Local anesthetics with selective sensory nerve blockade

Abstract

To provide a compound which is a local anesthetic and is useful for inducing selective sensory nerve block.SOLUTION: The compound is represented by formula (II).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62 / 928,177, filed October 30, 2019, and U.S. Provisional Application No. 62 / 941,624, filed November 27, 2019, both of which are incorporated by reference herein in their entireties.

[0002] Federally Sponsored Research This invention was made with government support under Grant No. GM1317282 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] background Local anesthetics can cause a reversible loss of sensation when applied to nerve tissue. When applied locally to nerve tissue in appropriate concentrations, local anesthetics reversibly block the action potentials responsible for nerve conduction. Anesthetics can act on any part of the nervous system, including any type of nerve fiber. Thus, when local anesthetics come into contact with nerve trunks, they can cause both sensory and motor blockade in the innervated area. Therefore, although the goal of local or regional anesthesia is to prevent pain by blocking signal transmission, administration of local anesthetics also results in numbness from blocking low-threshold baroreceptors and touch receptors, and paralysis from blocking motor axons and autonomic nerve fibers. Summary of the Invention

[0004] overview The present disclosure stems from the recognition that an effective strategy for producing pain-limited local anesthesia while preserving motor and autonomic responses is desirable in certain medical and / or surgical procedures (e.g., childbirth, dental procedures, treating nociceptor-driven chronic pain). Accordingly, the present disclosure recognizes that there is a need for compounds and methods that provide sensory-specific nerve blockade. Consequently, the present disclosure provides new compounds, compositions, and methods for achieving selective sensory nerve blockade.

[0005] In one aspect, provided is a compound of formula (II): [ka] and pharmaceutically acceptable co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, wherein: R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A is; R A is hydrogen or substituted or unsubstituted alkyl; X - is the counterion; and n is 1, 2, 3, 4, 5, or 6; However, A is NR A If so, then R 3 is H;R 8 is not substituted or unsubstituted aryl; and the compound is [ka] But it is not what is represented.

[0006] In some embodiments, the compound of Formula (II) has formula (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j): [ka] It is a compound represented by the formula:

[0007] Exemplary compounds of formula (II) include, but are not limited to, the following: [Table 1-1] [Table 1-2] [Table 1-3] Includes.

[0008] In another aspect, provided is a compound of the formula: [Table 2] It is a compound represented by the formula:

[0009] In another aspect, provided is a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound represented by formula (II)), and optionally a pharmaceutically acceptable excipient.

[0010] In another aspect, provided is a method of inducing selective sensory nerve blockade, the method comprising administering to a subject a compound of formula (I): [ka] During the ceremony: R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 Or R 6 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 Or R 5 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 9 is -(C=O)-AR 8 or -A 1 -(C=O)-R 10 is; R 8is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A is; A 1 is O, S, or NR A is; R A is hydrogen or substituted or unsubstituted alkyl; X - is the counterion; and n is 1, 2, 3, 4, 5, or 6; and pharmaceutically acceptable co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof to a subject in need thereof.

[0011] In some embodiments, the method comprises administering to a subject a compound of formula (II): [ka] The method includes administering a compound represented by the formula:

[0012] In some embodiments, the method comprises reacting a compound of formula (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), or (II-j): [ka] [ka] The method includes administering a compound represented by the formula:

[0013] In some embodiments, the method comprises administering to a subject a compound of formula (III): [ka] The method includes administering a compound represented by the formula:

[0014] In some embodiments, the method comprises reacting a compound of formula (III-b), (III-c), (III-d), (III-e), or (III-f): [ka] The method includes administering a compound represented by the formula:

[0015] In some embodiments, the method comprises administering to a subject a compound of the formula: [Table 3-1] [Table 3-2] The method includes administering a compound represented by the formula:

[0016] In another aspect, provided are compounds of Formula (I), (II), or (III), and pharmaceutical compositions comprising compounds of Formula (I), (II), or (III), for use in inducing selective sensory nerve blockade in a subject in need thereof.

[0017] In another aspect, provided is a kit comprising a compound of Formula (I), (II), or (III), or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III). In some embodiments, the kit further comprises instructions for administration (e.g., for human administration).

[0018] Details of certain aspects of the invention are presented in the detailed description of certain aspects, as set forth below. Other features, objects, and advantages of the invention will be apparent from the definition, examples, and claims.

[0019] definition Chemical Definition The definitions of specific functional groups and chemical terms are described in more detail below.Chemical elements are identified according to the CAS version of the Periodic Table of Elements in the inside cover of Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are generally defined as described therein.In addition, the general rules of organic chemistry, and specific functional moieties and reactivity are described in Organic Chemistry, University Science Books, Sausalito, 1999, Thomas Sorrell; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0020] The compounds described herein may contain one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched with one or more stereoisomers).Isomers can be isolated from mixtures 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 can 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, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1966); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses compounds as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0021] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen by deuterium or tritium, 18 By F 19 F replacement, or 13 C or 14 By C 12 Compounds having this structure except for the replacement of C are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0022] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 It is intended to cover alkyls of the formula:

[0023] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6Examples 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, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., a halogen such as F). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (unsubstituted C 1~6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C 1~10 Alkyl (substituted C 1~6 alkyl, for example, -CF3, Bn).

[0024] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0025] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s). In certain embodiments, a heteroalkyl group is a saturated group having from 1 to 20 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1~20 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 18 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~18 In some embodiments, heteroalkyl groups are saturated groups having 1 to 16 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~16 In some embodiments, heteroalkyl groups are saturated groups having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~14 In some embodiments, heteroalkyl groups are saturated groups having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~12 In some embodiments, heteroalkyl groups are saturated groups having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~10 In some embodiments, heteroalkyl groups are saturated groups having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and one heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and one heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom in the parent chain ("heteroCi alkyl"). In some embodiments, a heteroalkyl group, as defined herein, is a partially unsaturated group having one or more heteroatoms in the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may contain an amide or ester functionality in its parent chain where one or more carbon atoms is an unsaturated carbonyl group. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In some embodiments, a heteroalkyl group is an unsubstituted heteroC 1~20 In some embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 In some embodiments, the heteroalkyl group is a substituted heteroC 1~20 In some embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 It is alkyl.

[0026] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds but no triple bonds ("C 2~20In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). In some embodiments, the one or more carbon-carbon double bonds are internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C), 1-propenyl (C), 2-propenyl (C), 1-butenyl (C), 2-butenyl (C), butadienyl (C), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In some embodiments, the alkenyl group is a substituted C 2~10In alkenyl groups, the C=C double bond does not specify the stereochemistry (e.g., -CH=CHCH3 or [ka] may be an (E)-double bond or a (Z)-double bond.

[0027] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s). In certain embodiments, a heteroalkenyl group is a saturated group having from 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2~10 In some embodiments, heteroalkenyl groups have from 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC"). 2~9 In some embodiments, heteroalkenyl groups have from 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, heteroalkenyl groups have from 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkenyl groups have from 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkenyl groups have from 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5In some embodiments, heteroalkenyl groups have from 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkenyl groups have up to 2-3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkenyl groups have from 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In some embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0028] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). In some embodiments, the one or more carbon-carbon triple bonds are internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In some embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0029] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s). In certain embodiments, a heteroalkyl group is a saturated group having from 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroC 2~10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In some embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0030] The term "carbocyclyl" or "carbocyclic" refers to a ring system having from 3 to 14 ring carbon atoms ("C 3~14refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3~8 The carbocyclyl group may be any of the aforementioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group may be any of the aforementioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10 ), spiro[4.5]decanyl (C 10 ), and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic (a "monocyclic carbocyclyl") or polycyclic (e.g., a fused, bridged, or spiro ring system, such as a bicyclic (a "bicyclic carbocyclyl") or tricyclic (a "tricyclic carbocyclyl") ring system), which may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring is fused to one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the carbocyclyl ring; in such instances, the number of carbons is designated through the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In some embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0031] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, the cycloalkyl group is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups are the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups are the aforementioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In some embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0032] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). The point of attachment in a heterocyclyl group containing one or more nitrogen atoms can be a carbon or nitrogen atom, where valence allows. In some embodiments, a heterocyclyl group is either monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged, or spiro ring system, such as a bicyclic system (a "bicyclic heterocyclyl") or a tricyclic system (a "tricyclic carbocyclyl")), which can be saturated or contain one or more carbon-carbon double or triple bonds. A heterocyclyl polycyclic ring system can include one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclyl ring is fused to one or more carbocyclyl groups, as defined above, where the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring, or a heterocyclic ring is fused to one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the heterocyclyl ring; in such instances, the number of ring members is designated through the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0033] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0034] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, Examples include 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl.

[0035] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among the cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracyl). "Aryl" also encompasses ring systems in which the aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, but where the radical or point of attachment is on the aryl ring. In such instances, the number of carbon atoms is designated through the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In some embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0036] The term "heteroaryl" refers to a radical of a 5-14-membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" encompasses ring systems in which a heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the point of attachment is on the heteroaryl ring. In such instances, the number of ring members is designated through the number of ring members in the heteroaryl ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring is fused to one or more aryl groups, as defined above, but where the point of attachment is on either the aryl or heteroaryl ring. In such instances, the number of ring members is designated as the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0037] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0038] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0039] The terms "unsaturated" or "partially unsaturated" refer to a moiety that includes at least one double or triple bond.

[0040] The term "saturated" refers to a moiety that contains no double or triple bonds, ie, the moiety contains only single bonds.

[0041] The addition of the suffix "-ene" to a group indicates that the group is a divalent component, by way of example, alkylene is the divalent component of alkyl, alkenylene is the divalent component of alkenyl, alkynylene is the divalent component of alkynyl, heteroalkylene is the divalent component of heteroalkyl, heteroalkenylene is the divalent component of heteroalkenyl, heteroalkynylene is the divalent component of heteroalkynyl, carbocyclylene is the divalent component of carbocyclyl, heterocyclylene is the divalent component of heterocyclyl, arylene is the divalent component of aryl, and heteroarylene is the divalent component of heteroaryl.

[0042] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to substituted or unsubstituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon atom or a nitrogen atom) is replaced with a permissible substituent (e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously transform, such as by rearrangement, cyclization, elimination, or other reaction)). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when substituted at more than one position in any given structure, the substituents are either the same or different at each position. The term "substituted" is intended to include all permissible substituents of organic compounds and to include substitution with any substituent described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that fill the valence of the heteroatom and result in the formation of a stable moiety. This invention is not intended to be limited in any way by the exemplary substituents described herein.

[0043] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa 、-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 )3、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SRaa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; - is a counterion; or two geminal hydrogens on a carbon atom can be bonded to 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 has been replaced by; R aa In each case, independently, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb In each case, independently, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)Raa , -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 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; R cc In each case, independently, hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd In each case, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NRff 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 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may be joined to form =O or =S; where X - is the counterion; R ee In each case, independently, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted by a group; R ff In each case, independently, hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups are joined to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted by a group; and R gg In each case, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) +X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6alkyl), -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)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be joined to form =O or =S; where X - is the counter ion.

[0044] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0045] A "counterion" or "anionic counterion" is a negatively charged group attached to a positively charged group to maintain electronic neutrality. Anionic counterions may be monovalent (i.e., containing one formal negative charge). Anionic counterions may also be multivalent (i.e., containing more than one formal negative charge), such as divalent or trivalent. Exemplary counterions are halide ions (e.g., F - , Cl - , Br- , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - 、 HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, 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 counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- 、 B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0046] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above list of exemplary substituents.

[0047] Other definitions The following definitions are of more general terms that are used throughout this application.

[0048] The term "solvate" refers to a compound and its salt forms associated with a solvent, usually via a solvolysis reaction. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0049] The term "hydrate" refers to a compound associated with water molecules. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R·xH2O (where R is the compound and x is a number greater than 0). A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0050] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., reactions that provide tautomeric pairs) may be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different)enamine tautomerizations.

[0051] It will also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0052] Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center (e.g., it is bonded to four different groups), a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R and S sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0053] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates). Many compounds can exist in a variety of different crystalline forms (i.e., different polymorphs). Typically, such different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, and / or may vary in some or all of the following properties: melting point, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate in a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0054] The term "co-crystal" refers to a crystal structure composed of at least two components. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more other components, including, but not limited to, atoms, ions, molecules, or solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more solvent molecules. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more acids or bases. In certain embodiments, a co-crystal contains a compound of the present disclosure and one or more components of the compound, including isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of the compound.

[0055] The term "prodrug" refers to a compound having a cleavable group that can be removed by solvolysis or under physiological conditions to provide a compound described herein that is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-labile form often offers advantages of solubility, tissue compatibility, or delayed release to mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from pendant acidic groups on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester prodrugs, such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy) alkyl esters. The C 1~8 Alkyl esters, C 2~8 Alkenyl esters, C 2~8 Alkynyl esters, aryl esters, C 7~12 Substituted aryl esters, and C 7~12 Aryl alkyl esters are sometimes preferred.

[0056] The terms "composition" and "formulation" are used interchangeably.

[0057] A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., a minor, 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 a rhesus monkey), a commercially relevant mammal (e.g., a cattle, 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 may be male or female at any stage of development. The non-human animal may be a transgenic animal or a genetically modified animal. The term "patient" refers to a human subject in need of disease treatment. The subject may also be a plant. In some embodiments, the plant is a terrestrial plant. In some embodiments, the plant is a non-vascular terrestrial plant. In some embodiments, the plant is a vascular terrestrial plant. In some embodiments, the plant is a seed plant. In some embodiments, the plant is a cultivated plant. In some embodiments, the plant is a dicotyledonous plant. In some embodiments, the plant is a monocotyledonous plant. In some embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oats, barley, rye, or millet. In some embodiments, the plant is a legume, such as a bean plant, such as a soybean plant. In some embodiments, the plant is a tree or shrub.

[0058] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and centrifuging or otherwise separating their components). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from a first biological sample.

[0059] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into, into, or onto a subject.

[0060] The terms "treatment," "treat," and "treating" refer to halting, alleviating, delaying the onset, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, e.g., to delay and / or prevent recurrence.

[0061] The terms "disease," "disease," and "disorder" are used interchangeably.

[0062] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is the amount of a compound described herein in a single dose. In some embodiments, an effective amount is the combined amount of a compound described herein in multiple doses.

[0063] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a disease. In some embodiments, a therapeutically effective amount is an amount sufficient to induce sensory blockade. In some embodiments, a therapeutically effective amount is an amount sufficient to induce selective sensory blockade.

[0064] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, often beneficial, effect. For example, a therapeutic agent may treat, ameliorate, and / or prevent a disease. As disclosed herein, a therapeutic agent may be a biologic or a small molecule therapeutic, or a combination thereof.

[0065] The term "local anesthetic" refers to any agent that produces nerve blockade in a specific area, region, or site.

[0066] The term "sensory nerve blockade" may also be referred to as "nociceptive blockade," both of which refer to a deficit in the overt perception of painful stimuli, detected by the modified hot plate test herein, and likely resulting from defective signal transduction in nerves.

[0067] The term "motor function block" refers to a deficit in motor function, which is detected here by weight-bearing testing and is probably due to defective signal transduction in nerves. [Brief explanation of the drawings]

[0068] Brief description of the drawings [Figure 1] FIG. 1 is a plot displaying the cytotoxicity of exemplary compounds in comparison to ropivacaine and bupivacaine in PC12 cells. [Figure 2] FIG. 2 is a plot displaying the cytotoxicity of exemplary compounds in comparison to ropivacaine and bupivacaine in C212 cells. [Figure 3] FIG. 3 is two plots displaying the inhibition of hERG and Nav1.5 peaks by exemplary compounds in comparison to bupivacaine in HEK cells. DETAILED DESCRIPTION OF THE INVENTION

[0069] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Provided herein are compounds that are local anesthetics. The compounds described herein possess advantageous properties, such as selective blockade of sensory nerves over motor function, which may make them useful as local anesthetics in a variety of situations (e.g., childbirth, dental procedures, and treatment of nociceptor-driven chronic pain). In one aspect, the anesthetics provided are compounds represented by Formulas (I), (II), and (III), as well as pharmaceutically acceptable solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. In another aspect, the compounds represented by Formulas (I), (II), and (III), as well as pharmaceutically acceptable solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof, are particularly useful in methods for inducing selective sensory nerve blockade. As a result, the compounds are useful as local anesthesia in subjects in need thereof and surprisingly have superior anesthetic properties (e.g., duration of sensory blockade, selectivity for blocking sensory over motor function, low cytotoxicity) than existing anesthetics. The compounds may be provided for use in any of the compositions, kits, or methods described herein as their pharmaceutically acceptable co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0070] Compounds represented by formula (I) In one aspect, disclosed is a compound of formula (I): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 Or R 6 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 Or R 5 and form a heterocyclyl ring; Each R 7 are independently hydrogen, substituted or unsubstituted alkyl, or halogen; R 9 is -(C=O)-AR 8 or -A 1 -(C=O)-R 10 is; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A is; A 1 is O, S, or NR A is; R A is hydrogen or substituted or unsubstituted alkyl; X - is the counterion; and n is 1, 2, 3, 4, 5, or 6.

[0071] In some embodiments, disclosed are compounds of formula (Ia): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 Or R 6 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 Or R 5 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 9 is -(C=O)-AR 8 or -A 1 -(C=O)-R 10 is; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; R 10is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A is; A 1 is O, S, or NR A is; R A is hydrogen or substituted or unsubstituted alkyl; and X - is the counter ion.

[0072] R 1 and R 2 As described herein, R 1 is substituted or unsubstituted alkyl. In some embodiments, R 1 is unsubstituted alkyl. In some embodiments, R 1 is the unsubstituted C 1~6 In some embodiments, R 1 is the unsubstituted C 1~4 In some embodiments, R 1 is the unsubstituted C 1~3 In some embodiments, R 1 is the unsubstituted C 1~2 In some embodiments, R 1 is methyl. As described herein, R 2 is substituted or unsubstituted alkyl. In some embodiments, R 2 is unsubstituted alkyl. In some embodiments, R 2 is the unsubstituted C 1~6 In some embodiments, R 2 is the unsubstituted C 1~4 In some embodiments, R 2 is the unsubstituted C 1~3 In some embodiments, R 2 is the unsubstituted C 1~2 In some embodiments, R2 is methyl.

[0073] In some embodiments, R 1 is unsubstituted alkyl; and R 2 is unsubstituted alkyl. In some embodiments, R 1 is the unsubstituted C 1~6 alkyl; and R 2 is the unsubstituted C 1~6 In some embodiments, R 1 is the unsubstituted C 1~4 alkyl; and R 2 is the unsubstituted C 1~4 In some embodiments, R 1 is the unsubstituted C 1~3 alkyl; and R 2 is the unsubstituted C 1~3 In some embodiments, R 1 is the unsubstituted C 1~2 alkyl; and R 2 is the unsubstituted C 1~2 In some embodiments, R 1 is methyl; R 2 is methyl.

[0074] R 3 As described herein, R 3 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is substituted or unsubstituted alkyl. In some embodiments, R 3 is unsubstituted alkyl. In some embodiments, R 3 is the unsubstituted C 1~6 In some embodiments, R 3 is the unsubstituted C 1~4 In some embodiments, R 3 is the unsubstituted C 1~3 In some embodiments, R 3 is the unsubstituted C 1~2In some embodiments, R 3 is methyl.

[0075] R 4 , R 5 , and R 6 As described herein, R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 Or R 6 and R are joined to form a heterocyclyl ring; and R 6 is a substituted or unsubstituted alkyl, or R 4 Or R 5 When combined with the , they form a heterocyclyl ring.

[0076] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is substituted or unsubstituted alkyl. In some embodiments, R 4 is unsubstituted alkyl. In some embodiments, R 4 is the unsubstituted C 1~6 It is alkyl.

[0077] In some embodiments, R 4 is hydrogen or R 5 Or R 6 and form a heterocyclyl ring. 4 is R 5 or R 6 and form a heterocyclyl ring. 4 is R 5 or R 6 and combine to form a 4- to 7-membered heterocyclyl ring. 4 is R 5 or R6 and combine to form a 4- to 6-membered heterocyclyl ring. 4 is R 5 or R 6 and combine to form a 4- to 5-membered heterocyclyl ring. 4 is R 5 or R 6 and combine to form a 5- to 6-membered heterocyclyl ring. 4 is R 5 or R 6 and R are joined to form a 5-membered heterocyclyl ring. 4 is R 5 or R 6 and form a 6-membered heterocyclyl ring. 4 is R 5 or R 6 When combined with this, it forms a piperidinium ring.

[0078] R 4 But R 5 or R 6 When R is bonded to R to form a heterocyclyl ring, 5 and R 6 In some embodiments, the remaining variables that do not form the heterocyclyl ring are substituted or unsubstituted alkyl. 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 In some embodiments, the remaining variables that do not form a heterocyclyl ring are unsubstituted alkyl. 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 The remaining variables that do not form a heterocyclyl ring are unsubstituted C 1~6In some embodiments, R 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 The remaining variables that do not form a heterocyclyl ring are unsubstituted C 1~4 In some embodiments, R 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 The remaining variables that do not form a heterocyclyl ring are unsubstituted C 1~3 In some embodiments, R 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 The remaining variables that do not form a heterocyclyl ring are unsubstituted C 1~2 In some embodiments, R 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 In some embodiments, the remaining variables that do not form a heterocyclyl ring are methyl, ethyl, n-propyl, or n-butyl. 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 In some embodiments, the remaining variables that do not form a heterocyclyl ring are methyl. 4 is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 In some embodiments, the remaining variables that do not form a heterocyclyl ring are n-propyl. 4is R 5 or R 6 and R form a heterocyclyl ring; 5 and R 6 In the formula, the remaining variable that does not form a heterocyclyl ring is n-butyl.

[0079] In some embodiments, R 4 is R 5 and form a heterocyclyl ring. 4 is R 5 and form a 4- to 7-membered heterocyclyl ring. 4 is R 5 and form a 4- to 6-membered heterocyclyl ring. 4 is R 5 and form a 4- to 5-membered heterocyclyl ring. 4 is R 5 and form a 5- to 6-membered heterocyclyl ring. 4 is R 5 and R are joined to form a 5-membered heterocyclyl ring. 4 is R 5 and form a 6-membered heterocyclyl ring. 4 is R 5 When combined with this, it forms a piperidinium ring.

[0080] In some embodiments, R 4 is R 6 and form a heterocyclyl ring. 4 is R 6 and combine to form a 4- to 7-membered heterocyclyl ring. 4 is R 6 and combine to form a 4- to 6-membered heterocyclyl ring. 4 is R 6and combine to form a 4- to 5-membered heterocyclyl ring. 4 is R 6 and combine to form a 5- to 6-membered heterocyclyl ring. 4 is R 6 and R are joined to form a 5-membered heterocyclyl ring. 4 is R 6 and form a 6-membered heterocyclyl ring. 4 is R 6 When combined with this, it forms a piperidinium ring.

[0081] In some embodiments, R 4 But R 5 or R 6 When combined with R to form a heterocyclyl ring, the heterocyclyl group is further substituted. 4 But R 5 or R 6 When joined to form a heterocyclyl ring, the heterocyclyl group is not further substituted.

[0082] In some embodiments, R 5 is substituted or unsubstituted alkyl. In some embodiments, R 5 is unsubstituted alkyl. In some embodiments, R 5 is the unsubstituted C 1~6 In some embodiments, R 5 is the unsubstituted C 1~4 In some embodiments, R 5 is the unsubstituted C 1~3 In some embodiments, R 5 is the unsubstituted C 1~2 In some embodiments, R 5 is n-butyl, n-propyl, ethyl, or methyl. 5 is n-butyl. In some embodiments, R 5is n-propyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is methyl.

[0083] In some embodiments, R 6 is substituted or unsubstituted alkyl. In some embodiments, R 6 is unsubstituted alkyl. In some embodiments, R 6 is the unsubstituted C 1~6 In some embodiments, R 6 is the unsubstituted C 1~4 In some embodiments, R 6 is the unsubstituted C 1~3 In some embodiments, R 6 is the unsubstituted C 1~2 In some embodiments, R 6 is n-butyl, n-propyl, ethyl, or methyl. 6 is n-butyl. In some embodiments, R 6 is n-propyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is methyl.

[0084] In some embodiments, R 5 is unsubstituted alkyl; and R 6 is unsubstituted alkyl. In some embodiments, R 5 is C 1~6 unsubstituted alkyl; and R 6 is C 1~6 In some embodiments, R 5 is C 1~4 unsubstituted alkyl; and R 6 is C 1~4 In some embodiments, R 5 is C 1~3 unsubstituted alkyl; and R 6 is C 1~3 In some embodiments, R 5is C 1~2 unsubstituted alkyl; and R 6 is C 1~2 In some embodiments, R 5 is C 1~6 ethyl; and R 6 is C 1~6 It is ethyl.

[0085] As described herein, R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 When combined with the , they form a heterocyclyl ring.

[0086] R 7 As described herein, R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen. 7 is hydrogen. In some embodiments, R 7 is halogen. In some embodiments, R 7 is fluoro. In some embodiments, R 7 is substituted or unsubstituted alkyl. Unsubstituted alkyl. In some embodiments, R 7 is the unsubstituted C 1~6 In some embodiments, R 7 is the unsubstituted C 1~4 In some embodiments, R 7 is the unsubstituted C 1~3 In some embodiments, R 7 is the unsubstituted C 1~2 It is alkyl.

[0087] R 9 As described herein, R 9 is -(C=O)-AR 8 or -A 1 -(C=O)-R 10 R 8is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A A 1 is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl.

[0088] In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8is substituted or unsubstituted alkyl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is unsubstituted alkyl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~6 alkyl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~4 alkyl; A is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl.

[0089] In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and A is O or S. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and A is O or S. In some embodiments, R 9 is -(C=O)-AR 8 R 8is substituted or unsubstituted alkyl; and A is O or S. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is unsubstituted alkyl; and A is O or S. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~6 and A is O or S. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~4 and A is O or S.

[0090] In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; A is O or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl; A is O or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8is unsubstituted alkyl; A is O or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~6 alkyl; A is O or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~4 alkyl; A is O or NR A and R A is hydrogen or substituted or unsubstituted alkyl.

[0091] In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; A is NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl; A is NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R9 is -(C=O)-AR 8 R 8 is unsubstituted alkyl; A is NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~6 A is alkyl; A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~4 A is alkyl; A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~4 A is alkyl; A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is methyl; A is NR A and R A is hydrogen or substituted or unsubstituted alkyl.

[0092] In some embodiments, A is NR A If so, then R 3 is hydrogen. In some embodiments, A is NR A If so, then R 8 is not substituted or unsubstituted aryl. In some embodiments, A is NR A If so, then R 3 is hydrogen, and R 8is not substituted or unsubstituted aryl. In some embodiments, A is NR A If so, then R 8 and R A Both of these substitutions are 12 Alkyl but unsubstituted C 12 It's not alkyl.

[0093] In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is substituted or unsubstituted alkyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is a substituted or unsubstituted C 1~6 and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is the unsubstituted C 1~4 and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is benzyl, t-butyl, n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8is t-butyl, n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is n-butyl, isopropyl, n-propyl, or methyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is n-butyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is isopropyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is n-propyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is methyl; and A is O. In some embodiments, R 9 is -(C=O)-AR 8 R 8 is benzyl; and A is O.

[0094] In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A 1 is O, S, or NR A and R Ais hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; A 1 is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is a substituted or unsubstituted alkyl; A 1 is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is unsubstituted alkyl; A 1 is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is the unsubstituted C 1~4 Alkyl; A 1 is O, S, or NR A and R A is hydrogen or substituted or unsubstituted alkyl.

[0095] In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and A 1is O or S. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and A 1 is O or S. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is a substituted or unsubstituted alkyl; A 1 is O or S. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is unsubstituted alkyl; and A 1 is O or S. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is the unsubstituted C 1~4 alkyl; and A 1 is O or S.

[0096] In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10is substituted or unsubstituted alkyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is a substituted or unsubstituted C 1~4 alkyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is the unsubstituted C 1~4 alkyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is t-butyl, n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is n-butyl, n-propyl, ethyl, or methyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is n-butyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is n-propyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R 10 is ethyl; and A 1 is O. In some embodiments, R 9 -A 1 -(C=O)-R 10 R10 is methyl; and A 1 is O.

[0097] X - As described herein, X - is a counter ion. - is a halide ion. - is F - , Cl - , Br - , or I - In some embodiments, X - is Cl - or Br - In some embodiments, X - is Cl - In some embodiments, X - Br - is.

[0098] n As described herein, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0099] Certain aspects In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , A, n, and X - is as defined herein.

[0100] In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A is; RA is hydrogen or substituted or unsubstituted alkyl; X - is the counterion; and n is 1, 2, 3, 4, 5, or 6.

[0101] In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O, S, or NR A is; RA is hydrogen or substituted or unsubstituted alkyl; X - is the counterion; and n is 1, 2, 3, 4, 5, or 6; However, A is NR A If so, then R 3 is H;R 8 is not a substituted or unsubstituted aryl; and the compound is [ka] do not have.

[0102] In certain embodiments of the compound of Formula (II), R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O or S; X - is the counterion; and n is 1, 2, 3, 4, 5, or 6.

[0103] In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O or S; and X - is a counter ion; provided that the compound is: [ka] isn't it.

[0104] In some embodiments, the compound of formula (I) has formula (II-a): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, and X - is as defined herein.

[0105] In certain embodiments of the compound of Formula (II-a), R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O or S; and X - is the counter ion.

[0106] In some embodiments, the compound of formula (II) has formula (II-a): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl; R 3 is hydrogen or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or R 5 Or R 6 and form a heterocyclyl ring; R 5 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 6 is a substituted or unsubstituted alkyl, or R 4 and form a heterocyclyl ring; R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen; R 8is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; A is O or S; and X - is a counter ion; provided that the compound is: [ka] isn't it.

[0107] In some embodiments, the compound of formula (II) has formula (II-b): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 4 , R 7 , R 8 , n, and X - is as defined herein.

[0108] In some embodiments, the compound of formula (II) has formula (II-b-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and X - is as defined herein.

[0109] In some embodiments, the compound of formula (II) has formula (II-c): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 4 , R 7 , R 8 , n, A, and X - is as defined herein.

[0110] In some embodiments, the compound of formula (II) has formula (II-c-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 4 , R 7 , R 8 , A, and X - is as defined herein.

[0111] In some embodiments, the compound of formula (II) has formula (II-d): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 4 , R 7 , R 8 , n, and X - is as defined herein.

[0112] In some embodiments, the compound of formula (II) has formula (II-d-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 4 , R 7 , R 8 , and X - is as defined herein.

[0113] In some embodiments, the compound of formula (II) has formula (II-e): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 5 , R 7 , R 8 , A, n, and X - is as defined herein.

[0114] In some embodiments, the compound of formula (II) has formula (II-e-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and X - is as defined herein.

[0115] In some embodiments, the compound of formula (II) has formula (II-f): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 5 , R 7 , R 8 , A, n, and X - is as defined herein.

[0116] In some embodiments, the compound of formula (II) has formula (II-f-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and X - is as defined herein.

[0117] In some embodiments, the compound of formula (II) has formula (II-g): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 7 , R 8 , A, n, and X - is as defined herein.

[0118] In some embodiments, the compound of formula (II) has formula (II-g-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 7 , R 8 , A, and X - is as defined herein.

[0119] In some embodiments, the compound of formula (II) has formula (II-h): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 7 , R 8 , n, and X - is as defined herein.

[0120] In some embodiments, the compound of formula (II) has formula (II-h-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 7 , R 8 , and X - is as defined herein.

[0121] In some embodiments, the compound of formula (II) has formula (II-i): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof;5 , R 8 , A, n, and X - is as defined herein.

[0122] In some embodiments, the compound of formula (II) has formula (II-i-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 8 , A, and X - is as defined herein.

[0123] In some embodiments, the compound of formula (II) has formula (II-j): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 8 , n, and X - is as defined herein.

[0124] In some embodiments, the compound of formula (II) has formula (II-j-1): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 8 , and X - is as defined herein.

[0125] In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , A 1 , n, and X - is as defined herein.

[0126] In some embodiments, the compound of Formula (I) has the formula (III-a): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , A 1 , and X - is as defined herein.

[0127] In some embodiments, the compound of formula (III) has formula (III-b): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 4 , R 7, R 10 , and X - is as defined herein.

[0128] In some embodiments, the compound of formula (III) has formula (III-c): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 4 , R 7 , R 10 , and X - is as defined herein.

[0129] In some embodiments, the compound of formula (III) has formula (III-d): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 1 , R 2 , R 3 , R 5 , R 7 , R 10 , and X - is as defined herein.

[0130] In some embodiments, the compound of formula (III) has formula (III-e): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 7 , R 10 , and X - is as defined herein.

[0131] In some embodiments, the compound of formula (III) has formula (III-f): [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; 5 , R 10 , and X - is as defined herein.

[0132] In some embodiments, the compound of formula (I) is the following compound: [Table 4-1] [Table 4-2] [Table 4-3] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0133] In some embodiments, the compound of formula (I) is the following compound: [Table 5-1] [Table 5-2] [Table 5-3] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0134] In some embodiments, the compound of formula (I) is the following compound: [Table 6-1] [Table 6-2] [Table 6-3] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0135] In some embodiments, the compound of formula (I) is the following compound: [Table 7-1] [Table 7-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0136] In some embodiments, the compound of formula (I) is the following compound: [Table 8-1] [Table 8-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0137] In some embodiments, the compound of formula (I) is the following compound: [Table 9-1] [Table 9-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0138] In some embodiments, the compound of formula (I) is the following compound: [Table 10-1] [Table 10-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0139] In some embodiments, the compound of formula (I) is the following compound: [Table 11-1] [Table 11-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0140] In some embodiments, the compound of formula (I) is the following compound: [Table 12] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0141] In some embodiments, the compound of formula (I) is the following compound: [Table 13] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0142] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0143] In some embodiments, the compound of formula (I) is the following compound: [Table 14] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0144] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0145] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0146] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0147] In some embodiments, the compound of formula (I) is the following compound: [Table 15] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0148] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0149] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0150] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0151] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0152] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0153] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0154] In certain embodiments, the compound of Formula (I) is a mixture of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [ka]

[0155] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0156] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0157] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0158] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0159] In some embodiments, the compound of formula (I) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0160] In some embodiments, the compound of formula (I) is the following compound: [Table 16] Not one or more of.

[0161] In some embodiments, the compound of formula (II) is the following compound: [Table 17-1] [Table 17-2] [Table 17-3] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0162] In some embodiments, the compound of formula (II) is the following compound: [Table 18-1] [Table 18-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0163] In some embodiments, the compound of formula (II) is the following compound: [Table 19] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0164] In some embodiments, the compound of formula (II) is the following compound: [Table 20-1] [Table 20-2] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0165] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0166] In some embodiments, the compound of formula (II) is the following compound: [Table 21] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0167] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0168] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0169] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0170] In some embodiments, the compound of formula (II) is the following compound: [Table 22] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0171] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0172] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0173] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0174] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0175] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0176] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0177] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0178] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0179] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0180] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0181] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0182] In some embodiments, the compound of formula (II) is the following compound: [ka] or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0183] In some embodiments, the compound of formula (II) has the formula: [ka] But it is not expressed.

[0184] In some embodiments, the compound of formula (III) is the following compound: [Table 23] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0185] In some embodiments, the compound of formula (III) is the following compound: [Table 24] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0186] In some embodiments, the compound of formula (III) is the following compound: [Table 25] or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0187] In some embodiments, the compound of formula (III) is the following compound: [Table 26] Not one or more of.

[0188] In some embodiments, provided compounds (e.g., compounds represented by Formulas (I), (II), and (III)) selectively induce sensory blockade over motor blockade. In some embodiments, the compounds selectively induce sensory blockade over motor blockade in a subject in need thereof, such that the ratio of duration of sensory blockade:duration of motor blockade is at least 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, or 100:1.

[0189] Pharmaceutical Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising the disclosed compounds (e.g., compounds represented by Formula (I), (II), or (III)), or a pharmaceutically acceptable cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise a compound represented by Formula (I), (II), or (III) and a pharmaceutically acceptable excipient.

[0190] In some embodiments, a compound represented by Formula (I), (II), or (III) is provided in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective to induce selective sensory nerve blockade in a subject in need thereof.

[0191] In some embodiments, an effective amount is an amount effective to provide a duration of sensory blockade that is longer than the duration of motor blockade in a subject in need thereof. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory blockade:duration of motor blockade in a subject in need thereof of at least 1.1:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory blockade:duration of motor blockade in a subject in need thereof of at least 1.2:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory blockade:duration of motor blockade in a subject in need thereof of at least 1.3:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory blockade:duration of motor blockade in a subject in need thereof of at least 1.4:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory blockade:duration of motor blockade in a subject in need thereof of at least 1.5:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory nerve blockade to duration of motor function blockade in a subject in need thereof of at least 2:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory nerve blockade to duration of motor function blockade in a subject in need thereof of at least 3:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory nerve blockade to duration of motor function blockade in a subject in need thereof of at least 5:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory nerve blockade to duration of motor function blockade in a subject in need thereof of at least 10:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory nerve blockade to duration of motor function blockade in a subject in need thereof of at least 20:1. In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory nerve blockade to duration of motor function blockade in a subject in need thereof of at least 50:1.In some embodiments, an effective amount is an amount effective to provide a ratio of duration of sensory blockade to duration of motor blockade in a subject in need thereof of at least 100: 1. In some embodiments, an effective amount is an amount effective to provide sensory blockade without motor blockade in a subject in need thereof.

[0192] In some embodiments, the subject to be treated or administered a compound described herein is an animal. The animal may be of either sex and at any stage of development. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a mammal. In some embodiments, the subject described herein is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate animal. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the subject is a transgenic animal (e.g., a transgenic mouse, a transgenic pig). In some embodiments, the subject is a fish or reptile.

[0193] In some embodiments, the compound or pharmaceutical composition is a solid. In some embodiments, the compound or pharmaceutical composition is a powder. In some embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to create a solution. In some embodiments, the compound or pharmaceutical composition can be dissolved in water to create an aqueous solution. In some embodiments, the pharmaceutical composition is a liquid for parenteral injection. In some embodiments, the pharmaceutical composition is a liquid for topical administration. In some embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for intravenous injection. In some embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for subcutaneous injection.

[0194] After formulation with appropriate pharmaceutically acceptable excipients in the desired dosage, the pharmaceutical compositions of the present disclosure can be administered to humans and other animals parenterally, intracisternally, intraperitoneally, intramuscularly, topically, bucally, intravenously, epidurally, intranasally, intrathecally, subcutaneously, topically in the ear, epicorneally, perineurally, by infiltration, or the like, depending on the desired location of the anesthetic effect. In some embodiments, the compound or pharmaceutical composition can be administered by any method for administering a local anesthetic known to those skilled in the art. The composition can be formulated for local anesthesia, infiltration anesthesia, peritoneal infiltration anesthesia, nerve block anesthesia, intravenous local anesthesia, spinal anesthesia, and / or epidural anesthesia.

[0195] In some embodiments, pharmaceutical compositions comprising a compound of Formula (I), (II), or (III) are administered topically or parenterally at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more dose administrations. In certain embodiments, the effective amount per dose ranges from about 0.001 mg / kg of subject's body weight / day to about 200 mg / kg of subject's body weight / day, from about 0.001 mg / kg of subject's body weight / day to about 100 mg / kg of subject's body weight / day, from about 0.01 mg / kg of subject's body weight / day to about 100 mg / kg of subject's body weight / day, from about 0.01 mg / kg of subject's body weight / day to about 50 mg / kg of subject's body weight / day, preferably from about 0.1 mg / kg of subject's body weight / day to about 40 mg / kg of subject's body weight / day, preferably from about 0.5 mg / kg of subject's body weight / day to about 30 mg / kg of subject's body weight / day, from about 0.01 mg / kg of subject's body weight / day to about 10 mg / kg of subject's body weight / day, from about 0.1 mg / kg of subject's body weight / day to about 10 mg / kg of subject's body weight / day, one or more times per day to obtain the desired anesthetic effect. In certain embodiments, the compounds described herein are administered at a dose of from about 0.001 mg / kg of subject's body weight / day to about 200 mg / kg of subject's body weight / day, from about 0.001 mg / kg of subject's body weight / day to about 100 mg / kg of subject's body weight / day, from about 0.01 mg / kg of subject's body weight / day to about 100 mg / kg of subject's body weight / day, from about 0.01 mg / kg of subject's body weight / day to about 50 mg / kg of subject's body weight / day, preferably one or more times per day to achieve the desired anesthetic effect. may be at a dosage level sufficient to deliver from about 0.1 mg / kg body weight of subject / day to about 40 mg / kg body weight of subject / day, preferably from about 0.5 g / kg body weight of subject / day to about 30 mg / kg body weight of subject / day, from about 0.01 mg / kg body weight of subject / day to about 10 mg / kg body weight of subject / day, from about 0.1 mg / kg body weight of subject / day to about 10 mg / kg body weight of subject / day, and more preferably from about 1 mg / kg body weight of subject / day to about 25 mg / kg body weight of subject / day. In some embodiments, the desired dosage may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).In certain embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes non-specific effects.

[0196] In some embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0197] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods include bringing into association a composition comprising a compound of Formula (I), (II), or (III) with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single-dose or multi-dose unit.

[0198] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses.As used herein, " unit dose " is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of active ingredient that will be administered to a subject, and / or a convenient fraction of this dosage, for example, half or one-third of this dosage.

[0199] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions of the present disclosure may vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is to be administered. As an example, the composition may contain between 0.1% and 100% (w / w) of the active ingredient.

[0200] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the compositions.

[0201] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0202] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0203] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), and the like. sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80) ), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate,Triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer®-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0204] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0205] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0206] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0207] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malate and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0208] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0209] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0210] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0211] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GlydantPlus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0212] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0213] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0214] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, loofah, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0215] The liquid dosage form for parenteral administration includes but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active agent, liquid dosage form can contain the inert diluent commonly used in this field, for example, water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and their mixtures. In certain embodiments for parenteral administration, the agents of the present invention are mixed with a solubilizing agent such as CREMOPHOR EL® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0216] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0217] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0218] Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug in a dermatologically acceptable carrier such as a lotion, cream, ointment, or soap. Useful carriers can form a film or layer over the skin that localizes application and prevents removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to tissue surfaces. For example, hydroxypropyl cellulose or fibrinogen / thrombin solutions can be used to advantage. Alternatively, tissue coating solutions such as formulations containing pectin can be used. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this disclosure. In addition, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of agents to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the agent across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the agent in a polymer matrix or gel.

[0219] In addition, carriers for topical formulations can be in the form of hydroalcoholic systems (e.g., liquids and gels), anhydrous oil or silicone-based systems, or emulsion systems, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. Emulsions can range in consistency, including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, etc. Emulsions can also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semi-solids (such as gels and sticks); and aqueous-based mousse systems.

[0220] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). The provided kits may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single-unit dosage form.

[0221] Thus, in one aspect, provided is a kit comprising a first container containing a compound or pharmaceutical composition described herein. In some embodiments, the kit is useful for inducing sensory nerve blockade in a subject in need thereof. In some embodiments, the kit is useful for inducing selective sensory nerve blockade in a subject in need thereof.

[0222] In some embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information from regulatory authorities, such as the U.S. Food and Drug Administration (FDA), as needed. In some embodiments, the information included in the kit is prescribing information.

[0223] Treatment method The present disclosure provides methods for inducing sensory nerve blockade. In some aspects, the present application provides methods for inducing selective sensory nerve blockade.

[0224] In some embodiments, the method comprises administering to a subject in need thereof a compound that induces sensory nerve blockade. In some embodiments, the method comprises administering to a subject in need thereof a compound that induces selective sensory nerve blockade. In some embodiments, the method comprises administering to a subject in need thereof a compound of the present disclosure (e.g., a compound represented by Formula (I), (II), or (III)), or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, or a composition thereof. In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound represented by Formula (I), (II), or (III)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0225] In some embodiments, the method for inducing sensory nerve blockade comprises providing a duration of sensory nerve blockade that is longer than the duration of motor function blockade in a subject in need thereof. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 1.1:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 1.2:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 1.3:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 1.4:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 1.5:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 2:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 3:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 4:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 5:1.In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 10:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 20:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 30:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 40:1. In some embodiments, the method for inducing sensory nerve blockade comprises providing a ratio of duration of sensory nerve blockade:duration of motor function blockade in a subject in need thereof of at least 50:1. In some embodiments, the method for inducing sensory blockade comprises providing in a subject in need thereof a ratio of duration of sensory blockade to duration of motor blockade of at least 100: 1. In some embodiments, the method for inducing sensory blockade comprises providing in a subject in need thereof sensory blockade without motor blockade.

[0226] example In order that the invention described herein may be more fully understood, the following examples are set forth: The examples described in this application are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0227] Synthesis method The compounds of the present disclosure were prepared according to the procedures detailed below. 2-((2,6-dimethylphenyl)amino)-N,N-diethyl-N-(2-methoxy-2-oxoethyl)-2-oxoethan-1-aminium bromide (1) [ka]

[0228] To a 50 mL round-bottom flask, lidocaine (2.5 mmol), methyl bromoacetate (10 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction was heated to 80 °C for 1 hour and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give the title compound as a white solid (0.94 g, 97%). 1 H NMR(CDCl3):δ10.39(s,1H),6.97-7.12(m,3H),5.17(s,2H),4.67(s,2H),3.91-4.02(m,2H),3.75-3.87(m,5H),2.24(s,6H),1.52(t,J=7.2Hz) 6H). 13 C NMR(CDCl3):δ164.8,162.0,135.1,132.7,128.2,127.6,58.1,57.3,53.4,46.7,18.8,8.7. HRMS(ESI):m / z[M -Br] + Calculated value for C17H27N2O3: 307.2016; Found value: 307.2024.

[0229] Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-methoxy-2-oxoethyl)piperidin-1-ium bromide (2) [ka] To a 50 mL round-bottom flask, bupivacaine (racemic; 2.5 mmol), methyl bromoacetate (10 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80 °C for 1 h and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give two products as white solids.

[0230] The first product isolated (compound 2a; ZYK2412-1) (0.41 g, 37%) was determined by 2D NMR techniques to be a mixture of two stereoisomers shown below: [ka] It was decided that: 1 H NMR(CDCl3):δ10.59(s,1H),6.98-7.07(m,3H),6.14(dd,J1=9.2Hz,J2=3.6Hz,1H),4.81(dd,J1=317.6Hz,J2=17.2Hz,2H),4.20-4.29(m,1H) ),3.95-4.05(m,1H),3.81(s,3H),3.61-3.80(m,2H),2.45-2.57(m,1H ),2.25(s,6H).1.85-2.13(m,7H),1.33-1.48(m,2H),1.00(t,J=7.2Hz 3H). 13 C NMR(CDCl3): δ165.7,164.8,135.0,132.7,128.2,127.6,69.3,62.5,62.5,59.0,53.4,25.4,24.7,20.0,19.9,19.3,18.8,13.4. HRMS(ESI):m / z[M-Br] + Theoretical value for C21H33N2O3: 361.2486; Found: 361.2492.

[0231] The second product isolated (compound 2b; ZYK2412-2) (0.35 g, 32%) was determined by 2D NMR techniques to be a mixture of two stereoisomers shown below: [ka] It was decided that: 1 H NMR(CDCl3):δ10.36(s,1H),7.00-7.11(m,3H),6.15(dd,J1=4.4Hz,J2=4.4Hz,1H),4.62(dd ,J1=244.0Hz,J2=16.4Hz,2H),4.48-4.57(m,1H),3.87-3.98(m,2H),3.86(s,3H),3.73(td,Jt =13.6Hz,J d =4.8Hz,1H),2.49-2.63(m,1H),2.31-2.44(m,1H),2.26(s,6H).1.86-2.25(m,5H),1.65-1.76(m,1H),1.23-1.48(m,2H),0.97(t,J=7.2Hz) 3H). 13 C NMR (CDCl3): δ165.0,164.3,135.0,132.7,128.3,127.6,69.9,60.4,58.2,55.1,53.6,25.3,24.4,20.1,19.8,18.7,17.7,13.1. HRMS(ESI):m / z[M-Br] + Theoretical value for C21H33N2O3: 361.2486; Measured value: 361.2491.

[0232] 2-((2,6-dimethylphenyl)carbamoyl)-1-(2-methoxy-2-oxoethyl)-1-methylpiperidin-1-ium bromide (3) [ka] To a 50 mL round-bottom flask, mepivacaine (racemic; 1 mmol), methyl bromoacetate (3 mmol), and 1 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80° C. for 1 hour and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give two products as white solids.

[0233] The first product isolated (compound 3a; ZYK2212-1) (77 mg, 19%) was determined by 2D NMR techniques to be a mixture of two stereoisomers shown below: [ka] It was decided that: 1H NMR(CDCl3):δ10.02(s,1H),6.98-7.07(m,3H),6.01(dd,J1=10.0Hz,J2=3.6Hz,1H),4.81(dd,J1=338.8Hz ,J2=16.8Hz,2H),4.18-4.28(m,1H),3.67-3.79(m,4H),3.49(s,3H),2.11-2.30(m,8H),1.76-2.04(m,4H). 13 C NMR(CDCl3):δ164.7,164.2,135.0,132.7,128.2,127.6,70.7,61.9,61.8,53.4,43.5,24.6,20.0,19.9,18.8. HRMS(ESI):m / z[M -Br] + Theoretical value for C18H27N2O3: 319.2016; Measured value: 319.2022.

[0234] The second product isolated (compound 3b; ZYK2212-2) (0.31 g, 75%) was determined by 2D NMR techniques to be a mixture of two stereoisomers shown below: [ka] It was decided that: 1 H NMR(3-2,CDCl3):δ10.14(s,1H),6.92-7.08(m,3H),5.45(dd,J1=9.6Hz,J2=3.6Hz,1H),4.74(dd,J1=290.4Hz,J2=17.2Hz,2H ),4.15-4.24(m,1H),3.77-3.87(m,1H),3.75(s,3H),3.57((s,3H),2.26-2.37(m,1H),2.11-2.23(m,7H),1.76-1.90(m,4H). 13 C NMR(CDCl3):δ165.2,164.6,135.0,132.2,128.2,127.8,72.2,61.0,54.6,53.2,50.1,24.8,19.9,19.2,18.3. HRMS(ESI):m / z[M -Br] + Theoretical value for C18H27N2O3: 319.2016; Measured value: 319.2022.

[0235] 2-((2,6-dimethylphenyl)carbamoyl)-1-(2-methoxy-2-oxoethyl)-1-propylpiperidin-1-ium bromide (4S) [ka] To a 50 mL round-bottom flask, (S)-ropivacaine (single enantiomer; 3 mmol), methyl bromoacetate (10 mmol), and 2 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80 °C for 1 h and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give two products as white solids.

[0236] The first product isolated (compound 4Sa; ZYK2312-1) (0.77 g, 60%) was identified by 2D NMR techniques as the stereoisomers shown below: [ka] It was decided that: H NMR(CDCl3):δ10.59(s,1H),7.00-7.10(m,3H),6.20(dd,J1=9.6Hz,J2=3.6Hz,1H),4.84(dd,J1=342.8Hz,J2=17.2Hz,2H),4.21-4.29 (m,1H),3.95-4.04(m,1H),3.83(s,3H),3.63-3.75(m,2H),2.48-2.57(m,1H),2.18-2.32(m,7H),1.85-2.18(m,6H),1.04(t,J=7.2Hz 3H). 13 C NMR(CDCl3):δ165.6,164.7,135.0,132.7,128.1,127.5,69.2,63.5,59.1,55.8,53.3,25.3,19.7,19.3,18.6,16.4,10.7. HRMS(ESI):m / z[M -Br] + Theoretical value for C20H31N2O3: 347.2329; Measured value: 347.2332.

[0237] The second product isolated (compound 4Sb; ZYK2312-2) (0.11 g, 8.6%) was identified by 2D NMR techniques as the stereoisomers shown below: [ka] It was decided that: 1 H NMR(CDCl3):δ10.25(s,1H),7.00-7.10(m,3H),6.21(dd,J1=4.4Hz,J2=4.4Hz,1H),4. 60(dd,J1=254.8Hz,J2=16.8Hz,2H),4.50-4.60(m,1H),3.82-3.95(m,5H),3.69(td,J t =13.2Hz,J d =4.8Hz,1H),2.47-2.60(m,1H),2.33-2.43(m,1H),2.25(s,6H).1.83-2.16(m,5H),1.70-1.81(m,1H),0.97(t,J=7.2Hz 3H). 13 C NMR(CDCl3):δ165.0,164.3,135.0,132.7,128.2,127.6,67.9,62.0,58.2,55.0,53.4,25.1,20.1,18.7,17.6,16.4,10.7. HRMS(ESI):m / z[M -Br] + Theoretical value for C20H31N2O3: 347.2329; Measured value: 347.2332.

[0238] Compounds 5-8 may be prepared in a manner similar to the synthesis of the compounds above. [Table 27-1] [Table 27-2]

[0239] 1-(Acetoxymethyl)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)piperidin-1-ium bromide (9) [ka] To a 50 mL round-bottom flask, bupivacaine (2.5 mmol), bromomethyl acetate (5 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80° C. for 1 hour and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give a white solid (0.83 g, 75%). 1 H NMR(CDCl3):δ10.48(s,1H),7.02-7.08(m,3H),6.30(dd,J1=8.0Hz,J2=4.0Hz,2H),5.79(dd,J1=21.2Hz,J2=9.6Hz,2H),3.89-3.92(m,1H),3.73(td,J t =13.2Hz,J d =4.8Hz 1H), 3.50(td,J t =13.2Hz,J d =4.8Hz 1H),3.35-3.45(m,1H),2.45-2.53(m,1H),2.33(s,3H),2.27(s,6H).1.84-2.06(m,7H),(tq,J t =7.2Hz,J q =7.2Hz 2H),1.01(t,J=7.2Hz 3H). 13 C NMR(CDCl3): δ168.1,165.4,135.0,132.3,128.2,127.6,75.1,68.5,60.3,55.0,25.4,24.3,20.8,20.0,19.6,19.2,18.7,13.5. HRMS(ESI):m / z[M-Br] + Theoretical value for C21H33N2O3: 361.2486; Measured value: 361.2491.

[0240] 1-(acetoxymethyl)-2-((2,6-dimethylphenyl)carbamoyl)-1-propylpiperidin-1-ium bromide (10S) [ka] To a 50 mL round-bottom flask, (S)-ropivacaine (single enantiomer; 2.5 mmol), bromomethyl acetate (5 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction was heated to 80° C. for 1 hour and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol:25:1) to give a white solid (0.85 g, 80%). 1 H NMR (DMSO-d6): δ10.3(s,1H),7.06-7.16(m,3H),5.68-5.76(m,2H),4.73-4.80(m,1H),3.85-3.95(m, 1H),3.30-3.50(m,4H),2.25-2.40(m,2H),2.23(s,3H),2.14(s,6H).1.60-90(m,6H),0.94(t,J=7.2Hz 3H).HRMS(ESI):m / z[M-Br] + Theoretical value for C20H31N2O3: 347.2329; Measured value: 347.2335.

[0241] 1-((Butyryloxy)methyl)-2-((2,6-dimethylphenyl)carbamoyl)-1-propylpiperidin-1-ium chloride (11S) [ka] To a 50 mL round-bottom flask, (S)-ropivacaine (single enantiomer; 2.5 mmol), chloromethyl butyrate (10 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80° C. for 6 hours and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=25:1) to give a white solid (0.62 g, 60%). 1 H NMR(CDCl3):δ10.09(s,1H),6.98-7.08(m,3H),6.12(dd,J1=9.2Hz,J2=3.6Hz,1H),5.86(dd,J1=34.4Hz,J2=9.6Hz,2H),3.73-3.84(m,1H),3.63(td,J t =13.2Hz,Jd =4.8Hz 1H),3.43-3.55(m,2H),2.15-2.38(m,8H).1.86-2.09(m,5H),1.68(tq,J t =7.2Hz,J q =7.2Hz 2H),1.03(t,J=7.2Hz 3H),0.96(t,J=7.2Hz 3H). 13 C NMR(CDCl3): δ170.8,165.4,134.9,133.0,128.1,127.4,75.0,69.9,68.9,62.7,35.5,25.4,19.7,19.5,18.6,18.0 16.1,13.4,10.9. HRMS(ESI):m / z[M-Cl] + Theoretical value for C22H35N2O3: 375.2642; Measured value: 375.2648.

[0242] Butyl-1-((butyryloxy)methyl)-2-((2,6-dimethylphenyl)carbamoyl)piperidin-1-ium chloride (12) [ka] To a 50 mL round-bottom flask, bupivacaine (2.5 mmol), chloromethyl butyrate (10 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80° C. for 6 hours and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give a white solid (0.58 g, 55%). 1 H NMR(CDCl3):δ11.13(s,1H),6.95-7.07(m,3H),6.09(dd,J1=8.8Hz,J2=4.0Hz,1H),5.86(dd,J1=26.0Hz,J2=9.6Hz,2H),3.75-3.87(m,1H),3.66(td,J t =13.2Hz,J d =4.8Hz 1H),3.34 3-3.53(m,2H),2.40-2.68(m,4H),2.13-2.33(m,7H),1.80-2.02(m,6H),1.65(tq,J t =7.2Hz,Jq =7.2Hz 2H), 1.37(tq,J t =7.2Hz,J q =7.2Hz 2H),0.97(t,J=7.2Hz 3H),0.94(t,J=7.2Hz 3H). HRMS(ESI):m / z[M -Cl] + Theoretical value for C23H37N2O3: 389.2799; Measured value: 389.2806.

[0243] N-(acetoxymethyl)-2-((2,6-dimethylphenyl)amino)-N,N-diethyl-2-oxoethan-1-aminium bromide (13) [ka] To a 50 mL round-bottom flask, lidocaine (2.5 mmol), methyl bromoacetate (5 mmol), and 3 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80° C. for 1 hour and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=25:1) to give a white solid (0.87 g, 90%). 1 H NMR(CDCl3): δ10.32(s,1H),6.93-7.10(m,3H),5.58(s,2H),4.99(s,2H),3.58-3.78(m,4H),2.31(s,3H),2.24(s,6H),1.45(t,J=7.2Hz 6H). 13 C NMR(CDCl3):δ168.2,161.6,135.1,132.8,128.1,127.6,76.5,55.8,54.1,20.8,18.8,8.2. HRMS(ESI):m / z[M -Br] + Theoretical value for C17H27N2O3: 307.2016; Measured value: 307.2022.

[0244] 2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(methylamino)-2-oxoethyl)-1-propyl-1λ 4 -Piperidin-2-ylium bromide (26S) [ka] To a 50 mL round-bottom flask, (S)-ropivacaine (single enantiomer; 3 mmol), 2-bromo-N-methylacetamide (10 mmol), and 1 mL of acetonitrile were added under nitrogen protection. The reaction mixture was heated to 80° C. for 16 hours and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give a white solid.

[0245] The first product isolated (compound 26Sa; ZYK3312-1) (0.45 g, 35%) was identified by 2D NMR techniques as the stereoisomers shown below: [ka] It was decided that: 1 H NMR(CDCl3):δ9.98(s,1H),8.63(q,J=4.0Hz,1H),6.95-7.06(m,3H),5.38(dd,J1=12Hz,J2=3 .6Hz,1H),4.81(dd,J1=64Hz,J2=16Hz,2H),4.11-4.28(m,1H),3.83-3.99(m,1H),3.49(dt,J t =12Hz,J d =4.0Hz,1H),3.27-3.41(m,1H),2.67(d,J=4.0Hz,3H),2.43-2.59(m,1H),2.03-2.38(m,9H),1.58-1.91(m,4H),0.91(t,J=8.0Hz 3H). 13 C NMR(CDCl3):δ165.7,164.0,135.1,132.6,128.2,127.6,69.3,58.3,56.2,25.8,25.3,20.0,18.6,18.5,16.3,11.1,10.7. HRMS(ESI):m / z[M -Br] + Theoretical value for C20H30N2O3: 346.2489; Measured value: 346.2493.

[0246] Compounds 14-25 and 27-31 may be prepared in a manner analogous to the synthesis of the compounds above. [Table 28-1] [Table 28-2]

[0247] Biological Assay Data and Procedures Duration of sensory and motor block in rats Sciatic nerve block and neurobehavioral testing. Animals were cared for in accordance with protocols approved by the Children's Hospital Animal Care and Use Committee and the Massachusetts Institute of Technology Committee on Animal Care, which conform to the guidelines of the International Association for the Study of Pain. Adult male Sprague-Dawley rats (Charles River Laboratories) weighing 320-450 g were housed in groups under a 6 AM to 6 PM light-dark cycle. Under brief isoflurane oxygen anesthesia, a 23-gauge needle was introduced posteromedially into the greater trochanter until it contacted the bone, and 0.3 mL of the test solution was injected onto the sciatic nerve. Thermal nociception was assessed using a modified hot plate test, and motor function was assessed via a weight-bearing test.

[0248] The duration of thermal nociceptive block was calculated as the time required for the thermal latency to return from a higher value to 7 s; 7 s is the midpoint between the thermal latency baseline of 2 s and the maximum latency of 12 s in adult rats. Locomotor intensity was assessed by a weight-bearing test. Briefly, animals were held on a digital scale so that they could support their weight on one hind paw at a time. The maximum weight supported by the animal was recorded. The duration of motor block was defined as the time for weight-bearing to return halfway from maximum block to normal. The halfway point for each rat was defined as [(maximum weight supported by either paw)(minimum weight supported by the blocked paw)] / 2(minimum weight supported by the blocked paw).

[0249] The exemplary compounds were evaluated under the experimental conditions described. The results in Table 1 demonstrate that the compounds of the present disclosure are effective sensory nerve blocking agents. Surprisingly, the compounds of the present disclosure also exhibit high selectivity for sensory nerve blockade over motor function blockade, particularly compared to standard therapeutic local anesthetics such as ropivacaine and bupivacaine. Table 1. [Table 29]

[0250] cytotoxicity C2C12 mouse myoblasts [American Type Culture Collection (ATCC) CRL-1772] were expanded by culturing in DMEM supplemented with 20% FBS and 1% penicillin-streptomycin. Cell culture supplies were obtained from Invitrogen unless otherwise noted. Cells were plated at 50,000 cells per mL in DMEM with 2% horse serum and 1% Penn Strep and allowed to differentiate into myotubes for 10–14 days. Medium was changed every 2–3 days during differentiation. Cell viability and proliferation were studied up to 24 h after drug exposure. PC12 cells (ATCC, CRL-1721), originating from a rat adrenal pheochromocytoma, were grown in F-12K (ATCC) supplemented with 12.5% ​​horse serum (Gibco), 2.5% FBS (Gibco), and 1% Penn Strep (Sigma) in 24-well tissue culture dishes (CellBind; Corning). For neuronal induction (PC12), cells were cultured at 5 × 10 4 cells / cm 2 Cells were seeded at a relatively low density of 1000 μg / ml, and 50 ng / mL NGF was added 24 h after seeding. Cell viability and proliferation were assessed for C2C12 cells. Experiments with PC12 cells were performed for up to 24 h.

[0251] Figures 1 and 2 display the results of cytotoxicity assays for compounds 10S (ZYK1312), 11S (ZYK1331), 1 (ZYK2112), 4Sa / 4Sb (mixture; ZYK2312-1 / ZYK2312-2), and 2a / 2b (mixture; ZYK2412-1 / ZYK2412-2), demonstrating that the compounds of the present disclosure are significantly less cytotoxic than ropivacaine and bupivacaine. Table 2 displays the results of additional experiments and also demonstrates that compounds 4Sa (ZYK2312-1), 4Sb (ZYK2312-1), and 26Sa (ZYK3312-1) are significantly less cytotoxic than ropivacaine and bupivacaine. Table 2. Cytotoxicity of compounds [Table 30]

[0252] In Vitro Effects on hERG and Nav1.5 Peaks These experiments were designed to examine the acute effects of 4Sa (ZYK2312-1), 4Sb (ZYK2312-2), and bupivacaine on hERG currents and Nav1.5 peak currents recorded from stably transfected HEK cells.

[0253] Experimental Method: Currents were measured using the whole-cell variant of the patch clamp technique. Glass pipettes were pulled from borosilicate glass using a horizontal puller (Sutter Instruments, USA). The resistance of the pipette tip was approximately 1–2 MΩ when filled with the internal solution. Series resistance was electronically compensated for by approximately 60–80%. Bath temperature was measured using a thermistor placed near the cell under study. An Axopatch 1-B amplifier (Axon Instruments, Foster City, CA) was used for whole-cell voltage clamp. Voltage clamp pulse generation and data acquisition were controlled by a computer running pCLAMP software (ver 9.2 Axon Instruments). After cell membrane rupture (entering whole-cell mode), the kinetics and amplitude of currents were allowed to stabilize (typically 2–3 min) while the cells were dialyzed with the internal solution and stabilized every 5 s. Na Peaks were elicited using a fixed amplitude pulse pattern (conditioning prepulse: -120 mV for 50 ms; depolarizing test step to -30 mV for 20 ms). hERG currents were elicited with a 500 ms pulse to +10 mV, followed by a 500 ms pulse to -40 mV (holding potential = 75 mV). Cells were perfused with each test concentration until a steady state was reached.

[0254] Raw data and mean ± SEM are presented. Data are presented as the percent reduction in current amplitude, measured after a steady-state effect in the presence of drug was reached, compared to the current amplitude before drug introduction (control). Each cell served as its own control. A three-parameter Hill equation was fitted to the results using Micro Cal Origin, version 6.0 software, utilizing a nonlinear curve-fitting routine. The equation is:

number

[0255] The effects of 4Sa (ZYK2312-1), 4Sb (ZYK2312-2), and bupivacaine on hERG and Nav1.5 peak currents were characterized in stably transfected HEK cells at physiological temperatures. As shown in Tables 3 and 4 and Figure 3, bupivacaine was associated with a concentration-dependent block of both hERG and Nav1.5 peak currents over the tested concentration range of 1 to 100 μM. IC 50 The values ​​were 16.4 μM for hERG and 9.8 μM for the Nav1.5 peak.

[0256] In contrast, 4Sa (ZYK2312-1) had little effect on the Nav1.5 peak (concentration range 1–1000 μM) and reduced hERG currents with an IC of 813.9 μM. 50 4Sa (ZYK2312-1) and 4Sb (ZYK2312-2) were weak blockers of these cardiac currents over the concentration range tested. 4Sa (ZYK2312-1) and 4Sb (ZYK2312-2) were thus weak blockers of these cardiac currents over the concentration range of 1 to 1000 μM. In contrast, bupivacaine had IC values ​​of 16.4 μM for hERG and 9.8 μM for the Nav1.5 peak.50 At this value, both currents were blocked. Table 3. Effect of compounds on hERG current amplitude (percent reduction in current amplitude) [Table 31] Values ​​are means ± standard errors Table 4. Effect of compounds on Nav1.5 peak current amplitude (percent reduction in current amplitude) [Table 32] Values ​​are means ± standard errors

[0257] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless the context clearly dictates otherwise. A claim or description including "or" between one or more members of a group is considered to satisfy that one, more than one, or all of the members of the group are present in, employed in, or otherwise relevant to a given product or process, unless the context clearly dictates otherwise. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all of the members of the group are present in, employed in, or otherwise relevant to a given product or process.

[0258] Moreover, the present invention covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same base claim. Where elements are presented as enumerated in Markush group format, by way of example, each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, when the invention, or aspects of the invention, are described as including particular elements and / or features, it should be understood that certain embodiments of the invention or certain aspects of the disclosure consist of, or consist essentially of, such elements and / or features. For purposes of brevity, those embodiments have not been specifically recited herein. Note also that the terms "comprising" and "containing" are intended to be open and permit the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Moreover, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges set forth in different embodiments of the invention, up to 10 times the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0259] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular aspect of the present invention that is within the prior art may be expressly excluded from any one or more of the claims. Because such aspects would be known to those of skill in the art, they may be excluded even if the exclusion is not expressly stated herein. Any particular aspect of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0260] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

[Claim 1] The invention described herein.

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