Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

• Local anesthetics can produce a reversible loss of sensation when applied to nerve tissues. When applied locally to a nerve tissue in appropriate concentrations, local anesthetics reversibly block the action potentials responsible for nerve conduction.
• the anesthetics act on any part of the nervous system, including every type of nerve fiber.
• a local anesthetic in contact with a nerve trunk can cause both sensory and motor nerve block in the area innervated. Therefore, although the goal of topical or regional anesthesia is to block the transmission of signals to prevent pain, the administration of local anesthetics also produces numbness from block of low-threshold pressure and touch receptors, paralysis from block of motor axons, and block of autonomic fibers.
• the present disclosure stems from the recognition that effective strategies for generating pain-restricted local anesthesia while preserving motor and autonomic responses are desirable in certain medical and/or surgical procedures (e.g., childbirth, dental procedures, treating nociceptor-driven chronic pain).
• the present disclosure recognizes there is a need for compounds and methods that provide sensory-specific nerve blockade. Accordingly, the present disclosure provides new compounds, compositions, and methods for achieving selective sensory nerve blockade.
• 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 ;
• R A is hydrogen or substituted or unsubstituted alkyl
• X- is a counterion; and n is 1, 2, 3, 4, 5, or 6; provided that if A is NR A , then R 3 is H; R 8 is not substituted or unsubstituted aryl; and the compound is not:
• the compounds of Formula (II) are compounds of Formula
• Exemplary compounds of Formula (II) include, but are not limited to:
• compositions comprising a compound of the disclosure (e.g., a compound of Formula (II)), and optionally a pharmaceutically acceptable excipient.
• a compound of Formula (I) and pharmaceutically acceptable co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 or R 6 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 or R 5 to 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;
• 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 ;
• R A is hydrogen or substituted or unsubstituted alkyl
• X- is a counterion; and n is l, 2, 3, 4, 5, or 6.
• the method comprises administering a compound of Formula (II):
• the method comprises administering a compound of Formula (Il-b), (II-c), (Il-d), (Il-e), (Il-f), (Il-g), (II-h), (Il-i), or (Il-j):
• the method comprises administering a compound of Formula (III):
• the method comprises administering a compound of Formula (Ill-b), (III-c), (Ill-d), (Ill-e), or (Ill-f): [0015] In certain embodiments, the method comprises administering a compound of formula:
• kits comprising a compound of Formula (I), (II), or (III), or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III).
• the kits further comprise instructions for administration (e.g ., human administration).
• Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
• HPLC high pressure liquid chromatography
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
• Such compounds are useful, for example, as analytical tools or probes in biological assays.
• C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1- 3, C 1-2 , C 2-6 , C 2-5 , C 2- , C 2-3 , C 3- 6, C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C5-6 alkyl.
• alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“CMO alkyl”).
• an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
• an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
• C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g ⁇ , n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
• alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
• substituents e.g., halogen, such as F
• the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., -CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
• the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g.
• haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
• the haloalkyl moiety has 1 to 8 carbon atoms (“C 1-8 haloalkyl”).
• the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
• the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”).
• the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”). Examples of haloalkyl groups include -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CC1 3 , -CFC1 2 , -CF 2 Cl, and the like.
• heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g ., l, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within ( i.e ., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-2 o alkyl”).
• a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-18 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-16 alkyl”).
• a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”).
• a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”).
• a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”).
• the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group.
• a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups.
• each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
• the heteroalkyl group is an unsubstituted heteroC 1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
• alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds ( e.g ., l, 2, 3, or 4 double bonds).
• an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
• an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”).
• an alkenyl group has 2 to 7 carbon atoms (“C 2- 7 alkenyl”).
• an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”).
• an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
• the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
• Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
• Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C5), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
• each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
• the alkenyl group is an unsubstituted C 2-10 alkenyl.
• the alkenyl group is a substituted C 2-10 alkenyl.
• heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., l, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”).
• a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”).
• a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”).
• a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). 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, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
• alkynyl refers to a 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 ., l, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2- 7 alkynyl”).
• an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
• Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
• Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
• each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
• the alkynyl group is an unsubstituted C 2-10 alkynyl.
• the alkynyl group is a substituted C 2-10 alkynyl.
• heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g ., l, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within ( i.e ., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
• a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2- 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”).
• a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”).
• a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). 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, the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
• carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
• a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
• a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
• a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”).
• a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
• Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
• Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
• Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
• the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
• Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
• each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
• the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
• the carbocyclyl group is a substituted C 3-14 carbocyclyl.
• “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
• a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
• C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
• Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
• each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
• the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl.
• the cycloalkyl group is a substituted C 3-14 cycloalkyl.
• heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”).
• heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
• Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
• Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
• each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
• the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
• a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
• a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
• a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
• the heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
• 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
• Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
• Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
• Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
• Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
• Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
• 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
• Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
• Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
• Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
• bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][l,4-
• aryl refers to a radical of a monocyclic or polycyclic (e.g ., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
• aromatic ring system e.g., having 6, 10, or 14 p electrons shared in a cyclic array
• an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
• an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
• an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
• Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
• each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
• the aryl group is an unsubstituted C 6-14 aryl.
• the aryl group is a substituted C 6-14 aryl.
• heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
• Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
• a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
• a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
• a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
• the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
• Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
• Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
• Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
• 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
• Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
• Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
• 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
• Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
• Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
• Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
• Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
• saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
• alkylene is the divalent moiety of alkyl
• alkenylene is the divalent moiety of alkenyl
• alkynylene is the divalent moiety of alkynyl
• heteroalkylene is the divalent moiety of heteroalkyl
• heteroalkenylene is the divalent moiety of heteroalkenyl
• heteroalkynylene is the divalent moiety of heteroalkynyl
• carbocyclylene is the divalent moiety of carbocyclyl
• heterocyclylene is the divalent moiety of heterocyclyl
• arylene is the divalent moiety of aryl
• heteroarylene is the divalent moiety of heteroaryl.
• a group is optionally substituted unless expressly provided otherwise.
• the term “optionally substituted” refers to being substituted or unsubstituted.
• “Optionally substituted” refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsub
• substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
• a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
• substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
• the present invention contemplates any and all such combinations in order to arrive at a stable compound.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
• the invention is not intended to be limited in any manner by the exemplary substituents described herein.
• halo or halogen refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
• a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
• An anionic counterion may be monovalent (i.e., including one formal negative charge).
• An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
• Exemplary counterions include halide ions (e.g ., F , CE, Br , E), NO 3 , CIO 4 , OH , H 2 PO 4 , HCO 3 , HSO 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid- 2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4 E PF 4 , PF 6 , AsF 6 , , S
• Exemplary counterions which may be multivalent include CO 3 2- , HPO 4 2- ,PO 4 3- , B 4 0 7 2- , SO 4 2- , S 2 O 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
• carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
• carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate
• solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
• solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
• the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
• the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
• “Solvate” encompasses both solution-phase and isolatable solvates.
• Representative solvates include hydrates, ethanolates, and methanolates.
• hydrate refers to a compound that is associated with water molecules.
• the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H 2 O, wherein R is the compound, and x is a number greater than 0.
• a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than l, e.g., hemihydrates (R-0.5 H 2 O)), and polyhydrates (x is a number greater than l, e.g., dihydrates (R-2 H 2 O) and hexahydrates (R-6 H 2 O)).
• monohydrates x is 1
• lower hydrates x is a number greater than 0 and smaller than l, e.g., hemihydrates (R-0.5 H 2 O)
• polyhydrates x is a number greater than l, e.g., dihydrates (R-2 H 2 O) and hexahydrates (R-6 H 2 O)
• tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
• the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
• Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
• isomers compounds that have the same molecular formula but 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”.
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers”.
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
• polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). Many compounds can adopt a variety of different crystal forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and/or can vary in some or all properties such as melting points, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate a given preparation. Various polymorphs of a compound can be prepared by crystallization under different conditions.
• co-crystal refers to a crystalline structure composed of at least two components.
• a co-crystal contains a compound of the present disclosure and one or more other component(s), including, but not limited to, atoms, ions, molecules, or solvent molecules.
• a co-crystal contains a compound of the present disclosure and one or more solvent molecules.
• a cocrystal contains a compound of the present disclosure and one or more acid or base.
• a co-crystal contains a compound of the present disclosure and one or more components related to said compound, including, but not limited to, an isomer, tautomer, salt, solvate, hydrate, synthetic precursor, synthetic derivative, fragment, or impurity of said compound.
• prodrugs refers to compounds that have cleavable groups that are removed, by solvolysis or under physiological conditions, to provide the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs , pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
• Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.
• composition and “formulation” are used interchangeably.
• a “subject” to which administration is contemplated refers to a human (i.e ., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
• the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
• primate e.g., cynomolgus monkey or rhesus monkey
• commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
• bird e.g., commercially relevant bird, such
• the non-human animal is a fish, reptile, or amphibian.
• the non-human animal may be a male or female at any stage of development.
• the non-human animal may be a transgenic animal or genetically engineered animal.
• the term “patient” refers to a human subject in need of treatment of a disease.
• the subject may also be a plant.
• the plant is a land plant.
• the plant is a non- vascular land plant.
• the plant is a vascular land plant.
• the plant is a seed plant.
• the plant is a cultivated plant.
• the plant is a dicot.
• the plant is a monocot.
• the plant is a flowering plant.
• the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet.
• the plant is a legume, e.g., a bean plant, e.g., soybean plant.
• the plant is a tree or shrub.
• tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
• tissue samples such as tissue sections and needle biopsies of a tissue
• cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
• samples of whole organisms such as samples of yeasts or bacteria
• cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
• biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
• administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
• treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
• treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
• treatment may be administered in the absence of signs or symptoms of the disease.
• treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
• an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
• An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
• an effective amount is a therapeutically effective amount.
• an effective amount is the amount of a compound described herein in a single dose.
• an effective amount is the combined amounts of a compound described herein in multiple doses.
• a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit. In certain embodiments, a therapeutically effective amount is an amount sufficient for inducing sensory nerve blockade. In certain embodiments, a therapeutically effective amount is an amount sufficient for inducing selective sensory nerve blockade.
• therapeutic agent refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect.
• therapeutic agents may treat, ameliorate, and/or prevent disease.
• therapeutic agents, as disclosed herein, may be biologies or small molecule therapeutics, or combinations thereof.
• local anesthetic refers to any agent that produces nerve blockade within a specific area, region or site.
• sensor nerve blockade may also be referred to as “nociceptive blockade,” both of which refer to deficits in apparent perception of a painful stimulus, herein detected by modified hotplate testing, and presumably due to impairment of signal conduction in nerves.
• motor function blockade refers to deficits in motor function, here detected by a weight-bearing test, and presumably due to impairment of signal conduction in nerves.
• FIG. 1 is a plot showing the cytotoxicity of exemplary compounds in comparison to ropivacaine and bupivacaine in PC 12 cells.
• FIG. 2 is a plot showing the cytotoxicity of exemplary compounds in comparison to ropivacaine and bupivacaine in C 2 12 cells.
• FIG. 3 is two plots showing the inhibition of hERG and peak Navi.5 by exemplary compounds in comparison to bupivacaine in HEK cells.
• the provided anesthetics are compounds of Formula (I), (II), and (III), and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof.
• compounds of Formula (I), (II), and (III), and pharmaceutically acceptable solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof are particularly useful in methods of inducing selective sensory nerve blockade. Accordingly, the compounds are useful as local anesthesia in a subject in need thereof, and have surprisingly superior anesthetic properties (e.g., duration of sensory nerve blockade, selectivity of sensory nerve blockade over motor function, low cytotoxicity) over existing anesthetics.
• the compounds may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
• a compound of Formula (I) 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 or R 6 to form a heterocyclyl ring;
• 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 ;
• a 1 is O, S, or NR a ;
• R A is hydrogen or substituted or unsubstituted alkyl; X- is a counterion; and n is l, 2, 3, 4, 5, or 6.
• 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 or R 6 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 or R 5 to 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;
• 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 ;
• R A is hydrogen or substituted or unsubstituted alkyl; and X- is a counterion.
• R 1 is substituted or unsubstituted alkyl. In certain embodiments, R 1 is unsubstituted alkyl. In certain embodiments, R 1 is unsubstituted Ci-6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-4 alkyl. In certain embodiments, R 1 is unsubstituted C 1-3 alkyl. In certain embodiments, R 1 is unsubstituted C 1-2 alkyl. In certain embodiments, R 1 is methyl.
• R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is unsubstituted alkyl. In certain embodiments, R 2 is unsubstituted C 1-6 alkyl. In certain embodiments, R 2 is unsubstituted C 1-4 alkyl. In certain embodiments, R 2 is unsubstituted C 1-3 alkyl. In certain embodiments, R 2 is unsubstituted C 1-2 alkyl. In certain embodiments, R 2 is methyl.
• R 1 is unsubstituted alkyl; and R 2 is unsubstituted alkyl. In certain embodiments, R 1 is unsubstituted C 1-6 alkyl; and R 2 is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-4 alkyl; and R 2 is unsubstituted C 1-4 alkyl. In certain embodiments, R 1 is unsubstituted C 1-3 alkyl; and R 2 is unsubstituted C 1-3 alkyl. In certain embodiments, R 1 is unsubstituted C 1-2 alkyl; and R 2 is unsubstituted C 1-2 alkyl. In certain embodiments, R 1 is methyl; R 2 is methyl.
• R 3 is hydrogen, or substituted or unsubstituted alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is substituted or unsubstituted alkyl. In certain embodiments, R 3 is unsubstituted alkyl. In certain embodiments, R 3 is unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is unsubstituted C 1-4 alkyl. In certain embodiments, R 3 is unsubstituted C 1-3 alkyl. In certain embodiments, R 3 is unsubstituted C 1-2 alkyl. In certain embodiments, R 3 is methyl.
• R 4 is hydrogen, substituted or unsubstituted alkyl, or is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 or R 6 to form a heterocyclyl ring; and
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 or R 5 to form a heterocyclyl ring.
• R 4 is hydrogen. In certain embodiments, R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is unsubstituted alkyl. In certain embodiments, R 4 is unsubstituted C 1-6 alkyl.
• R 4 is hydrogen, or is joined with R 5 or R 6 to form a heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a 4-7 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a 4-6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a 4-5 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a 5-6 membered heterocyclyl ring.
• R 4 is joined with R 5 or R 6 to form a 5 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a 6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 or R 6 to form a piperidinium ring.
• R 4 When R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is a substituted or unsubstituted alkyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is an unsubstituted alkyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is an unsubstituted C 1-6 alkyl.
• R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is an unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is an unsubstituted C 1-3 alkyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is an unsubstituted C 1-2 alkyl.
• R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is methyl, ethyl, n-propyl, or n-butyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is methyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is n-propyl. In certain embodiments, R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, and the remaining variable of R 5 and R 6 that does not form the heterocyclyl ring is n-butyl.
• R 4 is joined with R 5 to form a heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a 4-7 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a 4-6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a 4-5 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a 5-6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a 5 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a 6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 5 to form a piperidinium ring.
• R 4 is joined with R 6 to form a heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a 4-7 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a 4-6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a 4-5 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a 5-6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a 5 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a 6 membered heterocyclyl ring. In certain embodiments, R 4 is joined with R 6 to form a piperidinium ring.
• the heterocyclyl ring when R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, the heterocyclyl ring is further substituted. In certain embodiments, when R 4 is joined with R 5 or R 6 to form a heterocyclyl ring, the heterocyclyl ring is not further substituted.
• R 5 is substituted or unsubstituted alkyl. In certain embodiments, R 5 is unsubstituted alkyl. In certain embodiments, R 5 is unsubstituted C 1-6 alkyl. In certain embodiments, R 5 is unsubstituted C 1-4 alkyl. In certain embodiments, R 5 is unsubstituted C 1-3 alkyl. In certain embodiments, R 5 is unsubstituted C 1-2 alkyl. In certain embodiments, R 5 is n-butyl, n-propyl, ethyl, or methyl. In certain embodiments, R 5 is n-butyl. In certain embodiments, R 5 is n-propyl.
• R 5 is ethyl. In certain embodiments, R 5 is methyl.
• R 6 is substituted or unsubstituted alkyl. In certain embodiments, R 6 is unsubstituted alkyl. In certain embodiments, R 6 is unsubstituted C 1-6 alkyl. In certain embodiments, R 6 is unsubstituted C 1-4 alkyl. In certain embodiments, R 6 is unsubstituted C 1-3 alkyl. In certain embodiments, R 6 is unsubstituted C 1-2 alkyl. In certain embodiments, R 6 is n-butyl, n-propyl, ethyl, or methyl. In certain embodiments, R 6 is n-butyl. In certain embodiments, R 6 is n-propyl. In certain embodiments, R 6 is ethyl. In certain embodiments, R 6 is methyl.
• R 5 is unsubstituted alkyl; and R 6 is unsubstituted alkyl. In certain embodiments, R 5 is C 1-6 unsubstituted alkyl; and R 6 is C 1-6 unsubstituted alkyl. In certain embodiments, R 5 is C 1-4 unsubstituted alkyl; and R 6 is C 1-4 unsubstituted alkyl. In certain embodiments, R 5 is C 1-3 unsubstituted alkyl; and R 6 is C 1-3 unsubstituted alkyl. In certain embodiments, R 5 is C 1-2 unsubstituted alkyl; and R 6 is C 1-2 unsubstituted alkyl. In certain embodiments, R 5 is C 1-6 ethyl; and R 6 is C 1-6 ethyl.
• R 4 is hydrogen, substituted or unsubstituted alkyl, or is joined with R 5 or R 6 to form a heterocyclyl ring.
• R 7 is hydrogen, substituted or unsubstituted alkyl, or halogen. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is halogen. In certain embodiments, R 7 is fluoro. In certain embodiments, R 7 is substituted or unsubstituted alkyl, unsubstituted alkyl. In certain embodiments, R 7 is unsubstituted C 1-6 alkyl. In certain embodiments, R 7 is unsubstituted C 1-4 alkyl. In certain embodiments, R 7 is unsubstituted C 1-3 alkyl. In certain embodiments, R 7 is unsubstituted C 1-2 alkyl.
• 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 ;
• a 1 is O, S, or NR A ; and
• R A is hydrogen or substituted or unsubstituted alkyl.
• 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.
• 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.
• 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.
• R 8 is unsubstituted C 1-4 alkyl;
• A is O or NR A ; and
• R A is hydrogen or substituted or unsubstituted alkyl.
• 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.
• R 3 is hydrogen. In certain embodiments, if A is NR a , then R 8 is not substituted or unsubstituted aryl. In certain embodiments, if A is NR a , then R 3 is hydrogen, and R 8 is not substituted or unsubstituted aryl. In certain embodiments, if A is NR A , then neither R 8 nor R A is substituted or unsubstituted Cn alkyl.
• 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.
• R 8 is benzyl, t-butyl, n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A is O.
• R 8 is t-butyl, n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A is O.
• R 8 is n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A is O.
• R 8 is n-butyl, isopropyl, n-propyl, or methyl; and A is O.
• R 8 is isopropyl; and A is O.
• 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 A is hydrogen or substituted or unsubstituted alkyl.
• R 10 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;
• a 1 is O, S, or NR a ; and
• R A is hydrogen or substituted or unsubstituted alkyl.
• R 10 is substituted or unsubstituted alkyl;
• a 1 is O, S, or NR a ; and
• R A is hydrogen or substituted or unsubstituted alkyl.
• R 10 is unsubstituted alkyl;
• a 1 is O, S, or NR A ; and
• R A is hydrogen or substituted or unsubstituted alkyl.
• R 10 is unsubstituted C 1-4 alkyl;
• a 1 is O, S, or NR A ; and
• R A is hydrogen or substituted or unsubstituted alkyl.
• 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 or S.
• 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.
• R 10 is t-butyl, n-butyl, isopropyl, n-propyl, ethyl, or methyl; and A 1 is O.
• R 10 is n-butyl, n-propyl, ethyl, or methyl; and A 1 is O.
• R 10 is n-butyl; and A 1 is O.
• X- is a counterion.
• X- is a halide ion.
• X- is F , Cl , Br , or I .
• X- is Cl or Br .
• X- is Cl .
• X- is Br . n
• n is l, 2, 3, 4, 5, or 6. In certain embodiments, n is l, 2, 3, 4, or 5. In certain embodiments, n is l, 2, 3, or 4. In certain embodiments, n is l, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.
• the compound of Formula (I) is of Formula (II): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, n, and X- are as defined herein.
• the compound of Formula (I) is of Formula (II): 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 ;
• R A is hydrogen or substituted or unsubstituted alkyl
• X- is a counterion; and n is l, 2, 3, 4, 5, or 6.
• the compound of Formula (I) is of Formula (II): 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 ;
• R A is hydrogen or substituted or unsubstituted alkyl
• X- is a counterion; and n is l, 2, 3, 4, 5, or 6; provided that if A is NR A , then R 3 is H; R 8 is not substituted or unsubstituted aryl; and the compound is not:
• 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 a counterion; and n is l, 2, 3, 4, 5, or 6.
• the compound of Formula (I) is of Formula (II):
• 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 a counterion; provided that the compound is not:
• the compound of Formula (I) is of Formula (Il-a): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, and X- are as defined herein.
• 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring;
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 counterion.
• the compound of Formula (II) is of Formula (II-a): 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 is joined with R 5 or R 6 to form a heterocyclyl ring;
• R 5 is substituted or unsubstituted alkyl, or is joined with R 4 to form a heterocyclyl ring
• R 6 is substituted or unsubstituted alkyl, or is joined with R 4 to 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 a counterion; provided that the compound is not:
• the compound of Formula (II) is of Formula (Il-b): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , n, and X- are as defined herein.
• the compound of Formula (II) is of Formula (II-b-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and X- are as defined herein.
• the compound of Formula (II) is of Formula (II-c): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 4 , R 7 , R 8 , n, A, and
• X- are as defined herein.
• the compound of Formula (II) is of Formula (II-c-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 4 , R 7 , R 8 , A, and
• X- are as defined herein.
• the compound of Formula (II) is of Formula (Il-d): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 4 , R 7 , R 8 , n, and X are as defined herein.
• the compound of Formula (II) is of Formula (II-d-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 4 , R 7 , R 8 , and X are as defined herein.
• the compound of Formula (II) is of Formula (Il-e): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , A, n, and X- are as defined herein.
• the compound of Formula (II) is of Formula (II-e-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and X- are as defined herein.
• the compound of Formula (II) is of Formula (Il-f): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , A, n, and X- are as defined herein.
• the compound of Formula (II) is of Formula (II-f-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and X- are as defined herein.
• the compound of Formula (II) is of Formula (Il-g): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 7 , R 8 , A, n, and
• X- are as defined herein.
• the compound of Formula (II) is of Formula (II-g-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 7 , R 8 , A, and
• X- are as defined herein.
• the compound of Formula (II) is of Formula (Il-h): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 7 , R 8 , n, and X are as defined herein.
• the compound of Formula (II) is of Formula (II-h-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 7 , R 8 , and X are as defined herein.
• the compound of Formula (II) is of Formula (Il-i): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 8 , A, n, and X are as defined herein.
• the compound of Formula (II) is of Formula (II-i-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 8 , A, and X are as defined herein.
• the compound of Formula (II) is of Formula (Il-j): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 8 , n, and X- are as defined herein.
• the compound of Formula (II) is of Formula (II-j-1): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 8 , and X- are as defined herein.
• the compound of Formula (I) is of Formula (III): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , A 1 , n, and X- are as defined herein.
• the compound of Formula (I) is of Formula (Ill-a): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , A 1 , and X- are as defined herein.
• the compound of Formula (III) is of Formula (Ill-b): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 7 , R 10 , and X- are as defined herein.
• the compound of Formula (III) is of Formula (III-c): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 4 , R 7 , R 10 , and X " are as defined herein.
• the compound of Formula (III) is of Formula (Ill-d): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 2 , R 3 , R 5 , R 7 , R 10 , and X- are as defined herein.
• the compound of Formula (III) is of Formula (Ill-e): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 7 , R 10 , and X are as defined herein.
• the compound of Formula (III) is of Formula (Ill-f): or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 5 , R 10 , and X- are as defined herein.
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate,
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof: [00144] In certain embodiments, the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof: [00150] In certain embodiments, the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodmgs thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [00157] In certain embodiments, the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (I) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (I) is not one or more of the following compounds:
• the compound of Formula (II) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof: [00167] In certain embodiments, the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof: [00173] In certain embodiments, the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [00180] In certain embodiments, the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is the following compound, or a pharmaceutically acceptable co-crystal, tautomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (II) is a mixture of the following compounds, or pharmaceutically acceptable co-crystals, tautomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof:
• the compound of Formula (II) is not of formula: [00184]
• the compound of Formula (III) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (III) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: [00186] In certain embodiments, the compound of Formula (III) is one of the following compounds, or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof:
• the compound of Formula (III) is not one or more of the following compounds:
• the provided compounds selectively induce sensory nerve blockade over motor function blockade.
• the compounds selectively induce sensory nerve blockade over motor function blockade such that the ratio of the duration of sensory nerve blockade to duration of motor function 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 in a subject in need thereof.
• compositions comprising a disclosed compound (e.g., a compound of Formula (I), (II), or (III)), or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
• a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof and optionally a pharmaceutically acceptable excipient.
• the pharmaceutical composition described herein comprises a compound of Formula (I), (II), or (III), and a pharmaceutically acceptable excipient.
• the compound of Formula (I), (II), or (III) is provided in an effective amount in the pharmaceutical composition.
• the effective amount is a therapeutically effective amount.
• the effective amount is a prophylactically effective amount.
• the effective amount is an amount effective for inducing selective sensory nerve blockade in a subject in need thereof.
• the effective amount is an amount effective for providing a longer duration of sensory nerve blockade than duration of motor function blockade in a subject in need thereof.
• the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.1:1 in a subject in need thereof.
• the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.2:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.3:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.4:1 in a subject in need thereof.
• the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.5:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 2: 1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 3:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 5:1 in a subject in need thereof.
• the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 10:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 20:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 50: 1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 100:1 in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for providing sensory nerve blockade without motor function blockade in a subject in need thereof.
• the subject being treated or administered a compound described herein is an animal.
• the animal may be of either sex and may be at any stage of development.
• the subject is a non-human animal.
• the subject is a mammal.
• the subject described herein is a human.
• the subject is a non-human mammal.
• the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
• the subject is a companion animal, such as a dog or cat.
• the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
• the subject is a zoo animal.
• the subject is a research animal, such as a rodent (e.g ., mouse, rat), dog, pig, or non-human primate.
• the animal is a genetically engineered animal.
• the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
• the subject is a fish or reptile.
• the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for topical administration. In certain embodiments, the pharmaceutical composition is a liquid ( e.g ., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.
• 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, ototopically, on the cornea, perineurally, by infiltration, or the like, depending on the desired location of the anesthetic effect.
• the compound or pharmaceutical composition can be administered by any of the methods for administering local anesthetics known to one of ordinary skill in the art.
• the composition can be formulated for topical anesthesia, infiltration anesthesia, field block anesthesia, nerve block anesthesia, intravenous regional anesthesia, spinal anesthesia and/or epidural anesthesia.
• a pharmaceutical composition comprising a compound of Formula (I), (II), or (III) is 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.
• the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired anesthetic effect.
• the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired anesthetic effect.
• the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
• the composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects.
• the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose.
• the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose.
• the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose.
• pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.
• compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a compound of Formula (I), (II), or (III) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
• compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
• a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
• the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
• compositions of the disclosure will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
• Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
• 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, cornstarch, powdered sugar, and mixtures thereof.
• Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, 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), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
• crospovidone cross-linked poly(vinyl-pyrrolidone)
• sodium carboxymethyl starch sodium starch glycolate
• Exemplary surface active agents 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.
• 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 (mag
• stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), 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
• polyoxyethylene esters e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
• sucrose fatty acid esters e.g.
• CremophorTM polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), 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.
• polyoxyethylene ethers e.g. polyoxyethylene lauryl ether (Brij 30)
• poly(vinyl-pyrrolidone) diethylene glycol monolaurate
• triethanolamine oleate sodium oleate
• potassium oleate ethyl oleate
• oleic acid ethyl laurate
• Exemplary binding agents include starch (e.g ., cornstarch 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, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and
• Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
• the preservative is an antioxidant.
• the preservative is a chelating agent.
• antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
• Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
• EDTA ethylenediaminetetraacetic acid
• salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
• citric acid and salts and hydrates thereof e.g., citric acid mono
• 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.
• Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
• Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
• 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.
• preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
• BHA butylated hydroxyanisol
• BHT butylated hydroxytoluened
• SLS sodium lauryl sulfate
• SLES sodium lauryl ether sulfate
• sodium bisulfite sodium metabisulfite
• potassium sulfite potassium metabisulfite
• Glydant Plus Phenoni
• 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 sa
• Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
• Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, camauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buck
• 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.
• Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, l,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for
• agents of the invention are mixed with solubilizing agents such as CREMOPHOR EL ® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
• solubilizing agents such as CREMOPHOR EL ® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
• injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• Sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• 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.
• 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 with a dermatologically acceptable carrier such as a lotion, cream, ointment, or soap.
• Useful carriers are capable of forming a film or layer over the skin to localize application and inhibit removal.
• the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface.
• hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage.
• tissue-coating solutions such as pectin-containing formulations can be used.
• Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
• transdermal patches which have the added advantage of providing controlled delivery of an agent to the body.
• dosage forms can be made by dissolving or dispensing 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.
• the carrier for a topical formulation can be in the form of a hydroalcoholic system (e.g ., liquids and gels), an anhydrous oil or silicone based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in- water, and oil-in- water- in- silicone emulsions.
• the emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like.
• the emulsions can also include microemulsion systems.
• Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and aqueous based mousse systems.
• kits e.g., pharmaceutical packs
• the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
• a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
• provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
• the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
• kits including a first container comprising a compound or pharmaceutical composition described herein.
• the kits are useful for inducing sensory nerve blockade in a subject in need thereof.
• the kits are useful for inducing selective sensory nerve blockade in a subject in need thereof.
• kits described herein further includes instructions for using the kit.
• a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
• the information included in the kits is prescribing information.
• the present disclosure provides methods for inducing sensory nerve blockade.
• the application provides a method of inducing selective sensory nerve blockade.
• the methods comprise administering to a subject in need thereof a compound that induces sensory nerve blockade. In certain embodiments, the methods comprise administering to a subject in need thereof a compound that induces selective sensory nerve blockade. In certain embodiments, the methods comprise administering a compound of the disclosure (e.g ., a compound of Formula (I), (II), or (III)), or a pharmaceutically acceptable co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof.
• a compound of the disclosure e.g ., a compound of Formula (I), (II), or (III)
• the method comprises administering a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of Formula (I), (II), or (III)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, thereof, to a subject in need thereof.
• a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of Formula (I), (II), or (III)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, thereof, to a subject in need thereof.
• methods for inducing sensory nerve blockade comprise providing a longer duration of sensory nerve blockade than duration of motor function blockade in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.1:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.2:1 in a subject in need thereof.
• methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.3:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.4:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 1.5:1 in a subject in need thereof.
• methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 2: 1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 3:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 4:1 in a subject in need thereof.
• methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 5:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 10:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 20: 1 in a subject in need thereof.
• methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 30:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 40: 1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 50:1 in a subject in need thereof.
• methods for inducing sensory nerve blockade comprise providing a ratio of the duration of sensory nerve blockade to duration of motor function blockade of at least 100:1 in a subject in need thereof. In certain embodiments, methods for inducing sensory nerve blockade comprise providing sensory nerve blockade without motor function blockade in a subject in need thereof.
• Compounds 5-8 may be prepared in a manner analogous to the syntheses of the compounds above.
• the duration of thermal nociceptive block was calculated as the time required for thermal latency to return to a value of 7 s from a higher value; 7 s is the midpoint between a baseline thermal latency of 2 seconds in adult rats, and a maximal latency of 12 s. Motor strength was assessed with a weight-bearing test. In brief, the animal was held over a digital balance such that it could bear weight with 1 hind paw at a time. The maximum weight that it could bear was recorded. The duration of motor blockade was defined as the time for weight bearing to return halfway to normal from maximal block. The halfway point for each rat was defined as [(highest weight borne by either leg) (lowest weight borne by blocked leg)]/2 (lowest weight borne by blocked leg).
• C 2 C12 Mouse myoblasts [American Type Culture Collection (ATCC) CRL-1772] were cultured to proliferate 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 left to differentiate into myotubules for 10-14 days. During differentiation, media were exchanged every 2 to 3 days. Cell viability and proliferation were studied after exposures to drugs for up to 24 h.
• ATCC American Type Culture Collection
• PC 12 cells (ATCC, CRL-1721) originating from rat adrenal gland pheochromocytoma were grown in 24-well tissue culture dishes (CellBind; Coming) with F- 12K (ATCC) supplemented with 12.5% horse serum (Gibco), 2.5% FBS (Gibco), and 1% Penn Strep (Sigma).
• F- 12K ATCC
• FBS FBS
• 1% Penn Strep Sigma
• PC 12 neuronal induction
• cells were seeded at a relative low density of 5 x 104 cells/cm2 and 50 ng/mL NGF was added 24 h after seeding. Cell viability and proliferation were evaluated as for C 2 C12 cells. Experiments with PC 12 cells were conducted for up to 24 hours.
• FIG. 1 and FIG. 2 show results of the cytotoxicity assays with compounds 10S (ZYK1312), US (ZYK1331), 1 (ZYK2112), 4Sa/4Sb (mixture; ZYK2312-1/ZYK2312-2), 2a/2b (mixture; ZYK2412-1/ZYK2412-2) demonstrating that compounds of the disclosure are significantly less cytotoxic than ropivacaine and bupivacaine.
• Table 2 shows the results of additional experiments, also demonstrating that compounds 4Sa (ZYK2312-1), 4Sb (ZYK2312-1), and 26Sa (ZYK3312-1) are significantly less cytotoxic than ropivacaine and bupivacaine.
• An Axopatch 1-B amplifier (Axon Instruments, Foster City, CA) was used for whole-cell voltage clamping. Creation of voltage clamp pulses and data acquisition was controlled by a computer running pClamp software (ver 9.2 Axon Instruments). After rupture of the cell membrane (entering whole-cell mode), current kinetics and amplitudes were allowed to stabilize as the cell was dialyzed with internal solution and paced every 5 seconds (typically 2 to 3 minutes). Peak I Na was elicited using a pulse pattern with fixed amplitudes (conditioning prepulse: -120 mV for 50 ms; depolarizing test step to -30 mV for 20 ms).
• the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
• any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
• elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Anesthesiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (6)

Applications Claiming Priority (4)

Publications (1)

Family

ID=75714697

Family Applications (1)

Country Status (6)

Cited By (1)

Citations (5)

Family Cites Families (6)

• 2020
  • 2020-10-29 EP EP20882228.8A patent/EP4051254A4/en active Pending
  • 2020-10-29 JP JP2022525711A patent/JP7803855B2/ja active Active
  • 2020-10-29 US US17/773,171 patent/US12454509B2/en active Active
  • 2020-10-29 AU AU2020373030A patent/AU2020373030A1/en active Pending
  • 2020-10-29 CA CA3159752A patent/CA3159752A1/en active Pending
  • 2020-10-29 WO PCT/US2020/057963 patent/WO2021087113A1/en not_active Ceased
• 2025
  • 2025-08-15 JP JP2025135404A patent/JP2026004274A/ja active Pending

Patent Citations (5)

Non-Patent Citations (13)

Also Published As

Similar Documents

Legal Events