileptic seizure condition is progressive myoclonic epilepsy. In some embodiments, the epileptic seizure condition is Rasmussen syndrome. In some embodiments, the epileptic seizure condition is ring chromosome 20 syndrome. In some embodiments, the epileptic seizure condition is reflex epilepsy. In some embodiments, the epileptic seizure condition is temporal lobe epilepsy. In some embodiments, the epileptic seizure condition is Lafra progressive myoclonic epilepsy. In some embodiments, the epileptic seizure condition is neurocutaneous syndrome. In some embodiments, the epileptic seizure condition is tuberous sclerosis. In some embodiments, the epileptic seizure condition is early-onset epileptic encephalopathy. In some embodiments, the epileptic seizure condition is early-onset epileptic encephalopathy. In some embodiments, the epileptic seizure condition is generalized epilepsy. In some embodiments, the epileptic seizure condition is generalized epilepsy with febrile seizures+. In some embodiments, the epileptic seizure condition is Rett syndrome. In some embodiments, the epileptic seizure condition is multiple sclerosis. In some embodiments, the epileptic seizure condition is Alzheimer's disease. In some embodiments, the epileptic seizure condition is autism. In some embodiments, the epileptic seizure condition is ataxia. In some embodiments, the epileptic seizure condition is hypotonia. In some embodiments, the epileptic seizure condition is paroxysmal dyskinesia.In some implementations, the epileptic seizure condition is a generalized paroxysmal seizure. In some implementations, the epileptic seizure condition is a focal paroxysmal seizure (also known as a partial paroxysmal seizure).

[0309] In some implementations, the disease, symptom, or disorder is depression. "Depression" is a mood disorder characterized by depressed mood. In some implementations, depression includes major depressive disorder (MDD), disruptive mood disorder, persistent depression, bipolar disorder, postpartum depression, premenstrual mood disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with melancholic mood, chronic depressive reaction, or a combination thereof. This disclosure also covers the treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, social phobia, agoraphobia, agoraphobia with panic disorder, hypochondriasis, post-traumatic stress disorder (PTSD), treatment-resistant bipolar disorder, generalized anxiety disorder, attention deficit / hyperactivity disorder (ADHD), type I bipolar disorder, type II bipolar disorder, mania, cyclothymic mood disorder and unspecified bipolar disorder, mild depression, unspecified depression, mild depression, recurrent transient depression, depressive psychosis, impulse control disorder, schizophrenia, schizophrenia-like disorder, schizoaffective disorder, Parkinson's disease, dementia, Alzheimer's disease, Huntington's disease, Tourette's syndrome, aggression and substance use and / or abuse or combinations thereof.

[0310] In some implementations, depression is major depressive disorder (MDD). In some implementations, depression is disruptive mood disorder. In some implementations, depression is persistent depression. In some implementations, depression is bipolar spectrum disorder. In some implementations, depression is postpartum depression. In some implementations, depression is premenstrual mood disorder (PMDD). In some implementations, depression is seasonal affective disorder (SAD). In some implementations, depression is atypical depression. In some implementations, depression is treatment-resistant depression (TRD). In some implementations, depression is depression associated with agitation or anxiety. In some implementations, depression is adjustment disorder with melancholic mood. In some implementations, depression is chronic depressive reaction.

[0311] In some implementations, disease, symptom, or disorder is pain. As used herein, “pain” means all categories of pain and includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgia, orofacial pain, burn pain, burning mouth syndrome, somatic pain, visceral pain, myofibril pain, toothache, cancer pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, labor pain, contractions, reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder disorder, acute pain (e.g., musculoskeletal and postoperative pain), chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, familial hemiplegic migraine, headache-related disorders, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, thalamic lesions, radiculopathy, HIV pain, postherpetic neuralgia, noncardiac chest pain, irritable bowel syndrome, and pain associated with intestinal disorders and indigestion, and combinations thereof.

[0312] In some implementations, illness, symptom, or disorder is defined as anhedonia. As used herein, "anhedonia" refers to a significant reduction in interest or pleasure in all or almost all activities. Mild anhedonia is sometimes referred to as hypohedonia. Social anhedonia is a type of anhedonia. As used herein, "social anhedonia" refers to a lack of interest in social contact and a lack of pleasure in social situations. Social anhedonia is characterized by social withdrawal and is often manifested as indifference to social interactions with others. This trait is considered a core feature and predictor of schizophrenia spectrum disorders.

[0313] On the other hand, this document provides the compounds disclosed herein, and their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs, and pharmaceutical compositions thereof, which are used as pharmaceutical agents. In some embodiments, the pharmaceutical agents are used to treat a subject with a disease, condition, or disorder associated with Kv7 potassium channel dysfunction (e.g., Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5 dysfunction, such as Kv7.2 / Kc7.3 dysfunction). In some embodiments, the pharmaceutical agents are used to treat a subject with seizure disorders, depression, pain, or anhedonia.

[0314] This document also provides a method for enhancing Kv7 potassium channels in in vitro cells, comprising contacting said cells with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or pharmaceutical composition thereof. In some embodiments, the Kv7 potassium channel is Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5. In some embodiments, the Kv7 potassium channel is Kv7.2. In some embodiments, the Kv7 potassium channel is Kv7.3. In some embodiments, the Kv7 potassium channel is Kv7.2 / Kv7.3. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2-Kv7.5 than for Kv7.1. In some embodiments, the compound or composition has higher selectivity for one or more of Kv7.2 / Kv7.3 than for Kv7.1.

[0315] This document provides a method for enhancing Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) in subjects or in vitro cells. In some embodiments, the activity of Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% relative to a control. In some embodiments, the activity of Kv7 potassium channels (e.g., Kv7.2 / Kv7.3) is increased by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, or at least 1000-fold relative to a control.

[0316] Additional implementation plan

[0317] Additional implementation plans are provided according to the following numbered implementation plans:

[0318] Implementation Scheme 1. A compound of formula (I):

[0319] (I),

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

[0321] R 1 C 4-8 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted;

[0322] R 2 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted;

[0323] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0324] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0325] R Y For H, C 1-6 Alkyl, C 3-7 cycloalkyl or nitrogen protecting group - , or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0326] Z 1 and Z 2 Each independently for CR Z Or N;

[0327] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0328] Z 3 Z4 Z 5 and Z 6 Each independently for CR 4 ;

[0329] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0330] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6- Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0331] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0332] m is 0 or 1;

[0333] n is 0, 1, 2, or 3;

[0334] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O;

[0335] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They bond with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl, or heterocyclic group is independently and optionally substituted; and

[0336] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6- An acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0337] Implementation Scheme 2. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

[0338] Implementation Scheme 3. The compound as described in Implementation Scheme 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

[0339] Implementation Scheme 4. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

[0340] Implementation Scheme 5. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia):

[0341] (Ia),

[0342] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0343] Implementation Scheme 6. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ib):

[0344] (Ib),

[0345] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0346] Implementation Scheme 7. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ic):

[0347] (Ic),

[0348] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0349] Implementation Scheme 8. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Id):

[0350] (Id),

[0351] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0352] Implementation Scheme 9. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-8 Cycloalkyl, 3-8 membered heterocyclic or C 6-10 Aryl group, wherein the cycloalkyl, heterocyclic or aryl group is optionally substituted.

[0353] Implementation Scheme 10. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 C 3-8 Cycloalkyl, 3-6 membered heterocyclic or phenyl groups, wherein the cycloalkyl, heterocyclic or phenyl group is optionally halogenated and / or unsubstituted C 1-6 One or more instances of alkyl groups are substituted.

[0354] Implementation Scheme 11. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 Selected from:

[0355] , , , , , and .

[0356] Implementation Scheme 12. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

[0357] Implementation Scheme 13. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

[0358] Implementation Scheme 14. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

[0359] Implementation Scheme 15. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a halogen.

[0360] Implementation Scheme 16. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is F.

[0361] Implementation Scheme 17. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0362] Implementation Scheme 18. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0363] Implementation Scheme 19. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

[0364] Implementation Scheme 20. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 For unreplaced C 1-4 alkyl.

[0365] Implementation Scheme 21. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

[0366] Implementation Scheme 22. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0367] Implementation Scheme 23. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-6 Cycloalkyl.

[0368] Implementation Scheme 24. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C can be optionally replaced by one or more Fs 3-6 Cycloalkyl.

[0369] Implementation Scheme 25. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for: .

[0370] Implementation Scheme 26. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Optionally substituted 3-7 membered heterocyclic groups.

[0371] Implementation Scheme 27. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

[0372] Implementation Scheme 28. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and optionally substituted by one or more F atoms.

[0373] Implementation Scheme 29. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for .

[0374] Implementation Scheme 30. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

[0375] Implementation Scheme 31. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

[0376] Implementation Scheme 32. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CR Z .

[0377] Implementation Scheme 33. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

[0378] Implementation Scheme 34. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 3 For CR 4 .

[0379] Implementation Scheme 35. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z3 For CH.

[0380] Implementation Scheme 36. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 4 For CR 4 .

[0381] Implementation Scheme 37. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 4 For CF.

[0382] Implementation Scheme 38. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 5 For CR 4 .

[0383] Implementation Scheme 39. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 5 For CH.

[0384] Implementation Scheme 40. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 6 For CR 4 .

[0385] Implementation Scheme 41. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 6 For CH.

[0386] Implementation Scheme 42. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is a halogen.

[0387] Implementation Scheme 43. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of F is F.

[0388] Implementation Scheme 44. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

[0389] Implementation Scheme 45. The compound as described in Implementation Scheme 1, wherein the compound is selected from those in Table 1, and pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives, and prodrugs thereof.

[0390] Implementation Scheme 46. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof.

[0391] Implementation Scheme 47. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0392] Implementation Scheme 48. A method for enhancing the Kv7 potassium channel in a subject, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0393] Implementation Scheme 49. A method for treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0394] Implementation Scheme 50. The method as described in Implementation Scheme 48 or 49, wherein the method enhances the opening of Kv7 potassium channels.

[0395] Implementation Scheme 51. The method of any one of Implementation Schemes 48 to 50, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0396] Implementation Scheme 52. The method of any one of Implementation Schemes 48 to 51, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0397] Implementation Scheme 53. A method for treating a subject in need of epileptic seizures, depression, pain, or anhedonia, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0398] Implementation Scheme 54. The method of any one of Implementation Schemes 48 to 53, wherein the subject is a human being.

[0399] Implementation Scheme 55. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for enhancing the Kv7 potassium channel in a subject.

[0400] Implementation Scheme 56. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

[0401] Implementation Scheme 57. The compound used in Implementation Scheme 55 or 56, wherein the compound enhances the opening of Kv7 potassium channels.

[0402] Implementation Scheme 58. The compound used in any of Implementation Schemes 55 to 57, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0403] Implementation Scheme 59. The compound used in any of Implementation Schemes 55 to 58, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0404] Implementation Scheme 60. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with seizure disorders, depression, pain or anhedonia.

[0405] Implementation Scheme 61. The compound used in any of Implementation Schemes 55 to 60, wherein the subject is a human being.

[0406] Implementation Scheme 62. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a pharmaceutical agent.

[0407] Additional implementation schemes are provided according to the following numbered schemes:

[0408] Implementation Scheme 1. A compound of formula (I):

[0409] (I),

[0410] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein:

[0411] R 1 C 4-8 Alkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted, or R 1 Selected from: , , and ;

[0412] R 2 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted;

[0413] R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;

[0414] Y represents a key, -CR'R"-, -O-, or -NR. Y -;

[0415] R Y For H, C 1-6 Alkyl, C 3-7 cycloalkyl or nitrogen protecting group - , or R Y and R 3It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted;

[0416] Z 1 and Z 2 Each independently for CR Z Or N;

[0417] R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group is optionally substituted independently;

[0418] Z 3 Z 4 Z 5 and Z 6 Each independently for CR 4 ;

[0419] R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted;

[0420] R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6- Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently;

[0421] When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0422] m is 0 or 1;

[0423] n is 0, 1, 2, or 3;

[0424] Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O;

[0425] R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They bond with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl, or heterocyclic group is independently and optionally substituted; and

[0426] R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6- An acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

[0427] Implementation Scheme 2. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

[0428] Implementation Scheme 3. The compound as described in Implementation Scheme 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

[0429] Implementation Scheme 4. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

[0430] Implementation Scheme 5. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ia):

[0431] (Ia),

[0432] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0433] Implementation Scheme 6. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ib):

[0434] (Ib),

[0435] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0436] Implementation Scheme 7. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Ic):

[0437] (Ic),

[0438] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0439] Implementation Scheme 8. The compound as described in Implementation Scheme 1, wherein the compound is a compound of formula (Id):

[0440] (Id),

[0441] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

[0442] Implementation Scheme 9. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for: or .

[0443] Implementation Scheme 10. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for: , or .

[0444] Implementation Scheme 11. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For optional replacement of branch C 4-8 alkyl.

[0445] Implementation Scheme 12. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

[0446] Implementation Scheme 13. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

[0447] Implementation Scheme 14. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

[0448] Implementation Scheme 15. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a halogen.

[0449] Implementation Scheme 16. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is F.

[0450] Implementation Scheme 17. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CR'R"-.

[0451] Implementation Scheme 18. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Y is -CH2-.

[0452] Implementation Scheme 19. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

[0453] Implementation Scheme 20. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 For unreplaced C 1-4 alkyl.

[0454] Implementation Scheme 21. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

[0455] Implementation Scheme 22. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

[0456] Implementation Scheme 23. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-6 Cycloalkyl.

[0457] Implementation Scheme 24. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C can be optionally replaced by one or more Fs 3-6 Cycloalkyl.

[0458] Implementation Scheme 25. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for .

[0459] Implementation Scheme 26. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Optionally substituted 3-7 membered heterocyclic groups.

[0460] Implementation Scheme 27. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

[0461] Implementation Scheme 28. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 heteroalkyl group having one or two ring N atoms and optionally substituted with one or more F atoms.

[0462] Implementation Scheme 29. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for .

[0463] Implementation Scheme 30. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

[0464] Implementation Scheme 31. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

[0465] Implementation Scheme 32. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CR Z .

[0466] Implementation Scheme 33. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

[0467] Implementation Scheme 34. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z And Z 2 For CR Z .

[0468] Implementation Scheme 35. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH and Z 2 For CH.

[0469] Implementation Scheme 36. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z And Z 2 Let N be the number of elements in the array.

[0470] Implementation Scheme 37. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH and Z 2 Let N be the number of elements in the array.

[0471] Implementation Scheme 38. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 3 For CH.

[0472] Implementation Scheme 39. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 4 For CF.

[0473] Implementation Scheme 40. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 5 For CH.

[0474] Implementation Scheme 41. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 6For CH.

[0475] Implementation Scheme 42. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is a halogen.

[0476] Implementation Scheme 43. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of F is F.

[0477] Implementation Scheme 44. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

[0478] Implementation Scheme 45. The compound as described in Implementation Scheme 1, wherein the compound is selected from the following:

[0479]

[0480]

[0481] And its pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs.

[0482] Implementation Scheme 46. The compound as described in any of the preceding implementation schemes, or a pharmaceutically acceptable salt thereof.

[0483] Implementation Scheme 47. A pharmaceutical composition comprising the compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof.

[0484] Implementation Scheme 48. A method for enhancing the Kv7 potassium channel in a subject, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

[0485] Implementation Scheme 49. A method for treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0486] Implementation Scheme 50. The method as described in Implementation Scheme 48 or 49, wherein the method enhances the opening of Kv7 potassium channels.

[0487] Implementation Scheme 51. The method of any one of Implementation Schemes 48 to 50, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0488] Implementation Scheme 52. The method of any one of Implementation Schemes 48 to 51, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0489] Implementation Scheme 53. A method for treating a subject in need of epileptic seizures, depression, pain, or anhedonia, comprising administering to the subject a compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

[0490] Implementation Scheme 54. The method of any one of Implementation Schemes 48 to 53, wherein the subject is a human being.

[0491] Implementation Scheme 55. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for enhancing the Kv7 potassium channel in a subject.

[0492] Implementation Scheme 56. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

[0493] Implementation Scheme 57. The compound used in Implementation Scheme 55 or 56, wherein the compound enhances the opening of Kv7 potassium channels.

[0494] Implementation Scheme 58. The compound used in any of Implementation Schemes 55 to 57, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5.

[0495] Implementation Scheme 59. The compound used in any of Implementation Schemes 55 to 58, wherein the Kv7 potassium channel is Kv7.2 / Kv7.3.

[0496] Implementation Scheme 60. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with seizure disorders, depression, pain or anhedonia.

[0497] Implementation Scheme 61. The compound used in any of Implementation Schemes 55 to 60, wherein the subject is a human being.

[0498] Implementation Scheme 62. The compound of any one of Implementation Schemes 1 to 46, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a pharmaceutical agent.

[0499] Example

[0500] To provide a fuller understanding of this disclosure, the following embodiments are illustrated. The synthetic and biological embodiments described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0501] The examples provided below include procedures, intermediates, and characterization data that can be used, for example, to prepare the compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc., are included herein as aspects of this disclosure.

[0502] Compound Synthesis

[0503] Example 1. N-(2-(4,4-difluorocyclohexyl)-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide

[0504]

[0505] Step 1. Preparation of 4',4'-difluoro-3-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-amine

[0506]

[0507] [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.20 g, 0.27 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.72 g, 2.96 mmol) were added to a solution of 2-bromo-6-methylaniline (0.50 g, 2.69 mmol) and potassium carbonate (1.11 g, 8.06 mmol) in dioxane (5 mL) and water (1 mL) under nitrogen atmosphere. The mixture was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (10 g SepaFlash® Silica Flash column, 0–10% ethyl acetate / petroleum ether gradient eluent, 50 mL / min). The desired fraction was collected and concentrated under vacuum to obtain 0.45 g of crude 4',4'-difluoro-3-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-amine as a white solid, which was used directly without further purification. 1 H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 7.2 Hz, 1H),6.69 (d, J = 7.6 Hz, 1H), 6.55–6.48 (m, 1H), 5.43 (s, 1H), 3.88–3.38 (m, 1H),2.51 (t, J = 14.4 Hz, 2H), 2.42–2.33 (m, 2H), 2.02 (s, 3H), 2.00–1.94 (m,2H).

[0508] Step 2. Preparation of 2-(4,4-difluorocyclohexyl)-6-methylaniline

[0509]

[0510] Palladium on carbon (0.45 g, 10 wt%) was added to a solution of 0.45 g, 2.02 mmol, of 4',4'-difluoro-3-methyl-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-amine (10 mL) in methanol under a nitrogen atmosphere. The suspension was degassed and purged three times with hydrogen. The mixture was stirred for 12 h at 25 °C with hydrogen (15 Psi). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 0.43 g of crude 2-(4,4-difluorocyclohexyl)-6-methylaniline (95% yield) as a white solid, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.02 (J = 7.6,13.2 Hz, 2H), 6.79–6.73 (m, 1H), 3.65 (s, 2H), 2.65–2.54 (m, 1H), 2.33–2.25(m, 2H), 2.23 (s, 3H), 2.03–1.94 (m, 3H), 1.88–1.76 (m, 3H).

[0511] Step 3. Preparation of 4-bromo-2-(4,4-difluorocyclohexyl)-6-methylaniline

[0512]

[0513] N-bromosuccinimide (0.37 g, 2.10 mmol) was added to a cold (0°C) solution of 2-(4,4-difluorocyclohexyl)-6-methylaniline (0.43 g, 1.91 mmol) in dimethylformamide (5 mL). The mixture was stirred at 25°C for 3 h. Ethyl acetate (40 mL) and water (40 mL) were added, and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined extracts were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give 0.55 g of crude 4-bromo-2-(4,4-difluorocyclohexyl)-6-methylaniline as a yellow solid (96% yield). 1 H NMR (400MHz, CDCl3) δ 7.02 (s, 2H), 3.53 (s, 2H), 2.50–2.40 (m, 1H), 2.22–2.12 (m,2H), 2.09 (s, 3H), 1.86 (dd, J = 4.0, 14.4 Hz, 3H), 1.77–1.65 (m, 3H).

[0514] Step 4. Preparation of N-(4-bromo-2-(4,4-difluorocyclohexyl)-6-methylphenyl)-3,3-dimethylbutyramide

[0515]

[0516] 4-Bromo-2-(4,4-difluorocyclohexyl)-6-methylaniline (0.55 g, 1.82 mmol) was added to a cold (0°C) solution of dichloromethane (5 mL) along with pyridine (0.11 g, 1.82 mmol) and 3,3-dimethylbutyryl chloride (0.25 g, 1.82 mmol). The mixture was stirred at 25°C for 2 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (2 × 10 mL) and 1M hydrochloric acid (2 × 10 mL). The organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 g SepaFlash® Silica Flash column, eluent gradient of 0–23% ethyl acetate / petroleum ether, 80 mL / min). The desired fraction was collected and concentrated under vacuum to give 0.56 g of N-(4-bromo-2-(4,4-difluorocyclohexyl)-6-methylphenyl)-3,3-dimethylbutyramide as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.34 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 2.84 (t, J =12.4 Hz, 1H), 2.26 (s, 2H), 2.16–2.09 (m, 5H), 1.86–1.72 (m, 4H), 1.67–1.55 (m, 2H), 1.07 (s, 9H).

[0517] Step 5. Preparation of N-(2-(4,4-difluorocyclohexyl)-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide

[0518]

[0519] Tris(dibenzylacetone)dipalladium(0) (0.073 g, 0.799 mmol), and 2-(2-dicyclohexylphosphine)-N,N-dimethylaniline (0.063 g, 0.160 mmol) were added to a solution of N-(4-bromo-2-(4,4-difluorocyclohexyl)-6-methylphenyl)-3,3-dimethylbutyramide (0.100 g, 0.249 mmol), potassium tert-butoxide (0.112 g, 0.994 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.047 g, 0.249 mmol) in dioxane (2 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C under nitrogen for 12 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna 150 mm × 2 mm × 5 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 62%-92%, B, duration: 10 min). The desired fraction was collected and lyophilized to give 0.027 g of N-(2-(4,4-difluorocyclohexyl)-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide (22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.29 (dd, J= 6.0, 9.2 Hz, 1H), 7.05–6.97 (m, 2H), 6.75 (d, J = 2.4 Hz, 1H), 6.69 (d, J =2.8 Hz, 1H), 4.33 (s, 2H), 3.49 (t, J = 6.0 Hz, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.85–2.74 (m, 1H), 2.22 (s, 2H), 2.19–2.08 (m, 5H), 1.88–1.61 (m, 6H),1.07 (s, 9H); MS (ES+) m / z 473.3 (M + 1).

[0520] Example 2. N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide

[0521]

[0522] Step 1. Preparation of 4-bromo-2-cyclopropyl-6-methylaniline

[0523]

[0524] N-bromosuccinimide (0.40 g, 2.24 mmol) was added to a solution of 2-cyclopropyl-6-methylaniline (0.30 g, 2.04 mmol) in dimethylformamide (5 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was cooled to room temperature. Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (20 g SepaFlash® Silica Flash column, eluent of 0–9% ethyl acetate / petroleum ether gradient, 50 mL / min). The desired fraction was collected and concentrated under vacuum to give 0.43 g of crude 4-bromo-2-cyclopropyl-6-methylaniline as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 4.85 (s, 2H), 2.08 (s, 3H), 1.68 (J = 5.6, 8.0Hz, 1H), 0.93–0.82 (m, 2H), 0.54–0.41 (m, 2H).

[0525] Step 2. Preparation of N-(4-bromo-2-cyclopropyl-6-methylphenyl)-3,3-dimethylbutyramide

[0526]

[0527] Pyridine (0.89 g, 11.30 mmol) and 3,3-dimethylbutyryl chloride (0.51 g, 3.79 mmol) were added to a solution of 4-bromo-2-cyclopropyl-6-methylaniline (0.85 g, 3.76 mmol) in dichloromethane (10 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was washed with saturated sodium bicarbonate (2 × 10 mL) and 1 M hydrochloric acid (2 × 10 mL). The organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was milled with petroleum ether (5 mL) at 25 °C for 12 h. The filter cake was dried under vacuum to give 1.07 g of N-(4-bromo-2-cyclopropyl-6-methylphenyl)-3,3-dimethylbutyramide (88% yield) as a white solid. 1H NMR(400 MHz, CDCl3) δ 7.23 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.83(s, 1H), 2.33 (s, 2H), 2.23 (s, 3H), 1.92–1.83 (m, 1H), 1.16 (s, 9H), 0.97–0.91 (m, 2H), 0.66–0.61 (m, 2H).

[0528] Step 3. Preparation of N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide

[0529]

[0530] Tris(dibenzylacetone)dipalladium(0) (0.056 g, 0.062 mmol) and 2-(2-dicyclohexylphosphinophenyl)-N,N-dimethylaniline (0.049 g, 0.123 mmol) were added to a solution of N-(4-bromo-2-cyclopropyl-6-methylphenyl)-3,3-dimethylbutyramide (0.100 g, 0.308 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.058 g, 0.308 mmol), potassium tert-butoxide (0.138 g, 1.230 mmol) in dioxane (1 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C under nitrogen for 12 h. 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 (formic acid)-acetonitrile]; B%: 64%-84%, B, duration: 10 min). The desired fraction was collected and lyophilized to give 0.017 g of N-(2-cyclopropyl-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide (13% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.03 (dd, J = 5.6, 8.4 Hz, 1H), 6.85–6.76 (m,2H), 6.67–6.60 (m, 2H), 6.50–6.38 (m, 1H), 4.29–4.18 (m, 2H), 3.49–3.33 (m,2H), 2.95–2.82 (m, 2H), 2.24 (s, 2H), 2.17 (s, 3H), 1.87–1.77 (m, 1H), 1.08(s, 9H), 0.94 (s, 1H), 0.87–0.77 (m, 2H), 0.60–0.50 (m, 2H); MS (ES+) m / z 395.3 (M + 1).

[0531] Example 3. N-(2-(3,3-difluorocyclobutyl)-4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-6-methylphenyl)-3,3-dimethylbutyramide

[0532]

[0533] Step 1. Preparation of N-(2-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide

[0534]

[0535] Add pyridine (1.28 g, 16.10 mmol, 1.30 mL) and 3,3-dimethylbutyryl chloride (1.45 g, 10.70 mmol, 1.49 mL) to a cold (0 °C) solution of 2-bromo-6-methylaniline (2.00 g, 10.70 mmol, 14.0 mL) in dichloromethane (14.0 mL). Stir the mixture at 20 °C for 1 h. Slowly pour the mixture into 1.0 M HCl (10.0 mL) and extract with EtOAc (10.0 mL x 3). Wash the combined organic phases with brine (10.0 mL), dry to (Na2SO4), and concentrate under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 1.0 g of N-(2-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide (36% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 9.42 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.2 Hz,1H), 7.16 - 7.07 (m, 1H), 2.22 (s, 2H), 2.19 (s, 3H), 1.07 (s, 9H); MS (ES+)m / z 284.2 (M + 1).

[0536] Step 2. Preparation of N-[2-(3,3-difluorocyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butanamide

[0537]

[0538] Two parallel reactions were performed. N-(2-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide (0.50 g, 1.76 mmol), 3-bromo-1,1-difluoro-cyclobutane (0.36 g, 2.11 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (0.02 g, 0.18 mmol), NiCl2·dtbbpy (0.021 g, 0.052 mmol), tris(trimethylsilyl)silane (TTMSS) (0.44 g, 1.76 mmol, 0.54 mL), Na2CO3 (0.37 g, 3.52 mmol), and MeCN (20.0 mL) were added to 40.0 mL vials equipped with a stir bar. The vials were sealed and placed under nitrogen atmosphere. The reaction was stirred and irradiated with a 34 W blue LED lamp (7.00 cm away) while maintaining the reaction temperature at 25 °C using a cooling fan for 14 h. The two reactions were combined for post-processing. The mixture was filtered and concentrated under vacuum to give 0.64 g of N-[2-(3,3-difluorocyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butanamide as a white solid (62% yield). 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 7.22 - 7.16 (m, 2H), 7.14 (br d, J = 4.4 Hz, 1H), 3.44 (br t, J= 8.8 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.68 - 2.52 (m, 2H), 2.23 (s, 2H), 2.15 (s, 3H), 1.06 (s, 9H).

[0539] Step 3. Preparation of N-[4-bromo-2-(3,3-difluorocyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide

[0540]

[0541] N-bromosuccinimide (1.54 g, 8.67 mmol) was added to a solution of N-[2-(3,3-difluorocyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide (0.64 g, 2.17 mmol) in MeCN (6.4 mL). The mixture was stirred at 50 °C for 12 h. The mixture was slowly poured into water (5.00 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic phases were washed with brine (5.00 mL), dried over (Na2SO4), and concentrated under vacuum to give 0.25 g of N-[4-bromo-2-(3,3-difluorocyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide (31% yield) as a white solid: MS (ES+) m / z 374.0 (M + 1).

[0542] Step 4. Preparation of N-[2-(3,3-difluorocyclobutyl)-4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-6-methyl-phenyl]-3,3-dimethyl-butyramide

[0543]

[0544] A solution of Pd(dba)₂ (0.030 g, 0.053 mmol) and DavePhos (0.042 g, 0.106 mmol) in dry toluene (2.00 mL) was stirred under N₂ for 0.5 h, followed by the addition of t-BuOK (0.149 g, 1.340 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.120 g, 0.641 mmol HCl), and N-[4-bromo-2-(3,3-difluorocyclobutyl)-6-methyl-phenyl]-3,3-dimethyl-butyramide (0.200 g, 0.534 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered with MeOH (5.00 mL) and the filtrate was concentrated under vacuum to give 0.095 g of N-[2-(3,3-difluorocyclobutyl)-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethyl-butyramide (40% yield) as a white solid. 1H NMR (400 MHz, CDCl3-d) δ 8.90 (s, 1H), 7.27 (dd, J= 5.8, 9.2 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.77 (s, 1H), 6.75 (s, 1H), 4.36 (s, 2H), 3.52 (t, J = 5.8 Hz, 2H), 3.44 - 3.35 (m, 1H), 3.35 - 3.32 (m, 4H), 2.92 (br t, J = 5.6 Hz, 2H), 2.88 - 2.75 (m, 2H), 2.73 - 2.55 (m, 2H), 2.53 - 2.47(m, 7H), 2.19 (br s, 2H), 2.10 (s, 3H), 1.05 (s, 9H); MS (ES+) m / z 445.3 (M +1).

[0545] The following other examples (Table 2) were prepared in a similar manner to Example 3 (as described above), with appropriate starting materials substituted where necessary and experimental conditions appropriately modified according to common knowledge. Purification was performed by silica gel chromatography, reversed-phase preparative HPLC, or supercritical fluid chromatography (SFC).

[0546] Table 2

[0547]

[0548] Example 7. N-(4'-fluoro-5-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-3,3'-dimethyl-[1,1'-biphenyl]-2-yl)-3,3-dimethylbutyramide

[0549]

[0550] Step 1. Preparation of 4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-amine

[0551]

[0552] Potassium carbonate (1.12 g, 8.07 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.20 g, 0.27 mmol), and 2-bromo-6-methylaniline (0.50 g, 2.69 mmol) were added to a solution of (4-fluoro-3-methylphenyl)boronic acid (0.50 g, 3.23 mmol) in dioxane (10 mL) and water (1 mL). The mixture was stirred at 100 °C under nitrogen for 16 h. It was then cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (25 g SepaFlash® Silica Flash column, elution with a 0–50% ethyl acetate / petroleum ether gradient, 30 mL / min) to give 0.57 g of 4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-amine as a brown fluid (88% yield): 1 HNMR (400 MHz, DMSO-d6) δ 7.30–7.25 (m, 1H), 7.22–7.16 (m, 2H), 6.96 (d, J =6.8 Hz, 1H), 6.82 (dd, J = 7.6, 1.2 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 4.36(s, 2H), 2.27 (s, 3H), 2.13 (s, 3H); MS (ES+) m / z 216.1 (M + 1).

[0553] Step 2. Preparation of 5-bromo-4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-amine

[0554]

[0555] N-bromosuccinimide (0.43 g, 2.44 mmol) was added to a solution of 4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-amine (0.50 g, 2.32 mmol) in dimethylformamide (20 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25 g SepaFlash® Silica Flash column, elution buffer of 0–50% ethyl acetate / petroleum ether gradient, 30 mL / min) to give 0.68 g of 5-bromo-4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-amine as a black solid (81% yield): MS (ES+) m / z 294.0, 296.0 (M+1).

[0556] Step 3. Preparation of N-(5-bromo-4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-yl)-3,3-dimethylbutyramide

[0557]

[0558] Triethylamine (0.275 g, 2.720 mmol) and 3,3-dimethylbutyryl chloride (0.220 g, 1.630 mmol) were added to a solution of 4-bromo-2-(4-fluoro-3-methyl-phenyl)-6-methyl-aniline (0.400 g, 1.360 mmol) in dichloromethane (20 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25 g SepaFlash® Silica Flash column, elution with a 0–30% ethyl acetate / petroleum ether gradient, 30 mL / min) to give 0.37 g of N-(5-bromo-4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-yl)-3,3-dimethylbutyramide as a white solid (53% yield, 77% purity): 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 2.23 (s, 3H), 2.17 (s,3H), 1.98 (s, 2H), 0.87 (s, 9H).

[0559] Step 4. Preparation of N-(4'-fluoro-5-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-3,3'-dimethyl-[1,1'-biphenyl]-2-yl)-3,3-dimethylbutyramide

[0560]

[0561] 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (0.0050 g, 0.0128 mmol) and bis(dibenzylacetone)palladium (0.0037 g, 0.0064 mmol) were added to dry toluene (6 mL) and stirred under nitrogen for 30 min. Then, 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.0289 g, 0.0191 mmol), N-(5-bromo-4'-fluoro-3,3'-dimethyl-[1,1'-biphenyl]-2-yl)-3,3-dimethylbutyramide (0.0500 g, 0.1270 mmol) and potassium tert-butoxide (0.0358 g, 0.3190 mmol) were added, and the reaction mixture was stirred at 90 °C under nitrogen for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, 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]; B%: 70–100%, 10 min) and lyophilized to give 0.011 g of orange-yellow solid N-(4'-fluoro-5-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-3,3'-dimethyl-[1,1'-biphenyl]-2-yl)-3,3-dimethylbutyramide (18% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.29–7.26 (m, 1H), 7.25–7.23 (m, 1H), 7.15–7.13 (m, 1H), 7.12–7.06 (m, 1H), 7.04–6.99 (m, 2H), 6.91(s, 1H), 6.69 (d, J = 2.4 Hz, 1H), 4.37 (s, 2H), 3.53 (t, J = 5.6 Hz, 2H), 2.93 (t, J = 5.2 Hz, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 1.98 (s, 2H), 0.89 (s,9H); MS (ES+) m / z 463.3 (M + 1).

[0562] Example 10. N-(4-(4,4-difluorocyclohexyl)-2-fluoro-6-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)pyridin-3-yl)-3,3-dimethylbutyramide

[0563]

[0564] Step 1. Preparation of 4-bromo-6-chloro-2-fluoro-pyridine-3-amine

[0565]

[0566] N-bromosuccinimide (1.09 g, 6.14 mmol) was added to a solution of 6-chloro-2-fluoro-pyridin-3-amine (0.90 g, 6.14 mmol) in acetonitrile (20 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate) to give 0.50 g of 4-bromo-6-chloro-2-fluoro-pyridin-3-amine as a yellow solid (36% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.29 (s,1H), 4.20 (s, 2H); MS (ES-) m / z 225.0 (M + 1).

[0567] Step 2. Preparation of 6-chloro-4-(4,4-difluorocyclohexen-1-yl)-2-fluoropyridine-3-amine

[0568]

[0569] Add [1,1-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride (ii) (0.16 g, 0.22 mmol), 2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (ii) (0.65 g, 2.66 mmol), and potassium phosphate (ii) to a solution of 4-bromo-6-chloro-2-fluoropyridin-3-amine (0.50 g, 2.22 mmol), dioxane (10 mL), and water (2 mL) to the solution. Stir the mixture at 90 °C for 8 h. Concentrate the reaction mixture under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate) to give 0.45 g of 6-chloro-4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-pyridin-3-amine as a yellow oil (77% yield): 1 H NMR (400 MHz, CDCl3) δ ppm6.88 (s, 1H), 5.81 (s, 1H), 3.83 (s, 2H), 2.73 (t, J = 14.0 Hz, 2H), 2.50 -2.60 (m, 2H), 2.20 (tt, J = 13.6, 6.8 Hz, 2H); MS (ES-) m / z 263.0 (M + 1).

[0570] Step 3. Preparation of N-[6-chloro-4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-3-pyridyl]-3,3-dimethyl-butyramide

[0571]

[0572] Triethylamine (0.35 g, 3.43 mmol) and 3,3-dimethylbutyryl chloride (0.46 g, 3.43 mmol) were added to a solution of 6-chloro-4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-3-pyridyl]-3,3-dimethylbutyramide (0.46 g, 3.43 mmol) in acetonitrile (10 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether: ethyl acetate) to give 0.45 g of N-[6-chloro-4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-3-pyridyl]-3,3-dimethylbutyramide (73% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δppm 7.09 (s, 1H), 6.60 (s, 1H), 5.64 (s, 1H), 2.54 - 2.75 (m, 4H), 2.24 (s,2H), 2.16 (tt, J = 13.6, 6.8 Hz, 2H), 1.10 (s, 9H); MS (ES-) m / z 361.1 (M +1).

[0573] Step 4. Preparation of N-[4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-6-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-3-pyridyl]-3,3-dimethyl-butyramide

[0574]

[0575] Add 2-dicyclohexylphosphino-2,6-di-isopropoxy-1,1-biphenyl (0.08 g, 0.17 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.19 g, 1.25 mmol), cesium carbonate (0.81 g, 2.49 mmol), and methanesulfonate (2-dicyclohexylphosphino-2,6-di-isopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.07 g, 0.083 mmol) to a solution of N-[6-chloro-4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-3-pyridyl]-3,3-dimethyl-butyramide (0.30 g, 0.83 mmol) in dioxane (10 mL). The mixture was stirred at 75°C under nitrogen for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO2, petroleum ether: ethyl acetate) to give 0.30 g of N-[4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-6-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-3-pyridyl]-3,3-dimethyl-butyramide (76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm7.17 (dd, J = 8.0, 5.6 Hz, 1H), 6.87 - 6.98 (m, 2H), 6.41 (s, 1H), 6.26 (s,1H), 5.60 (s, 1H), 4.63 (s, 2H), 3.80 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 6.0Hz, 2H), 2.56 - 2.72 (m, 4H), 2.22 (s, 2H), 2.14 (tt, J = 13.6, 6.6 Hz, 2H), 1.12 (s, 9H); LCMS: m / z = 476.1 (M+H) + .

[0576] Step 5. Preparation of N-[4-(4,4-difluorocyclohexyl)-2-fluoro-6-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-3-pyridyl]-3,3-dimethyl-butyramide

[0577]

[0578] Add 10% palladium on carbon (0.67 g, 0.63 mmol) to a solution of N-[4-(4,4-difluorocyclohexen-1-yl)-2-fluoro-6-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-3-pyridyl]-3,3-dimethyl-butyramide (0.15 g, 0.32 mmol) in methanol (5 mL). Stir the mixture at 50 °C and 50 psi under hydrogen for 4 h. Filter the reaction mixture under nitrogen and concentrate under reduced pressure. Analyze by reversed-phase HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150). 25 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 56%-86% B, duration: 10 min) to purify the crude product to give 0.14 g of N-[4-(4,4-difluorocyclohexyl)-2-fluoro-6-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-3-pyridyl]-3,3-dimethyl-butyramide (93% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.24 (dd, J = 9.2,5.6 Hz, 1H), 6.84 - 7.01 (m, 2H), 6.49 (s, 1H), 4.63 (s, 2H), 3.80 (t, J =6.0 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.77 - 2.87 (m, 1H), 2.29 (s, 2H), 2.10 - 2.23 (m, 2H), 1.74 - 1.95 (m, 6H), 1.13 (s, 9H); LCMS: RT = 5.054 min, m / z = 478.3 (M+H) + .

[0579] The following other examples (Table 3) were prepared in a similar manner to Example 10 (as described above), with appropriate starting materials substituted where necessary and experimental conditions appropriately modified according to common knowledge. Purification was performed by silica gel chromatography, reversed-phase preparative HPLC, or supercritical fluid chromatography (SFC).

[0580] Table 3

[0581]

[0582] Bioactivity

[0583] Kv7.2 / Kv7.3 Potassium Channel Determination

[0584] This potassium flux assay uses the cell-permeable potassium-sensitive dye IPG-2 AM to quantify the potassium ion flux through potassium channels. Generally, TREX HEK 293 or HEK 293 cells are treated with a dye containing the human potassium encoding the desired potassium level. V 7.2 / K V 7.3 full-length cDNA in an inducible or non-inducible expression vector or with another encoding a second desired human K VA stable combination of full-length cDNA for the 7 potassium channels was transfected. If desired, potassium channel expression cell lines were induced with tetracycline (1 μg / mL) and plated in DMEM medium (containing 10% FBS and 1% L-glutamine) on 384-well poly-D-lysine (PDL) coated plates. After overnight incubation, the medium was removed, and cells were loaded with 5 μM IPG-2 AM dye for 1 hour in assay buffer (140 mM NaCl, 20 mM RbCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid buffer), 10 mM glucose, adjusted to pH 7.4 with Tris). Excess dye was removed, and cells were incubated at room temperature for 20 minutes with or without the test compound. For human K V 7.2 / K V 7.3 Using a Hamamatsu FDSS μCell, K excitation buffer (150 mM NaCl, 10 mM HEPES, 2 mM CaCl2, 10 mM KCl, 1 mM MgCl2, 10 mM glucose, adjusted to pH 7.4 with Tris) was added at a 1:1 ratio, and the plate was read simultaneously at an excitation wavelength of 530 nm and an emission wavelength of 558 nm. Non-potassium channel-mediated potassium influx was measured in the presence of DMSO, and the K0 was measured at known K0. V Maximum inflow was determined in the presence of a 7.x channel modulator. For each test compound, concentration-response curves were generated at 16 concentration points, starting with a 2-fold serial dilution from 30 μM, and EC was determined. 50 value.

[0585] The compounds presented in this paper are synergists for Kv7.2 / Kv7.3 potassium channels, as shown in Table 3.

[0586] Table 3

[0587]

[0588] For EC 50 value:

[0589] ++++ indicates a value less than 1 μM

[0590] +++ indicates a value from 1 to 10 μM.

[0591] ++ indicates a value of 10 to 30 μM.

[0592] + Indicates a value of 30 μM or greater.

[0593] Equivalents and scope

[0594] In the claims, articles such as "a / an" and "the" may refer to one or more, unless the contrary is indicated or the context otherwise becomes apparent. Unless the contrary is indicated or the context otherwise becomes apparent, a claim or description including "or" among one or more members of a group is deemed satisfied if one, more than one, or all members of a group are present, used in, or otherwise associated with a given product or process. This disclosure includes embodiments in which exactly one member of the group is present, used in, or otherwise associated with a given product or process. This disclosure includes embodiments in which more than one or all members of a group are present, used in, or otherwise associated with a given product or process.

[0595] Furthermore, this disclosure covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented in a list (e.g., in Markush group format), each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, when this disclosure or an aspect of this disclosure is referred to as comprising a particular element and / or feature, certain embodiments of this disclosure or an aspect of this disclosure consist of or are substantially composed of such elements and / or features. For simplicity, those embodiments are not specifically described verbatim herein. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. Where a scope is given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and to those skilled in the art, values ​​expressed as ranges may take any particular value or subrange within the range, up to one-tenth of the unit of the lower limit of the range, in different embodiments of this disclosure, unless the context explicitly indicates otherwise.

[0596] This application refers to all published patents, disclosed patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, the specification shall prevail. Furthermore, any particular embodiment of this disclosure that is prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if not expressly stated herein, as they are considered to be known to one of ordinary skill in the art. Any particular embodiment of this disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0597] Those skilled in the art will recognize or be able to determine many equivalents of the particular embodiments described herein using only conventional experiments. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of this disclosure as defined in the appended claims.

Claims

1. A compound of formula (I): (I)， Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, wherein: R 1 C 4-8 Alkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the alkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted, or R 1 Selected from: , , and ; R 2 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is optionally substituted; R 3 C 1-8 Alkyl, C 3-10 Cycloalkyl, 3-7 membered heterocyclic groups, or -(CR'R”) w -Ar 1 The alkyl, cycloalkyl, or heterocyclic group is optionally substituted; w is 0, 1, or 2; Ar 1 C 6-10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group is optionally substituted; Y represents a key, -CR'R"-, -O-, or -NR. Y -; R Y For H, C 1-6 Alkyl, C 3-7 cycloalkyl or nitrogen protecting group - , or R Y and R 3 It combines with intercalation atoms to form a 3-7 membered heterocyclic group, wherein the alkyl, cycloalkyl, acyl or heterocyclic group is optionally substituted; Z 1 and Z 2 Each independently for CR Z Or N; R Z Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; Z 3 Z 4 Z 5 and Z 6 Each independently for CR 4 ; R 4 Each instance is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -CN, -OR O -N(R) N )2 or C 1-6 Acyl group, wherein each alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group is independently and optionally substituted; R 5 Each instance is independently of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -CN, -OR O -N(R) N )2 or C 1-6- Acyl group, or two R groups attached to the same carbon atom 5 It combines with intercalated atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, or two R groups attached to the same carbon atom 5 Together they form =O, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently; When the valence is allowed, p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 0 or 1; n is 0, 1, 2, or 3; Each instance of R' is independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, where each instance of "R" is independently H, halogen, C. 1-6 Alkyl, -OR O or -N(R) N )2, or R' and R” connected to the same carbon atom bond together with intercalating atoms to form C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl or heterocyclic group is independently or optionally substituted, or R' and R” are attached to the same carbon atom to form =O; R N1 and R N Each instance is independently H, C 1-6 Alkyl, C 3-7 cycloalkyl, C 1-6 Acyl or nitrogen protecting group, or two R groups attached to the same nitrogen atom N They bond with intercalated atoms to form 3-7 membered heterocyclic groups, wherein each alkyl, cycloalkyl, acyl, or heterocyclic group is independently and optionally substituted; and R O Each instance is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6- An acyl or oxygen protecting group, wherein each alkyl, cycloalkyl, heterocyclic or acyl group is optionally substituted independently.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein m is 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein n is 1.

4. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R N1 For H.

5. The compound of claim 1, wherein the compound is a compound of formula (Ia): (I-a), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

6. The compound of claim 1, wherein the compound is a compound of formula (Ib): (I-b), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

7. The compound of claim 1, wherein the compound is a compound of formula (Ic-1): (I-c-1), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

8. The compound of claim 1, wherein the compound is a compound of formula (Ic): (I-c), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

9. The compound of claim 1, wherein the compound is a compound of formula (1d-1): (I-d-1), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

10. The compound of claim 1, wherein the compound is a compound of formula (1d): (I-d), Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug.

11. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for: or .

12. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 for: , or .

13. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 1 For optional replacement of branch C 4-8 alkyl.

14. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 C is arbitrarily replaced 1-6 alkyl.

15. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 For unreplaced C 1-3 alkyl.

16. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a methyl group.

17. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is a halogen.

18. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 2 It is F.

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

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

21. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 1-8 alkyl.

22. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 For unreplaced C 1-4 alkyl.

23. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is tert-butyl.

24. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-10 Cycloalkyl.

25. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C is arbitrarily replaced 3-6 Cycloalkyl.

26. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 C can be optionally replaced by one or more Fs 3-6 Cycloalkyl.

27. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for: .

28. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 Optionally substituted 3-7 membered heterocyclic groups.

29. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group with 1 or 2 ring N atoms that are optionally substituted.

30. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 It is a 3-6 membered heterocyclic group having one or two ring N atoms and optionally substituted by one or more F atoms.

31. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 3 for .

32. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z .

33. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH.

34. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CR Z .

35. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 2 For CH.

36. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z And Z 2 For CR Z .

37. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH and Z 2 For CH.

38. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CR Z And Z 2 Let N be the number of elements in the array.

39. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 1 For CH and Z 2 Let N be the number of elements in the array.

40. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 3 For CH.

41. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 4 For CF.

42. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 5 For CH.

43. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein Z 6 For CH.

44. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance is a halogen.

45. The compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein R 4 At least one instance of F is F.

46. ​​The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug thereof, wherein p is 0.

47. The compound of claim 1, wherein the compound is selected from the group consisting of: And its pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled derivatives and prodrugs.

48. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

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

50. A method for enhancing the Kv7 potassium channel in a subject, comprising administering to the subject a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof.

51. A method of treating a subject in need of a disease, condition, or disorder associated with Kv7 potassium channel dysfunction, comprising administering to the subject any of the compounds of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

52. The method of claim 50 or 51, wherein the method enhances the opening of Kv7 potassium channels.

53. The method of any one of claims 50 to 52, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.

5.

54. The method of any one of claims 50 to 53, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

55. A method of treating a subject in need of epileptic seizures, depression, pain, or anhedonia, comprising administering to the subject any of the compounds of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof.

56. The method of any one of claims 50 to 55, wherein the subject is a person.

57. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug thereof, or a pharmaceutical composition thereof, for enhancing the Kv7 potassium channel in a subject.

58. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug thereof, or a pharmaceutical composition thereof, for the treatment of a subject with a disease, condition or disorder associated with Kv7 potassium channel dysfunction.

59. The compound used in claim 57 or 58, wherein the compound enhances the opening of Kv7 potassium channels.

60. The compound used in any one of claims 57 to 59, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.

5.

61. The compound used in any one of claims 57 to 60, wherein the Kv7 potassium channel is Kv7.2 / Kv7.

3.

62. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, for the treatment of a subject with epileptic seizures, depression, pain or anhedonia.

63. The compound used in any one of claims 57 to 62, wherein the subject is a human being.

64. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled derivative or prodrug, or a pharmaceutical composition thereof, used as a pharmaceutical agent.

Images