WO2015088564A1 - Composés modulateurs du récepteur p2x4 - Google Patents

Composés modulateurs du récepteur p2x4 Download PDF

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Publication number
WO2015088564A1
WO2015088564A1 PCT/US2013/075118 US2013075118W WO2015088564A1 WO 2015088564 A1 WO2015088564 A1 WO 2015088564A1 US 2013075118 W US2013075118 W US 2013075118W WO 2015088564 A1 WO2015088564 A1 WO 2015088564A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
mmol
pain
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PCT/US2013/075118
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English (en)
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Jason S. Newcom
Kerry L. Spear
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Sunovion Pharmaceuticals Inc.
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Priority to PCT/US2013/075118 priority Critical patent/WO2015088564A1/fr
Publication of WO2015088564A1 publication Critical patent/WO2015088564A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • P2X4 receptor (P2X4R) modulating compounds useful for treating various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders, compositions comprising the compounds, and methods of use thereof.
  • Adenosine 5 '-triphosphate is known to be a cotransmitter in nerves of the peripheral and central nervous system (CNS) (Burnstock, G. Eur. J. Pharmacol. 2013, 716(1-3), 24-40).
  • ATP may be released upon cell damage and from non-neural cells during mechanical deformation.
  • purinergic P2 receptors which have been classified as ionotropic P2X and metabotropic P2Y receptors and are located on neurons as well as non-neural cells.
  • 7 subtypes of P2X and 8 subtypes of P2Y receptors have been identified.
  • P2X4R is a trimeric, ligand-gated cation channel first isolated from rat brains in 1995.
  • the endogenous ligand for P2X4R is ATP, though no selective agonists of P2X4R are known.
  • ivermectin selectively potentiates this P2XR in rodents.
  • P2X4R is widely distributed in the body, including the brain, spinal cord, sensory ganglia, testis, colon, and macrophages.
  • PGE2 prostaglandin E2
  • peripheral macrophages on which P2X4R activation results in calcium-mediated synthesis and release of prostaglandin E2 (PGE2), a key inflammatory mediator.
  • PGE2 prostaglandin E2
  • the development of intraplantar Complete Freund's Adjuvant- or carrageenan-induced tactile hypersensitivity was reduced compared to wild-type animals (Ulmann et al. EMBO J. 2010, 29, 2290-2300).
  • local PGE2 concentrations were reduced in knock-out versus wild- type mice (Ulmann et al. EMBO J. 2010, 29, 2290-2300).
  • P2X4R function on activated spinal microglia or peripheral macrophages may block synthesis and release of key pain-related factors, such as BDNF and PGE2, which may reduce nociceptive neurotransmission.
  • Limited preclinical data may suggest a role for P2X4R in other central and peripheral inflammatory conditions, such as multiple sclerosis, stroke, traumatic brain injury, asthma, diabetic nephropathy, etc.
  • P2X4R function on activated spinal microglia or peripheral macrophages may block synthesis and release of key pain-related factors, such as BDNF and PGE2, which may reduce nociceptive neurotransmission.
  • Limited preclinical data may suggest a role for P2X4R in other central and peripheral inflammatory conditions, such as multiple sclerosis, stroke, traumatic brain injury, asthma, diabetic nephropathy, etc.
  • published literature supports the use of P2X4R modulators in CNS indications, as increased P2X4R expression or function is seen in microglia, infiltrating macrophages or neurons in models of diseases such as multiple sclerosis, traumatic brain injury, stroke, glioma, spinal cord injury and Alzheimer's disease.
  • P2X4 ion channel receptor P2X4R
  • negative allosteric modulators P2X4 ion channel receptor (P2X4R) antagonists or negative allosteric modulators which represent a novel option for monotherapy or adjunctive treatment of chronic pain conditions in humans, including neuropathic and inflammatory pain states.
  • the disclosed compounds have therapeutic benefit for a broad range of inflammatory disorders.
  • R 1 , R 2 , R 3 and n are defined as described herein.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating a condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein; wherein the condition is selected from the group consisting of pain, chronic pain, central pain, somatic pain, acute pain, mixed etiology pain, dual mechanism pain, phantom limb pain, complex regional pain syndrome or reflex
  • a method of inhibiting or modulating a purinergic P2X4 ion channel receptor (P2X4R) in a subject comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.
  • P2X4R purinergic P2X4 ion channel receptor
  • P2X4R purinergic P2X4 ion channel receptor
  • the compounds are purinergic P2X4R antagonists.
  • the compounds disclosed herein are purinergic P2X4R negative allosteric modulators.
  • the compounds disclosed herein are selective purinergic P2X4 ion channel receptor (P2X4R) antagonists.
  • the compounds disclosed herein are selective purinergic P2X4R negative allosteric modulators.
  • compositions and dosage forms comprising a compound provided herein, and one or more pharmaceutically acceptable excipients.
  • Compositions and dosage forms provided herein may further comprise one or more additional active ingredients.
  • a subject such as a mammal, such as, e.g., human, rodent (such as, e.g., mice and rats), cat, dog, non-human primate, among others.
  • P2X4R purinergic P2X4 ion channel receptor
  • the compound is a P2X4R antagonist.
  • the compound is a P2X4R negative allosteric modulator.
  • the compound or pharmaceutical composition is administered in combination with another agent or therapy.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (Ci_io), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • linear Ci_ 6 and branched C 3 -6 alkyl groups are also referred as "lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl
  • Ci_ 6 alkyl refers to a linear saturated monovalent
  • the alkyl is optionally substituted as described herein elsewhere.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted with one or more substituents.
  • alkenyl also encompasses radicals having "cis” and “trans” configurations, or alternatively, "E” and “Z” configurations, as appreciated by those of ordinary skill in the art.
  • C 2 -6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C 2 _i 5 ), 2 to 12 (C2-12), 2 to 10 (C 2 _io), or 2 to 6 (C 2 _ 6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3 - 20 ), 3 to 15 (C 3 -15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-l-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
  • the alkenyl is optionally substituted as described herein elsewhere.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds.
  • the alkynyl may be optionally substituted with one or more substituents.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2 _ 20 ), 2 to 15 (C 2 _i 5 ), 2 to 12 (C 2 _ i2 ), 2 to 10 (C 2 _io), or 2 to 6 (C 2 _ 6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3 -20), 3 to 15 (C 3 -15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • C 2 -6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkynyl is optionally substituted as described herein elsewhere.
  • cycloalkyl refers to a cyclic fully or partially saturated bridged and/or non-bridged hydrocarbon radical or ring system, which may be optionally substituted with one or more substituents.
  • the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 12 (C3-12), from 3 to 10 (C 3 -10), or from 3 to 7 (C 3 -7) carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.
  • the cycloalkyl is optionally substituted as described herein elsewhere.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one or more, in one embodiment, one to three, heteroatoms selected from the group consisting of O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si can be placed at any position of the heteroalkyl group (e.g., interior or terminal position), including the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkyl is optionally substituted as described herein elsewhere.
  • alkoxyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one or more, in one embodiment, one to three, O atoms.
  • alkoxyl include, but are not limited to, -O-CH 3 , -O-CF 3 , -0-CH 2 -CH 3 , -O- CH2-CH2-CH3, -0-CH-(CH 3 ) 2 , and -0-CH 2 -CH 2 -0-CH 3 .
  • the alkoxyl is optionally substituted as described herein elsewhere.
  • aminoalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one or more, in one embodiment, one to three, N atoms.
  • examples of aminoalkyl include, but are not limited to, -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 -CH 3 , -N(CH 3 )-CH 2 -CH 3 , -NH-CH-(CH 3 ) 2 , -CH 2 -CH 2 -NH-CH 3 , and -CH 2 -CH 2 - N(CH 3 ) 2 .
  • the aminoalkyl is optionally substituted as described herein elsewhere. In some embodiments, the aminoalkyl is optionally substituted with one or more halo.
  • aryl refers to an optionally substituted monocyclic or multicyclic radical or ring system that contains at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20, from 6 to 15, or from 6 to 10 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • aryl also refers to bicyclic, tricyclic, or tetracyclic carbon rings, where one of the rings is aromatic and the other(s) of the rings may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • aryl may be a bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings is aromatic and one or more of the ring(s) is/are saturated or partially unsaturated containing one or more heteroatoms independently selected from O, S, and N.
  • the aryl is optionally substituted with one or more substituents as described herein elsewhere.
  • arylalkyl refers to a monovalent alkyl group substituted with aryl.
  • Example of aralkyl includes, but is not limited to, benzyl.
  • both alkyl and aryl may be optionally substituted with one or more substituents as described herein elsewhere.
  • cycloalkylalkyl refers to a monovalent alkyl group substituted with cycloalkyl. In certain embodiments, both the alkyl and cycloalkyl may be optionally substituted with one or more substituents as described herein elsewhere.
  • heteroaryl refers to an optionally substituted monocyclic or multicyclic radical or ring system which contains at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N.
  • each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings, where one of the rings is aromatic having one or more heteroatoms independently selected from O, S, and N, and the other(s) of the rings may be saturated, partially unsaturated, or aromatic and may be carbocyclic or contain one or more heteroatoms independently selected from O, S, and N.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, ⁇ -carbolinyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl is optionally substituted with one or more substituents as described herein elsewhere.
  • heterocycloalkyl refers to an optionally substituted monocyclic or multicyclic radical or ring system which contains at least one non-aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocycloalkyl group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl or heterocycloalkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, the ring carbon atoms may be optionally substituted with oxo, and some rings may be partially or fully saturated, but not aromatic.
  • the heterocycloalkyl or heterocyclyl may be attached to the main structure at a heteroatom or a carbon atom which results in the creation of a stable compound.
  • Examples include, but are not limited to, azepinyl, decahydroisoquinolinyl, dihydrofuryl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1 ,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl,
  • the heterocyclyl or heterocycloalkyl ring contains one or more O
  • heterocyclyl or heterocycloalkyl is optionally substituted with one or more substituents as described herein elsewhere.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • hydrogen encompasses proton ( 1 H), deuterium ( 2 H), tritium ( 3 H), and/or mixtures thereof.
  • one or more positions occupied by hydrogen may be enriched with deuterium and/or tritium.
  • isotopically enriched analogs may be prepared from suitable isotopically labeled starting material obtained from a commercial source or prepared using known literature procedures.
  • the term "optionally substituted” is intended to mean that a group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, cycloalkylalkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently selected from, e.g., (a) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q 1 ; and (b) halo, cyano (-CN), nitro (-N0 2 ), -C(0)R a , -C(0)OR a , -C
  • the term "pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • suitable non-toxic acids include inorganic and organic acids, such as, including but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and /?-to
  • solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90%) by weight of one stereoisomer of the compound and less than about 10%> by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • stereomerically enriched means a composition that comprises greater than about 50% by weight of one stereoisomer of a compound, greater than about 55% by weight of one stereoisomer of a compound, greater than about 60%) by weight of one stereoisomer of a compound, greater than about 70%> by weight, or greater than about 80% by weight of one stereoisomer of a compound.
  • enantiomerically pure means a stereomerically pure composition of a compound having one chiral center.
  • enantiomerically enriched means a stereomerically enriched composition of a compound having one chiral center.
  • optically active and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess or diastereomeric excess of no less than about 50%, no less than about 70%), no less than about 80%>, no less than about 90%>, no less than about 91%>, no less than about 92%), no less than about 93%>, no less than about 94%>, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%>, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer based on the total weight of the racemate in question..
  • R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or
  • (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • the terms “selective purinergic P2X4R antagonists” and “selective purinergic P2X4R negative allosteric modulators” mean selective for the indicated target over other P2X isoforms.
  • the disclosed compounds are at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater than 99% selective for the indicated target over other P2X isoforms.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain
  • the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or
  • each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • active ingredient and active substance refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • active ingredient and active substance may be an optically active isomer of a compound described herein.
  • drug and “therapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, managing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • the terms “treat,” “treating” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In one embodiment, such symptoms are those known to a person of skill in the art to be associated with the disease or disorder being treated. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. The terms encompass the inhibition or reduction of a symptom of the particular disease. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agent, after the onset of symptoms of the particular disease.
  • the terms “prevent,” “preventing” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In one embodiment, such symptoms are those known to a person of skill in the art to be associated with the disease or disorder being prevented. In certain embodiments, the terms refer to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of disease or disorders provided herein. The terms encompass the inhibition or reduction of a symptom of the particular disease. Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments. In addition, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term “prevention” may be interchangeably used with the term “prophylactic treatment.”
  • the terms “manage,” “managing,” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In one embodiment, such symptoms are those known to a person of skill in the art to be associated with the disease or disorder being managed. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term “managing” encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease or to prevent or minimize the severity of symptoms of the disease.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder.
  • therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the term “subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the subject is a human.
  • the term “pain” refers to an unpleasant sensory and emotional experience. Unless otherwise specified, the term “pain,” as used herein, refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g.
  • somatic pain normal nerve response to a noxious stimulus
  • neuropathic pain abnormal response of a injured or altered sensory pathway, often without clear noxious input
  • pain that is categorized temporally e.g., chronic pain and acute pain
  • pain that is categorized in terms of its severity e.g. , mild, moderate, or severe
  • pain that is a symptom or a result of a disease state or syndrome e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain ⁇ see, e.g., Harrison's Principles of Internal Medicine, pp.
  • Pain includes pain resulting from dysfunction of the nervous system: organic pain states that share clinical features of neuropathic pain and possible common pathophysiology mechanisms, but are not initiated by an identifiable lesion in any part of the nervous system.
  • the term "somatic pain,” as used herein, refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain ⁇ e.g., skin, muscle or joint derived) and visceral pain ⁇ e.g., organ-derived).
  • neuropathic pain refers to a heterogeneous group of neurological conditions that result from damage to the nervous system.
  • the term also refers to pain resulting from injury to or dysfunctions of peripheral and/or central sensory pathways, and from dysfunctions of the nervous system, where the pain often occurs or persists without an obvious noxious input. This includes pain related to peripheral neuropathies as well as central neuropathic pain.
  • diabetic neuropathy also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP
  • PPN post-herpetic neuralgia
  • TGN trigeminal neuralgia
  • neuropathic pain involving damage to the brain or spinal cord, can occur following stroke, spinal cord injury, and as a result of multiple sclerosis, and is also encompassed by the term.
  • Other types of pain that are meant to be included in the definition of neuropathic pain include, but are not limited to, neuropathic cancer pain, HIV/ AIDS induced pain, phantom limb pain, and complex regional pain syndrome. Unless otherwise specified, the term also encompasses the common clinical features of neuropathic pain including, but not limited to, sensory loss, allodynia (non-noxious stimuli produce pain), hyperalgesia and hyperpathia (delayed perception, summation, and painful after sensation). Pain is often a combination of nociceptive and neuropathic types, for example, mechanical spinal pain and radiculopathy or myelopathy.
  • acute pain refers to the normal, predicted physiological response to a noxious chemical, thermal or mechanical stimulus typically associated with invasive procedures, trauma and disease. It is generally time-limited, and may be viewed as an appropriate response to a stimulus that threatens and/or produces tissue injury. The term also refers to pain which is marked by short duration or sudden onset.
  • chronic pain encompasses the pain occurring in a wide range of disorders, for example, trauma, malignancies and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain may last more than about six months. In addition, the intensity of chronic pain may be disproportionate to the intensity of the noxious stimulus or underlying process. The term also refers to pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict. It may be subject to frequent recurrence.
  • inflammatory pain is pain in response to tissue injury and the resulting inflammatory process. Inflammatory pain is adaptive in that it elicits physiologic responses that promote healing. However, inflammation may also affect neuronal function. Inflammatory mediators, including PGE 2 induced by the COX2 enzyme, bradykinins, and other substances, bind to receptors on pain-transmitting neurons and alter their function, increasing their excitability and thus increasing pain sensation. Much chronic pain has an inflammatory component. The term also refers to pain which is produced as a symptom or a result of inflammation or an immune system disorder.
  • visceral pain refers to pain which is located in an internal organ.
  • mixed etiology pain refers to pain that contains both inflammatory and neuropathic components.
  • the term “dual mechanism pain” refers to pain that is amplified and maintained by both peripheral and central sensitization.
  • central pain refers to pain initiated by a primary lesion or dysfunction in the central nervous system.
  • hypoesthesia refers to increased sensitivity to stimulation, excluding the special senses.
  • hypopathia refers to a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. It may occur with allodynia,
  • hyperesthesia hyperesthesia, hyperalgesia, or dysesthesia.
  • dysesthesia refers to an unpleasant abnormal sensation, whether spontaneous or evoked.
  • dysesthesia include hyperalgesia and allodynia.
  • hypoalgesia refers to an increased response to a stimulus that is normally painful. It reflects increased pain on suprathreshold stimulation.
  • allodynia refers to pain due to a stimulus that does not normally provoke pain.
  • DPNP diabetic peripheral neuropathic pain
  • DN diabetic peripheral neuropathy
  • DN diabetic peripheral neuropathy
  • DN diabetic peripheral neuropathy
  • post-herpetic neuralgia also called “postherpetic neuralgia” (PHN)
  • PPN postherpetic neuralgia
  • VZV varicella zoster virus
  • neurodegeneration pain refers to peripheral neuropathic pain as a result of cancer, and can be caused directly by infiltration or compression of a nerve by a tumor, or indirectly by cancer treatments such as radiation therapy and chemotherapy (chemotherapy-induced neuropathy).
  • HIV/AIDS peripheral neuropathy or "HIV/ AIDS related neuropathy” refers to peripheral neuropathy caused by
  • HIV/ AIDS such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat
  • Phantom limb pain refers to pain appearing to come from where an amputated limb used to be. Phantom limb pain can also occur in limbs following paralysis (e.g., following spinal cord injury). "Phantom limb pain” is usually chronic in nature.
  • TN trigeminal neuralgia
  • TN a disorder of the fifth cranial (trigeminal) nerve that causes episodes of intense, stabbing, electric-shock-like pain in the areas of the face where the branches of the nerve are distributed (lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw). It is also known as the "suicide disease”.
  • CRPS complex regional pain syndrome
  • RSD reflex sympathetic dystrophy
  • fibromyalgia refers to a chronic condition characterized by diffuse or specific muscle, joint, or bone pain, along with fatigue and a range of other symptoms. Previously, fibromyalgia was known by other names such as fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and tension myalgias.
  • A is selected from CH 2 , O, NH, S, SO, and S0 2 ;
  • R 1 is selected from C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, each optionally substituted with one or more R 4 substituents;
  • R 2 is selected from hydrogen, halogen, CN, NR 5 R 6 , OR 7 , S0 2 R 7 , S0 3 R 7 ,S0 2 NR 5 R 6 , C(0)R 7 , C(0)OR 7 , C(0)NR 5 R 6 , Ci-C 6 haloalkyl, and Ci-C 6 alkyl optionally substituted with one or more R 8 substituents ; each R 3 is independently selected from halogen, CN, OR 9 , NR 10 R U , Ci-C 6 haloalkyl, and Ci-C 6 alkyl optionally substituted with one or more R 12 substituents; each R 4 is independently selected from halogen, CN, oxo, OR 13 , NR 14 R 15 , S0 2 R 13 , S0 3 R 13 , S0 2 NR 14 R 15 , NR 14 S0 2 R 13 , C(0)R 13 , OC(0)R 13 , C(0)OR 13 , C(0)NR 14 R 15 ,
  • Ci-C 6 haloalkyl Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, 6- to 14-membered aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl groups are optionally substituted with one or more R 16 substituents;
  • R 5 and R 6 are each independently selected from hydrogen, S0 2 R 17 , S0 3 R 17 , S0 2 NR 18 R 19 , C(0)R 17 , C(0)OR 17 , C(0)C(0)R 17 , C(0)C(0)OR 17 , C(0)NR 18 R 19 , C C 6 haloalkyl, C C 6 alkyl, C 3 -C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10- membered heterocyclyl, wherein the Ci-C 6 alkyl, C 3 -Cg cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl groups are optionally substituted with one or more R 20 substituents; or alternatively R 5 and R 6 taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl optionally substituted with one or more substituents each independently selected from
  • R 7 is selected from hydrogen, Ci-C 6 haloalkyl, Ci-C 6 alkyl, C 3 -Cg cycloalkyl, 6- to 14- membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C 6 alkyl, C 3 -Cg cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl groups are optionally substituted with one or more R 21 substituents; each R 8 is independently selected from halogen, CN, OR 22 , NR 23 R 24 , S0 2 R 22 , S0 3 R 22 , S0 2 NR 23 R 24 , C(0)R 22 , C(0)OR 22 , C(0)NR 23 R 24 , and NHC(0)R 22 ; 9 13 17 22
  • each R , R , R , and R is independently selected from hydrogen, Ci-C 6 haloalkyl, Ci- C 6 alkyl, C 3 -C 8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, 6- to 14-membered aryl,
  • 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl groups are optionally substituted with one or more substituents independently selected from halogen, CN, OR 25 , NR 25 R 26 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, and phenyl; each R 10 , R 11 , R 14 , R 15 , R 18 , R 19 , R 23 , and R 24 is independently selected from hydrogen, C(0)Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the C(0)Ci-C 6 alkyl, Ci-C 6 alkyl, C 3 -Cg cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-
  • each R 16 , R 20 , and R 21 is independently selected from halogen, CN, oxo, OR 25 , NR 25 R 26 , C(0)R 25 , C(0)OR 25 , C(0)NR 25 R 26 , C C 6 haloalkyl, C C 6 alkyl, and phenyl; each R 25 and R 26 is independently selected from hydrogen and Ci-C 6 alkyl optionally substituted with one or more halogens; and n is 0, 1 , 2, 3 or 4.
  • A is NH. In further embodiments, A is O. In still further embodiments, A is CH 2 . In still further embodiments, A is S.
  • R 1 is 6- to 14-membered aryl optionally substituted with one or more R 4 substituents. In further embodiments, R 1 is phenyl optionally substituted with one or more R 4 substituents. In still further embodiments, R 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CN, OR 13 , S0 2 R 13 , S0 2 NR 14 R 15 , and 5- to 10-membered heteroaryl. [0083] In some embodimetns, the compound is a compound of formula (la), or a
  • R 2 , R 3 and n are as defined herein, and
  • R ' and R"° are each independently selected from hydrogen, halogen, CN, OR , S0 2 R ,
  • At least one of R 27 and R 28 is selected from halogen, CN, methoxy, SO 2 CH 3 , S0 2 NH 2 , imidazole, triazole, tetrazole, oxazole, isoxazole, thiazole, and isothiazole.
  • R 1 is 3,4-dihydro-2H-benzo[£][l,4]oxazine or 3,4-dihydro- 2H-benzo[b][l,4]thiazine, each optionally substituted with one or more R 4 substituents.
  • R 1 is 5- to 10-membered heteroaryl optionally substituted with one or more R 4 substituents.
  • R 1 is pyridyl optionally substituted with one or more R 4 substituents.
  • the compound is a compound of formula (lb), or a
  • R 29 is selected from halogen, OR 13 , Ci-C 6 haloalkyl, Ci-C 6 alkyl, and 5- to 10- membered heteroaryl; and r is 0, 1, 2, 3, or 4.
  • the compound is a compound of formula (Ic), or a pharmaceutically acceptable salt thereof:
  • R 2 , R 3 and n are as defined herein;
  • R 29 is selected from halogen, OR 13 , Ci-C 6 haloalkyl, Ci-C 6 alkyl, and 5- to 10- membered heteroaryl; and r is 0, 1, 2, 3, or 4.
  • R 2 is Ci-C 6 alkyl optionally substituted with one or more R 8 substituents.
  • R 2 is selected from methyl, ethyl, propyl, and isopropyl.
  • R 2 is Ci-C 6 alkyl substituted with OH.
  • R 2 is CN
  • R 2 is halogen. In further embodiments, R 2 is CI.
  • R 2 is C(0)OR 7 and R 7 is selected from hydrogen and Ci-C 6 alkyl.
  • R 2 is hydrogen
  • R 2 is NR 5 R 6 .
  • R 5 is C(0)R 17
  • R 6 is hydrogen
  • R 17 is 5- to 10-membered heteroaryl.
  • R 5 is selected from C(0)C(0)R 17 and C(0)C(0)OR 17
  • R 6 is hydrogen
  • R 17 is Ci-C 6 alkyl.
  • R 5 and R 6 taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl optionally substituted with one or more substituents each independently selected from halogen, oxo, and Ci-C 6 alkyl.
  • n is 1 and R 3 is selected from halogen, CN, Ci-C 6 haloalkyl, and Ci-C 6 alkyl optionally substituted with one or more R 12 substituents.
  • R 3 is selected from F, CI, Ci-C 6 haloalkyl, and Ci-C 6 alkyl.
  • R 3 is CI.
  • n 0.
  • the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 are as defined herein.
  • the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof:
  • R 2 , R 3 and R 4 are as defined herein; and p is 0 or 1.
  • the compound is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:
  • R 2 , R 3 and R 4 are as defined herein;
  • p is 0 or 1 ;
  • q 0, 1, 2, 3, or 4.
  • the compound is a compound of formula (V), or a pharmaceutically acceptable salt thereof:
  • R 2 , R 3 and R 4 are as defined herein;
  • p is 0 or 1 ;
  • q 0, 1, 2, 3, or 4.
  • R 2 is not CN. In some embodiments, if A is O, then R 2 is not C(0)OR 7 . In some embodiments, if A is O, then R 2 is not C(0)OH. In some embodiments, if A is O, then R 2 is not C(0)OCH 3 . In some embodiments, if A is O, then R 2 is not C(0)OCH 2 CH 3 .
  • R 1 is not a 6-membered aryl. In some embodiments, if A is O and R 2 is C(0)OH, then R 1 is not a 6-membered aryl. In some embodiments, if A is O and R 2 is C(0)OCH 3 , then R 1 is not a 6-membered aryl. In some embodiments, if A is O and R 2 is C(0)OCH 2 CH 3 , then R 1 is not a 6-membered aryl or a 5- to 10-membered heteroaryl.
  • the compound of formula (I) is not:
  • the compound of formula (I) is not:
  • the depicted structure is to be accorded more weight.
  • the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it or mixtures thereof.
  • the compound provided herein contains an alkenyl or alkenylene group
  • the compound may exist as one of or a mixture of geometric cisl trans (or Z/E) isomers.
  • structural isomers are inter-convertible, the compound may exist as a single tautomer or a mixture of tautomers.
  • the compounds provided herein may be enantiomerically pure or diastereomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers and/or diastereomers, e.g., a racemic or enantioenriched mixture of two enantiomers; or a mixture of two or more diastereomers.
  • a compound in its (R) form is equivalent to administration of the compound in its (S) form, and vice versa.
  • Conventional techniques for the preparation/isolation of individual enantiomers or diastereomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of a stereomeric mixture, for example, by chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
  • the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al. J. Pharm. Sci. 1977, 66, 1- 19; and "Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, aspartic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, camphoric acid, (+)-camphoric acid,
  • camphorsulfonic acid (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, D-gluconic acid, glucuronic acid, D-glucuronic acid, glutamic acid, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isoethonic acid; (+)- L-lactic acid, ( ⁇ )-DL-lactic acid, lactobionic acid, lauri
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium
  • hydroxide potassium hydroxide, potassium carbonate, zinc hydroxide, sodium hydroxide, or ammonia
  • organic bases such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol,
  • diethanolamine diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl- glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l,3- propanediol, and tromethamine.
  • the term "compound” referred to herein such as, e.g., a compound of formula (I), (la), (lb), (Ic), (II), (III), (IV), or (V) is intended to encompass one or more of the following: a free base of the compound or a salt thereof, a stereoisomer or a mixture of two or more stereoisomers, a solid form ⁇ e.g., a crystal form or an amorphous form) or a mixture of two or more solid forms thereof, or a solvate ⁇ e.g., a hydrate) thereof.
  • the term "compound” referred to herein is intended to encompass a
  • the term "compound” referred to herein, such as, e.g., a compound of formula (I), (la), (lb), (Ic), (II), (III), (IV), or (V) is intended to encompass a solvate ⁇ e.g., a hydrate) thereof.
  • the compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula (I) and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al.
  • intermediate 1-3 Treatment of intermediate 1-3 with phosphonate 1-6 in presence of a tertiary amine in DCM followed by cyclization of the resulting amide using a base (such as DBU, NaH, LiHMDS, etc.) in THF affords compounds of the formula 1-7.
  • a base such as DBU, NaH, LiHMDS, etc.
  • compounds having the structure 1-9 can be synthesized by coupling intermediate 1-3, according to Method C, with 2- cyannoacetic acid 1-8 in DCM in the presence of a triazole peptide coupling reagent (e.g., HATU) and a tertiary amine.
  • the resulting amide can then be cyclized using a base such as sodium hydroxide in an alcohol solvent.
  • compounds having the formula 1-11 can be synthesized by coupling of intermediate 1-3, according to Method D, with 2-bromoacetyl bromide in the presence of an inorganic base, such as potassium carbonate in an aprotic solvent, such as acetonitrile. Cyclization can be effected by treatment with pyridine and the resulting pyridonium salt can be cleaved with hydrazine.
  • Scheme 3 depicts dihydro-inden-l-one 3-3, which can be obtained from commercial sources or prepared from appropriately substituted aldehydes 3-1.
  • Treatment of aldehyde 3-1 with ethyl (triphenylphosphoranylidene) acetate in DCM affords the corresponding ethyl cinnamate, which can be reduced in the presence of hydrogen and palladium.
  • the resulting dihydrocinnamate can be hydro lyzed using aqueous hydroxide to afford cinnamic acid 3-2.
  • Cyclization of acid 3-2 can be achieved in a two-step process by formation of the acid chloride using a chlorinating agent (such as thionyl chloride) in DCM followed by treatment with an appropriate lewis acid (such as A1C1 3 ).
  • a chlorinating agent such as thionyl chloride
  • an appropriate lewis acid such as A1C1 3
  • Compounds 3-6, 3-7 and 3-8 can be synthesized from dihydro-indene-l-one 3-3 in a single reaction vessel or in a stepwise fashion as also shown in Scheme 3.
  • dihydro-inden-l-one 3-3 is combined with aldehyde 3-4 and nitrile 3-5.
  • the cyclocondensation is accomplished at elevated temperatures as either a neat mixture or in a protic solvent (such as ethylene glycol or acetic acid) in the presence of ammonium acetate or sodium hydroxide.
  • a protic solvent such as ethylene glycol or acetic acid
  • dihydro-inden-l-one 3-3 is treated with aldehyde 3-4 and an alkoxide base (such as NaOMe or NaOEt) in an alcoholic solvent.
  • the resulting ene-one can then be treated with nitrile 3-5 a protic solvent (such as ethylene glycol) in the presence of ammonium acetate or sodium hydroxide.
  • Scheme 4 outlines the synthesis of sulfones 4-3, sulfonamides 4-6 and sulfonates 4- 8; wherein Cyl is defined as either an aryl or heteroaryl ring.
  • a copper(I) salt such as Cul or CuBr
  • inorganic carbonate for example CS 2 CO 3
  • a ligand such as L-proline
  • compounds 4-6 and 4-8 can be generated from intermediate 4-4.
  • Intermediate 4-4 is synthesized by treatment of compound 4-1 with a copper(I) salt (such as Cul or CuBr), amine base (for example ⁇ , ⁇ -diisopropylethyl amine or triethyl amine ), a ligand (such as 1,10-phenanthroline) and benzothioic S-acid in an aprotic solvent (such as toluene) at elevated temperatures (for instance 100 °C).
  • a chlorinating agent such as TCAA
  • phase transfer catalyst for example BnNMesCl
  • aqueous carbonate in acetonitrile
  • Scheme 5 outlines the derivatization of compound 1-11 to form amides of the structure 5-3.
  • an acid chloride (5-1) in the presence of an appropriate base (for example tertiary amine or inorganic carbonate) in a solvent such as DCM or acetone provides compounds of the structure 5-3.
  • an appropriate base for example tertiary amine or inorganic carbonate
  • a solvent such as DCM or acetone
  • a peptide coupling reagent such as HATU or HOBt
  • a tertiary amine for example triethyl amine or ⁇ , ⁇ -diisopropylethyl amine
  • PG protecting group, such as for instance Boc - see Green and Wuts, Protective Groups in Organic Synthesis 3 rd ed. New York: John Wiley & Sons, Inc. 1999
  • PG protecting group, such as for instance Boc - see Green and Wuts, Protective Groups in Organic Synthesis 3 rd ed. New York: John Wiley & Sons, Inc. 1999
  • compounds of the structure 7-3 can be synthesized from compounds 7-1 (wherein, X is F, CI, Br or I) by treatment with amine 7-2 in the presence of a copper(I) salt (such as Cul or CuBr) and alkoxide base (for example NaOEt) in an aprotic solvent (such as THF) as depicted in Scheme 7.
  • a copper(I) salt such as Cul or CuBr
  • alkoxide base for example NaOEt
  • aprotic solvent such as THF
  • Scheme 8 outlines the reduction of compounds 8-1 and 8-3.
  • Selective reduction of the ester moiety in compound 8-1 is accomplished by the addition of a reducing agent (such as LAH) in an ethereal solvent (such as Et 2 0 or THF) at ambient temperatures to afford compounds of the formula 8-2.
  • a reducing agent such as LAH
  • an ethereal solvent such as Et 2 0 or THF
  • reduction of the amide moiety in compound 8-1 is accomplished by the addition of a reducing agent (such as LAH) in an ethereal solvent (such as THF or MTBE) at elevated temperatures (for instance 60 °C).
  • Scheme 9 outlines the synthesis alcohol and amine derivatives 9-2 and 9-5 respectively.
  • a reducing agent such as LAH or DIBAL
  • an ethereal solvent such as Et 2 0 or THF
  • Oxidation of 9-2 with Dess-Martin periodinane followed by subsequent reductive amination of aldehyde 9-3 in the presence of amine 9-4 using sodium cyanoborohydride an alcoholic solvent affords compounds of the formula 9-5.
  • Scheme 10 outlines the synthesis of l,2,4-oxadiazol-3-yl compounds 10-3.
  • Compound 10-2 wherein Cyl can be either an aryl or heteroaryl ring, can be synthesized by treating nitrile 10-1 with hydroxyl amine hydrochloride in the presence of inorganic carbonate (such as sodium or potassium carbonate) in and alcoholic solvent (for instance EtOH) at elevated temperatures (such as 80 °C) under microwave irradiation. Cyclization of 10-2 with triethyl orthoformate in the presence of an acid (such as TFA) at elevated temperatures (for instance 140 °C) affords compounds of the structure 10-3.
  • inorganic carbonate such as sodium or potassium carbonate
  • EtOH alcoholic solvent
  • Cyclization of 10-2 with triethyl orthoformate in the presence of an acid (such as TFA) at elevated temperatures (for instance 140 °C) affords compounds of the structure 10-3.
  • Scheme 11 outlines the synthesis of compounds of the formula 11-4.
  • the synthesis of 11-4 begins with the hydrolysis of 11-1 (R 4 is defined as CN or C0 2 Et) using aqueous hydroxide in a protic from activation of acid 11-2 with regents such as for example ethyl chloroformate or EDCI, HOBt in the presence of a tertiary amine (such as triethyl amine) in an aprotic solvent (such as THF or DMF) followed by addition of amine 11-3.
  • regents such as for example ethyl chloroformate or EDCI, HOBt
  • a tertiary amine such as triethyl amine
  • aprotic solvent such as THF or DMF
  • Scheme 12 describes the synthesis of l,2,4-oxadiazol-5-yl compounds 12-3.
  • Scheme 13 describes the synthesis ketones 13-3.
  • Scheme 14 outlines the synthesis isoxazol-5-yl compounds 14-3.
  • the synthesis begins with protection of 14-1 (13-3; wherein Alk is CH 3 ) with ethyl chloro formate in an ethereal solvent (such as THF) in the presence of a tertiary amine (for example Et 3 N).
  • an ethereal solvent such as THF
  • a tertiary amine for example Et 3 N
  • Scheme 15 describes the synthesis of isoxazol-3-yl derivatives 15-2.
  • the synthesis begins with protection of 4-1 with ethyl chloro formate in an ethereal solvent (such as THF) in the presence of a tertiary amine (for example Et 3 N).
  • a Heck coupling with 3,3- dimethoxyprop-l-ene is accomplished in the presence of a Pd(II) species (such as Pd(OAc) 2 ), potassium acetate, an inorganic carbonate (for example potassium carbonate) in a polar aprotic solvent (such as DMF) at elevated temperatures (for example 80 °C) affords intermediate 15-1.
  • Intermediate 15-1 is then treated with N-hydroxy-4-methylbenzenesulfonamide and aqueous carbonate in an alcoholic solvent (such as MeOH) to provide compounds of the structure 15-2.
  • Scheme 16 outlines the synthesis of compounds 16-3, 16-4 and 16-5.
  • Conversion of nitrile 16-1 to imidate 16-2 can be accomplished by treating a solution of 16-1 in EtOH with hydrogen chloride gas.
  • Addition of formohydrazide to imidate 16-2 can be accomplished in a protic solvent (such as EtOH) in the presence of a tertiary amine (for example triethyl amine) to provide compounds of the structure 16-3.
  • imidate 16-2 can be treated with ethane- 1,2-diamine in a protic solvent (such as EtOH) to afford compounds of the structure 16- 4.
  • Oxidation of dihydroimidazole 16-4 to give compounds of the structure 16-5 can be performed in a polar aprotic solvent (such as DMSO) at elevated temperatures (for example 150 °C) while exposed to atmospheric oxygen.
  • a polar aprotic solvent such as DMSO
  • Scheme 17 illustrates the synthesis of compounds 17-2 wherein R 4 is a carbon linked heteroaryl group.
  • Treatment of compound 4-1 with stannane 17-1 and a palladium(O) species (for example Pd(PPh 3 ) 4 ) in an aprotic solvent (such as 1,4-dioxane) at elevated temperatures (for example 110 °C) provides compounds of the structure 17-2.
  • Scheme 18 illustrates the synthesis of compounds 17-2 wherein R 4 is a carbon linked heteroaryl group.
  • Scheme 18 outlines the synthesis of substituted secondary and tertiary amines as well as N-substituted heterocycles (i.e. R 14 , R 15 when taken together form a ring).
  • Compounds of structure 18-2 can be synthesized by copper mediated coupling of compound 4-1 with amine 18-1.
  • Treatment of the mixture 4-1 and 18-1 with an appropriate copper (I) species for example Cul or Cu 2 0), inorganic carbonate (such as CS 2 CO 3 ) in a polar aprotic solvent (such as DMF) at elevated temperatures (for example 100 °C) provides compounds of the structure 18-2.
  • an appropriate copper (I) species for example Cul or Cu 2 0
  • inorganic carbonate such as CS 2 CO 3
  • a polar aprotic solvent such as DMF
  • ligands such as (Z)-2-hydroxybenzaldehyde oxime may be employed.
  • Scheme 19 describes the synthesis of tetrazole compounds 19-2.
  • Treatment of compound 19-1 with sodium azide and ammonium chloride in a polar aprotic solvent (such as DMF) at elevated temperatures affords compounds of the structure 19-2.
  • a polar aprotic solvent such as DMF
  • Scheme 20 depicts the coupling of compounds of the structure 4-1 with 1-methyl- lH-tetrazole, which is accomplished by treatment with a copper (I) salt (such as Cul), a palladium (0) source (for example Pd(OAc) 2 ), an appropriate palladium ligand (for instance tris(2-furyl)phosphine) and an inorganic carbonate (such as CS 2 CO 3 ).
  • a copper (I) salt such as Cul
  • a palladium (0) source for example Pd(OAc) 2
  • an appropriate palladium ligand for instance tris(2-furyl)phosphine
  • an inorganic carbonate such as CS 2 CO 3
  • Scheme 22 outlines the synthesis of pyrrolidine compounds of the structure 22-2 and 22-5.
  • the protected pyrrolidine 22-1 (where PG is for example Boc) can be transformed into compound 22-2 by treatment with acid (for instance TFA or HC1).
  • acid for instance TFA or HC1.
  • Treatment of 22-2 in the presence of sulfonyl chloride 22-3 and a tertiary amine (such as triethyl amine) provides compounds of the structure 22-5.
  • the bis-sulfonamide (22-4) may be formed.
  • Selective hydrolysis of 22-4 with aqueous hydroxide in a protic solvent (such as EtOH) will afford compounds of the structure 22-5.
  • Scheme 23
  • Scheme 23 describes the synthesis of compounds of the structure 23-2, 23-3 and 23- 4.
  • the amide moiety in compound 23-1 (wherein G is defined as O or S) can be selectively reduced using borane in an ethereal solvent (such as THF) to provide compounds of the structure 23-2.
  • Compounds 23-2 can be further elaborated when R 4 is a protecting group (such as, for instance PMB).
  • Treatment of compound 23-2 with an acid (such as TFA) at elevated temperatures (for example 80 °C) provides compounds of the structure 23-3.
  • compounds 23-3 can be treated with sulfonyl chloride 22-3 in the presence of a tertiary amine (for example triethyl amine) in an aprotic solvent (such as DCM) to provide compounds of the structure 23-4.
  • a tertiary amine for example triethyl amine
  • an aprotic solvent such as DCM
  • Scheme 24 details the oxidation of 24-1 for examples wherein G, in compounds 23- 2, is a sulfur atom.
  • an oxidizing agent such as mCPBA
  • an aprotic solvent for example DCM
  • Scheme 25 outlines the synthesis of compounds 25-1.
  • Intermediate 1-3 can be treated with ethyl 4-chloro-4-oxobutanoate in the presence of a basic amine (for example pyridine) in an aprotic solvent (such as DCM).
  • a basic amine for example pyridine
  • an aprotic solvent such as DCM
  • the resulting amide may then be treated with sodium hydride in an ethereal solvent (such as THF) to provide compounds of the structure 25- 1.
  • THF ethereal solvent
  • intermediate 1-3 can be treated with acid chloride 26-1 in the presence of a basic amine (for example pyridine) in an aprotic solvent (such as DCM).
  • a basic amine for example pyridine
  • an aprotic solvent such as DCM
  • the resulting amide may then be treated with a base (such as DBU or NaH) in an ethereal solvent (such as THF) to provide compounds of the structure 26-2.
  • aldehydes of the structure 27-1 may be treated with a fluorinating reagent (such as DAST) in an aprotic solvent (for example DCM or a mixture of DCM and THF) to provide compounds of the structure 27-2 as shown in Scheme 27.
  • a fluorinating reagent such as DAST
  • an aprotic solvent for example DCM or a mixture of DCM and THF
  • Scheme 28 outlines the synthesis of alpha-halogenated ketones (intermediate 1-2).
  • Alpha-chloro keto derivatives of 1-2 can be generated from ester 28-1 by treatment with a strong base (such as LDA) in the presence of chloroiodomethane in an aprotic solvent (for example THF).
  • a strong base such as LDA
  • alpha-bromo keto derivatives of 1-2 can be synthesized from intermediates 28-2, 28-6 and 28-7.
  • Acid 28-2 can be purchased or obtained by hydrolysis of ester 28-1 using aqueous hydroxide in a protic solvent (for example ethanol).
  • a protic solvent for example ethanol
  • Formation of the acid chloride can be achieved by treatment of 28-2 with a chlorinating agent (such as thionyl chloride) at elevated temperatures (for example 60 °C). Addition of a basic solution of diazomethane to the resulting acid chloride followed by treatment with hydrobromic acid in an aprotic solvent (such as THF) affords intermediate 1-2. Additionally, intermediate can be synthesized form methyl ketone 28-6. The synthesis of intermediate 28-6 starts from nitrile 28- 3 or alcohol 28-4. Nitrile 28-3 can be treated with a reducing agent (such as DIBAL) an ethereal solvent (such as THF) to afford aldehyde 28-5.
  • a chlorinating agent such as thionyl chloride
  • hydrobromic acid in an aprotic solvent such as THF
  • intermediate can be synthesized form methyl ketone 28-6.
  • Nitrile 28-3 can be treated with a reducing agent (such as DIBAL) an ethereal solvent (such as
  • alcohol 28-4 can be treated with an oxidizing agent (such as Dess-Martin Periodinane) in an aprotic solvent (such as DCM) to afford aldehyde 28-5.
  • an oxidizing agent such as Dess-Martin Periodinane
  • an aprotic solvent such as DCM
  • Addition of methyl magnesium bromide to Aldehyde 28-5 in an aprotic solvent (such as THF) followed by addition of the resulting alcohol using an oxidizing agent (such as Dess-Martin Periodinane) in an aprotic solvent (such as DCM) results in methyl ketone 28-6.
  • Treatment of 28-6 under brominating conditions such as CuBr 2 in EtOAc or Br 2 in the presence of catalytic HO Ac in DCM affords intermediate 1-2.
  • intermediate 1-2 can be generated directly through Freidel-Crafts acylation of aromatic or heteroaromatic compound 28-7.
  • Treatment of 28-7 with 2-bromoacetyl bromide in the presence of a Lewis acid (such as A1C1 3 ) in an aprotic solvent (such as DCE) provides intermediates of the structure 1-2.
  • Scheme 29 shows the displacement of 2-chloropyridines to provide compounds of the structure 29-2.
  • Treatment of compound 29-1 with amine 18-1 in a protic solvent (such as EtOH or water) at elevated temperatures (80 °C) affords compounds of the structure 29-2.
  • a protic solvent such as EtOH or water
  • Scheme 30 outlines the synthesis of the phosphonate coupling partner 30-3.
  • R 2 is alkyl
  • ethyl 2-(diethoxyphosphoryl)acetate is treated with a base
  • acid chloride 30-3 can then be completed by first stirring compounds 30-2 in aqueous hydroxide followed by treating the resulting acid with a chlorinating agent (such as oxalyl chloride) in DCM.
  • a chlorinating agent such as oxalyl chloride
  • a method of treating a condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the condition is selected from the group consisting of pain, chronic pain, central pain, somatic pain, acute pain, mixed etiology pain, dual mechanism pain, phantom limb pain, complex regional pain syndrome or reflex sympathetic dystrophy, visceral pain, peripheral inflammatory pain, neuropathic pain, central neuropathic pain, neuropathy, diabetic neuropathy, diabetic peripheral neuropathic pain, cancer pain, HIV/ AIDS peripheral neuropathy (or HIV/AIDS-related neuropathy), neuropathy-related hypersensitivity, inflammatory pain, inflammatory diseases, central inflammatory conditions, peripheral inflammatory conditions, multiple sclerosis, stroke, traumatic brain injury, asthma, glioma, spinal cord injury, Alzheimer's disease, arthopathy, migraine, trigeminal neuralgia,
  • the condition is selected from the group consisting of pain; central pain; and peripheral pain.
  • a method of inhibiting or modulating a purinergic P2X4 ion channel receptor (P2X4R) in a subject comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition sdisclosed herien.
  • P2X4R purinergic P2X4 ion channel receptor
  • the compound is a P2X4R antagonist. In further embodiments, the compound is a P2X4R antagonist.
  • the compound is a P2X4R negative allosteric modulator.
  • the compound is administered in combination with another agent or therapy.
  • provided herein is a method of treating, preventing, and/or managing various disorders, including, but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.
  • a method of treating, preventing, and/or managing one or more symptoms of chronic pain, neuropathy, inflammatory diseases and central nervous system disorders comprises administering to a subject (e.g., human) a therapeutically or prophylactically effective amount of a composition or a compound provided herein or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the subject is a human.
  • the subject is an animal.
  • the compounds provided herein are highly brain penetrable in the subject.
  • the efficacious concentration of a compound provided herein is less than 10 nM, less than 100 nM, less than 1 ⁇ , less than 10 ⁇ , less than 100 ⁇ , or less than 1 mM.
  • a compound's activity may be assessed in various art-recognized animal models as described herein elsewhere or known in the literature.
  • the treatment, prevention, and/or management is accomplished by administering a compound provided herein that has shown in vivo efficacy in an animal model predictive of activity relevant to chronic pain, neuropathy, inflammatory diseases and central nervous system disorders in humans.
  • a compound provided herein that has shown in vivo efficacy in an animal model predictive of activity relevant to chronic pain, neuropathy, inflammatory diseases and central nervous system disorders in humans.
  • the phenotypic approach to develop antipsychotics has been used in psychopharmacology, with the antipsychotic chlorpromazine developed in this way.
  • the phenotypic approach may also offer advantages over compounds developed by traditional in vitro based drug discovery approach, because the compounds developed using the phenotypic approach have established pharmaceutical properties and in vivo activity, rather than activity toward a given molecular target, which may be less predictive and lead to attrition at later stages of, for example, clinical development.
  • provided herein is a method of treating, preventing, and/or managing chronic pain, neuropathy, inflammatory diseases and central nervous system disorders, comprising administering to a subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • chronic pain, neuropathy, inflammatory diseases and central nervous system disorders include diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathy, HIV/ AIDS related neuropathy, phantom limb pain, trigeminal neuralgia complex regional pain syndrome, fibromyalgia and multiple sclerosis.
  • P2X4R antagonists or negative allosteric modulators are useful for mitigation of pain in neuropathic and/or inflammatory pain states.
  • the compounds provided herein may increase the threshold for neuropathic pain, which is shown in models such as the chronic constriction injury (CCI) model, herpes virus-induced model, and capsaicin-induced allodynia model. Therefore, in some embodiments, the compounds provided herein are employed for their analgesic effects to treat, prevent, and/or manage disorders involving pain and the sensitization that accompanies many neuropathic pain disorders.
  • CCI chronic constriction injury
  • capsaicin-induced allodynia model capsaicin-induced allodynia model. Therefore, in some embodiments, the compounds provided herein are employed for their analgesic effects to treat, prevent, and/or manage disorders involving pain and the sensitization that accompanies many neuropathic pain disorders.
  • a method of effecting a therapeutic effect as described herein elsewhere comprises administering to a subject ⁇ e.g., a mammal) a therapeutically effective amount of a compound or composition provided herein.
  • a subject e.g., a mammal
  • the particular therapeutic effects may be measured using any model system known in the art and described herein, such as those involving an animal model of a disease.
  • Neuropathic pain includes, without limitation, post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use).
  • the compounds described herein treat, prevent, and/or manage a neurological disorder of the central nervous system, without causing addiction to said compounds.
  • Any suitable route of administration can be employed for providing the patient with a therapeutically or prophylactically effective dose of an active ingredient.
  • oral, mucosal e.g., nasal, sublingual, buccal, rectal, vaginal
  • parenteral e.g., intravenous, intramuscular
  • transdermal e.g., transdermal, and subcutaneous routes
  • routes of administration include oral, transdermal, and mucosal.
  • Suitable dosage forms for such routes include, but are not limited to, transdermal patches, ophthalmic solutions, sprays, and aerosols.
  • Transdermal compositions can also take the form of creams, lotions, and/or emulsions, which can be included in an appropriate adhesive for application to the skin or can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • An exemplary transdermal dosage form is a "reservoir type” or “matrix type” patch, which is applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
  • the patch can be replaced with a fresh patch when necessary to provide constant administration of the active ingredient to the patient.
  • the amount to be administered to a patient to treat, prevent, and/or manage the disorders described herein will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount required.
  • the physician or veterinarian could start doses of the compounds employed at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound provided herein will be that amount of the compound which is the lowest dose effective to produce a therapeutic or prophylactic effect. Such an effective dose will generally depend upon the factors described above.
  • oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds provided herein for a patient will range from about 0.005 mg per kilogram to about 5 mg per kilogram of body weight per day.
  • the oral dose of a compound provided herein will range from about 10 mg to about 300 mg per day.
  • the oral dose of a compound provided herein will range from about 20 mg to about 250 mg per day.
  • the oral dose of a compound provided herein will range from about 100 mg to about 300 mg per day.
  • the oral dose of a compound provided herein will range from about 10 mg to about 100 mg per day.
  • the oral dose of a compound provided herein will range from about 25 mg to about 50 mg per day.
  • the oral dose of a compound provided herein will range from about 50 mg to about 200 mg per day.
  • Each of the above-recited dosage ranges may be formulated as a single or multiple unit dosage formulations.
  • the compounds disclosed herein may be used in combination with one or more second active agents to treat, prevent, and/or manage disorders described herein.
  • the second active agent is an analgesic. In some embodiments, the second active agent is an analgesic.
  • the second active agent is an opioid analgesic, a non-opioid analgesic or an adjuvant analgesic.
  • the second agent is a non-opioid analgesic. In some embodiments, the second agent is an NSAID. In some embodiments, the second agent is a COX inhibitor (e.g., COX-2 inhibitors, COX-l/COX-2 inhibitors).
  • COX inhibitor e.g., COX-2 inhibitors, COX-l/COX-2 inhibitors.
  • the second agent is selected from aspirin, acetaminophen, ibuprofen, naproxen, naproxen sodium, flurbiprofen, diclofenac potassium, sulindac, oxaprozin, piroxicam, indomethacin, etodolac, meclofenamate, fenoprofen, ketoprofen, mefenamic acid, nabumetone, tolmetin, ketorolac and diclofenac sodium, or a combination thereof.
  • the second agent is an opioid analgesic. In some embodiments, the second agent is an opioid analgesic.
  • the second agent is morphine or a derivative thereof.
  • the second agent is selected from morphine, codeine, thebaine, hydrocodone, oxycodone, hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine,
  • the second agent is an adjuvant analgesic.
  • the second agent is selected from antidepressants (e.g., tricyclic antidepressants, SSRIs, SNRIs, SARIs, NRIs, NDRIs, NDRAs, TUIs), anticonvulsants, alpha-2-adrenergic agonists, NMDA-receptor antagonists, GABA agonists, steroids, cannabinoids, local anesthetics, muscle relaxants, and topical drugs.
  • antidepressants e.g., tricyclic antidepressants, SSRIs, SNRIs, SARIs, NRIs, NDRIs, NDRAs, TUIs
  • anticonvulsants e.g., tricyclic antidepressants, SSRIs, SNRIs, SARIs, NRIs, NDRIs, NDRAs, TUIs
  • anticonvulsants e.g., tricyclic antidepressants,
  • the second agent is selected from amitriptyline, imipramine, doxepin, desipramine, nortriptyline, duloxetine, minalcipran, venlafaxine, desvenlafaxine, fluoxetine, paroxetine, sertraline, nefazadone, gabapentinoids (e.g., gabapentin, pregabalin), levetiracetam, zonisamide, carbamazepine, phenytoin, valproate, clonazepam, topiramate, lamotrigine, sodium divalproex, oxcarbazepine, lamotrigine, lacosamide, tizanidine, clonidine, dexmedatomidine, ketamine, memantine, dextromethorphan, amantadine, baclofen, tiagabine, clonazepam, corticosteroids (e.g., dexamethasone), THC,
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions can be used in the preparation of individual, single unit dosage forms.
  • Pharmaceutical compositions and dosage forms provided herein comprise a compound provided herein, or a pharmaceutically acceptable salt, stereoisomer, clathrate, or prodrug thereof.
  • Pharmaceutical compositions and dosage forms can further comprise one or more excipients.
  • compositions and dosage forms provided herein can also comprise one or more additional active ingredients.
  • additional active ingredients examples of optional second, or additional, active ingredients are also disclosed herein.
  • Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial
  • topical e.g., eye drops or other ophthalmic preparations
  • transdermal or transcutaneous administration e.g., transcutaneous administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in- water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in- water e
  • composition, shape, and type of dosage forms will typically vary depending on their use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
  • compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
  • the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre- gelatinized starch, and/or magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • dosage forms comprise a compound provided herein in an amount of from about 0.10 to about 500 mg. In other embodiments, dosage forms comprise a compound provided herein in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • dosage forms comprise a second active ingredient in an amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
  • the specific amount of the second active agent will depend on the specific agent used, the diseases or disorders being treated or managed, and the amount(s) of a compound provided herein, and any optional additional active agents concurrently administered to the patient.
  • compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets ⁇ e.g., chewable tablets), caplets, capsules, and liquids ⁇ e.g., fiavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington 's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).
  • Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • oral dosage forms are tablets or capsules, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • Such dosage forms can be prepared by any of the methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free- flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives ⁇ e.g.
  • ethyl cellulose cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose
  • polyvinyl pyrrolidone methyl cellulose
  • pre-gelatinized starch hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101 , AVICEL-PH-103 AVICEL RC-581 , AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific example of a binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL200 syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
  • CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • a solid oral dosage form comprises a compound provided herein, and optional excipients, such as anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • excipients such as anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899;
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein.
  • administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • controlled-release pharmaceutical products improve drug therapy over that achieved by their non-controlled counterparts.
  • use of a controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • the controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side ⁇ e.g., adverse) effects.
  • the controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the drug in order to maintain a constant level of drug in the body, the drug can be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial.
  • administration of a parenteral dosage form bypasses patients' natural defenses against contaminants, and thus, in these embodiments, parenteral dosage forms are sterile or capable of being sterilized prior to administration to a patient.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's
  • water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.
  • cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Patent No. 5,134,127, which is incorporated herein by reference.
  • Topical and mucosal dosage forms include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington 's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005); and Introduction to
  • Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms. Examples of additional ingredients are well known in the art. See, e.g., Remington 's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).
  • the pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, or as a delivery-enhancing or penetration-enhancing agent.
  • salts, solvates, prodrugs, clathrates, or stereoisomers of the active ingredients can be used to further adjust the properties of the resulting composition.
  • active ingredients provided herein are not administered to a patient at the same time or by the same route of administration.
  • kits which can simplify the administration of appropriate amounts of active ingredients.
  • kits comprises a dosage form of a compound provided herein.
  • Kits can further comprise one or more second active ingredients as described herein, or a pharmacologically active mutant or derivative thereof, or a combination thereof.
  • kits can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
  • Kits can further comprise cells or blood for transplantation as well as
  • kits that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl alcohol,
  • Step 1 Preparation of l-(2-fluoro-3-methox henyl)ethanol
  • a diazomethane solution was generated by dropwise addition of a potassium hydroxide (80 g, 1428.57 mmol) in water (200 mL) to a 0 °C solution of N,4-dimethyl-N- nitrosobenzenesulfonamide (86.38 g, 403.2 mmol) in EtOH (260 mL) over a 1 h period.
  • a potassium hydroxide 80 g, 1428.57 mmol
  • EtOH 260 mL
  • 3-iodobenzoyl chloride 5.2g, 19.5 mmol
  • the diazomethane solution was introduced into the above 3-iodobenzoyl chloride solution via cannulation under positive N 2 pressure at 0 °C.
  • reaction mixture was stirred at room temperature for 30 min then cooled to 0 °C and aqueous HBr (19.6 g, 241.92 mmol, 40%) was added dropwise over 20 min.
  • the reaction mixture was stirred at that temperature for 30 min, warmed to room temperature and stirred for another 30 min.
  • Saturated aqueous NaHCC"3 (3 x 50 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated with EtOAc (4 x 100 mL).
  • Step 1 Preparation of 7-acetyl-4-(4-methoxybenzyl)-2H-benzo[b][l,4]oxazin-3(4H)-one
  • Step 2 Preparation of 7-(2-bromoacetyl)-4-(4-methoxybenzyl)-2H-benzo[b][l,4]oxazin-3(4H)- one
  • aldehyde precursors were synthesized as detailed below (Intermediates I-L).
  • Step 1 Preparation of ethyl 3-(3,4-difluorophenyl)acrylate
  • Step 5 Preparation of 5,6-difluoro-2,3-dihydro-lH-inden-l-one [00254] To a solution of aluminum trichloride (1.43 g, 10.76 mmol) in DCM (130 mL) was added 3-(3,4-difluorophenyl)propanoyl chloride (2.00 g, 9.78 mmol) in DCM(20 mL) under a ice-bath condition. The reaction was stirred at rt for 16 h. Cooled water (50 mL; 5 °C) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel.
  • Step 3 Preparation of diethyl (l-chloro-3 -methyl- l-oxobutan-2-yl)phosphonate
  • Step 1 Preparation of 2-(2-oxo-2-(p ridin-4- yl)ethoxy)benzonitrile
  • Step 3 Preparation of ethyl 2-oxo-4-(pyridin-4-yl)-l,2-dihydrobenzofuro[3,2-b]pyridine-3- carboxylate
  • Step 1 Preparation of ethyl 3-amin -2-(2-fluoro-3-methoxybenzoyl)-lH-indole-l-carboxylate
  • Step 2 Preparation of diethyl 4-(2-fiuoro-3-methoxyphenyl)-2-oxo-lH-pyrido[3,2-b]indole- 3,5(2H)-dicarboxylate
  • Step 3 Preparation of ethyl 4-(2-fluoro-3-methoxyphenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2- b]indole-3-carboxylate
  • reaction mixture was concentrated in vacuo, which provided a solid that was slurried with DCM/ether to provide ethyl 4-(2-fluoro-3-methoxyphenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-3-carboxylate (28 mg, 0.07 mmol).
  • Step 1 Preparation of ethyl 3-(2-(diethoxyphosphoryl)propanamido)-2-(2-fluoro-3- methoxybenzoyl)- 1 H-indole- 1 -carboxylate
  • Step 2 Preparation of ethyl 4-(2-fiuoro-3-methoxyphenyl)-3-methyl-2-oxo-lH-pyrido[3,2- b]indole-5(2H)-carboxylate
  • Step 3 Preparation of 4-(2-fluoro-3-methoxyphenyl)-3-methyl-lH-pyrido[3,2-b]indol-2(5H)- one
  • Step 1 Preparation of ethyl 5-chloro-3-(2-(diethoxyphosphoryl)-3-methylbutanamido)-2- nicotinoyl- 1 H-indole- 1 -carboxylate
  • Ethyl 5-chloro-3-(2-(diethoxyphosphoryl)-3-methylbutanamido)-2-nicotinoyl-lH- indole-1 -carboxylate was prepared by using the procedure described in Example 48: Step 1 with substitution of ethyl 3 -amino-2-(2-fluoro-3-methoxybenzoyl)-l H-indole- 1 -carboxylate and intermediate O by ethyl 3-amino-5-chloro-2-nicotinoyl-lH-indole-l-carboxylate and intermediate N respectively.
  • Step 2 Preparation of ethyl 8-chloro-3-isopropyl-2-oxo-4-(pyridin-3-yl)-lH-pyrido[3,2- b]indole-5(2H)-carboxylate
  • Step 3 Preparation of 8-chloro-3-iso ropyl-4-(pyridin-3-yl)-lH-pyrido[3,2-b]indol-2(5H)-one
  • Example 51 was prepared according to the procedure described in Example 47 with substitution of (3-aminobenzofuran-2-yl)(3-methoxyphenyl)methanone by (3-aminobenzofuran-2-yl)(3-bromophenyl)methanone.
  • Example 55 was prepared according to Example 48 with substitution of ethyl 3-amino-2-(2-fluoro-3-methoxybenzoyl)- 1 H-indole- 1 -carboxylate for (3 -aminobenzofuran-2-yl)(pyridin-3 -yl)methanone .
  • Step 1 Preparation of 8-chloro-4-(2-fluoro-3-methoxyphenyl)-2-oxo-2,5-dihydro
  • Step 2 Preparation of 8-chloro-4-(2-fluoro-3-methoxyphenyl)-lH-pyrido[3,2-b]indol-2(5H)- one
  • Example 141 was prepared according to the procedure described in Example 135 with substitution of diethyl 8-chloro-4-(2-fluoro-3-methoxyphenyl)- 2-oxo-lH-pyrido[3,2-b]indole-3,5(2H)dicarboxylate by ethyl 8-fluoro-4-(2-fluoro-3- methoxyphenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-3-carboxylate.
  • Step 1 Preparation of ethyl 8-chloro-3-cyano-2-oxo-4-phenyl-lH-pyrido[3,2-b]indole-5(2H)- carboxylate
  • Example 143 was prepared according to the procedure described in Example 142 with substitution of ethyl 3-amino-2-benzoyl-5-chloro-lH-indole-l-carboxylate by (3 -amino-5 -chlorobenzo [b]thiophen-2-yl)(6-methylpyridin-3 -yl)methanone.
  • Step 1 preparation of (E)-6-chloro-2-(pyridin-3-ylmethylene)-2,3-dihydro-lH-inden-l-
  • Step 1 preparation of (E)-6-chloro-2-((6-methylpyridin-3-yl)methylene)-2,3-dihydro inden-l-one
  • Step 2 preparation -chloro-4-(6-methylpyridin-3-yl)-lH-indeno[l,2-b]pyridin-2(5H)-one
  • Example 152 Preparation of 4-(3-(lH-imidazol-l-yl)phenyl)-8-chloro-2-oxo-2,5-dihydro-lH- indeno[ 1 ,2-b]pyridine-3-carbonitrile
  • Example 155 was prepared according to the procedure described in Example 147 with substitution benzaldehyde by nicotinaldehyde.
  • Step 1 Preparation of ethyl 2-benzoyl-3-(2-bromoacetamido)-lH-indole-l-carboxylate
  • Example 171 was prepared with substitution of ethyl 3 -aminos- benzoyl- lH-indole-1 -carboxylate by (3 -amino-5 -chlorobenzofuran-2-yl)(phenyl)methanone in Example 170: Step 1.
  • Example 192 was prepared with substitution of acetyl chloride in Example 190 by ethyl 2-chloro-2-oxoacetate and Example 192 was prepared with substitution of 3-amino-8-chloro-4-phenylbenzofuro[3,2-b]pyridin-2(lH)-one chloride in Example 190 by 3-amino-4-phenyl-lH-pyrido[3,2-b]indol-2(5H)-one.
  • Step 1 Preparation of ethyl (8-chloro-2-oxo-4-phenyl-2,5-dihydro-lH-pyrido[3,2-b]indol-3- yl)carbamate
  • the resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (35 %) and Hex (65 %) to EtOAc (50 %) and Hex (50 %) to provide 8-chloro-3-(methylamino)-4-phenyl-lH-pyrido[3,2-b]indol- 2(5H)-one (200 mg, 0.62 mmol) as a yellow solid.
  • Example 226 and 227 were prepared with substitution of ethyl 2-((8-chloro-2-oxo-4-phenyl-2,5-dihydro-lH-pyrido[3,2-b]indol-3-yl)amino)-2- oxoacetate in Examples 223 and 224 (respectively) by ethyl 2-oxo-2-((2-oxo-4-phenyl-2,5- dihydro-lH-pyrido[3,2-b]indol-3-yl)amino)acetate.
  • Example 228 was prepared by substitution of 3-amino-8-chloro-4-phenyl-lH-pyrido[3,2-b]indol-2(5H)-one in Example 225 with 3-amino-
  • Example 230 was prepared with substitution of 4-(3-cyanophenyl)- 2-oxo-l,2-dihydrobenzofuro[3,2-b]pyridine-3-carboxylate in Example 229 by ethyl 4-(3- cyanophenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-3-carboxylate.
  • Step 1 Preparation of ethyl 3 -methyl-4-(3-(l -methyl- lH-tetrazol-5 -yl)phenyl)-2-oxo-lH- pyrido[3,2-b]indole-5(2H)-carboxylate
  • the reaction was heated at 80 °C under N 2 for 4 h.
  • the reaction mixture was cooled to rt, water (20 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel.
  • the aqueous phase was washed with EtOAc (3 x 20 mL).
  • the combined organics were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • reaction mixture was cooled to rt, water (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel.
  • the aqueous phase was washed with EtOAc/MeOH (10/1, 5 x 50 mL). The combined organics were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • the resulting oil was purified by reverse phase HPLC with a gradient elution of MeOH (20%) and water(80%) to MeOH (70%) and water (30%) to provide 8-fluoro-3-methyl-4-(3- (methylsulfonyl)phenyl)benzofuro[3,2-b]pyridin-2(lH)-one (21 mg, 0.05 mmol) as a yellow solid.
  • Example 11 The compounds listed in Table 11 were prepared using the procedures described in Example 234. For instance Examples 235 and 241 were prepared with substitution of 8-fluoro- 4-(3-iodophenyl)-3-methylbenzofuro[3,2-b]pyridin-2(lH)-one in Example 234 by 8-chloro-4- (3-iodophenyl)-3-methylbenzofuro[3,2-b]pyridin-2(lH)-one and 3-acetyl-8-chloro-4-(3- iodophenyl)-lH-pyrido[3,2-b]indol-2(5H)-one respectively.
  • Step 1 Preparation of diethyl 4-(3-iodophenyl)-3-methyl-2-oxo-lH-pyrido[3,2-b]indole- 1 ,5(2H)-dicarboxylate
  • Step 2 Preparation of diethyl 4-(3-(benzoylthio)phenyl)-3-methyl-2-oxo-lH-pyrido[3,2- b]indole-l ,5(2H)-dicarboxylate
  • the reaction mixture was heated to 100 °C and stirred at that temperature for 16 h.
  • the reaction mixture was cooled to rt, saturated aqueous NaHC0 3 (200 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel.
  • the layers were separated and the aqueous layer was washed with EtOAc (2 x 150 mL).
  • the combined organics were washed with saturated aqueous NaCl (1 x 150 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • Step 3 Preparation of ethyl 3-methyl-2-oxo-4-(3-sulfamoylphenyl)-lH-pyrido[3,2-b]indole- 5(2H)-carboxylate
  • diethyl 4-(3- (benzoylthio)phenyl)-3-methyl-2-oxo-lH-pyrido[3,2-b]indole-l,5(2H)-dicarboxylate (0.20 g, 0.36 mmol) was dissolved in CH 3 CN (4 mL) to which the aforementioned clear yellow solution was added (dropwise over 2 min) followed by Na 2 C0 3 (0.04 g, 0.36 mmol). The reaction mixture was stirred for 20 min, aqueous NH 3 (0.13 g, 0.36 mmol) was added and the mixture was stirred for an additional 30 min.
  • Step 1 Preparation of ethyl 8-chloro-4-(3-iodophenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2- b]indole- 1 -carboxylate
  • reaction mixture was concentrated and purified by flash column chromatography eluted with Hex : EtOAc from 8: 1 to 6: 1 to provide ethyl 8-chloro-4-(3-iodophenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2- b]indole-l-carboxylate (700 mg, 1.42 mmol) of the desired product.
  • Step 2 Preparation of ethyl 4-(3-(benzoylthio)phenyl)-8-chloro-2-oxo-2,5-dihydro-lH- pyrido[3 ,2-b]indole- 1 -carboxylate
  • Step 3 Preparation of 3-(8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indol-4- yl)benzenesulfonamide
  • Example 254 was prepared with substitution of 8-chloro-4- (3-iodophenyl)-lH-pyrido[3,2-b]indol-2(5H)-one in Example 253 by 8-chloro-4-(3- iodophenyl)benzofuro[3,2-b]pyridin-2(lH)-one.
  • Example 261 was prepared with substitution of ethyl 4-(3-iodophenyl)-3-methyl-2-oxo-lH-pyrido[3,2-b]indole-5(2H)-carboxylate in Example 252 by ethyl 8-fluoro-4-(3-iodophenyl)-3-methyl-2-oxo-lH-pyrido[3,2-b]indole-5(2H)- carboxylate.
  • Example 275 Preparation of 4-phenyl-3-(piperazin-l-yl)-lH-pyrido[3,2-b]indol-2(5H)-one Step 1: Preparation of tert-butyl 4-(2-oxo-4-phenyl-2,5-dihydro-lH-pyrido[3,2-b]indol-3- yl)piperazin - 1 -carboxylate
  • Example 276 was prepared with substitution of 3-fluoro-4-phenyl- lH-pyrido[3,2-b]indol-2(5H)-one in Example 275 by 3-fluoro-4-(3-methoxyphenyl)-lH- pyrido[3,2-b]indol-2(5H)-one.
  • Step 2 Preparation of 3-((methylamino methyl)-4-phenyl-lH-pyrido[3,2-b]indol-2(5H)-one
  • Example 280 was prepared with substitution of methyl amine in Example 279: Step 2 by ammonia.
  • Example 283 was prepared with substitution of 3- (hydroxymethyl)-4-phenyl-lH-pyrido[3,2-b]indol-2(5H)-one
  • Example 279 by 3- (hydroxymethyl)-4-(3-methoxyphenyl)-lH-pyrido[3,2-b]indol-2(5H)-one.
  • the reaction mixture was cooled to rt and diluted with DCM (100 mL). The reaction mixture was filtered and washed by DCM (3 x 10 mL). Water (25 mL) was added to the filtrate and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with water (2 x 25 mL). The combined organics were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • reaction mixture was cooled and diluted with water (10 mL).
  • the aqueous layer was washed with EtOAc (3 x 20 mL).
  • the combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • reaction mixture was cooled to rt, water (20 mL) was added to the reaction vessel and the resulting biphasic mixture was washed with EtOAc (3 x 50 mL). The organic phase was washed with saturated aqueous NaCl (4 x 20 mL). The combined organics were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • the resulting solid was purified by reverse phase HPLC with a gradient elution of MeOH (10%) and water(90%) to MeOH (30%) and water (70%) to provide 4-(5 -( 1 H-imidazol- 1 -yl)pyridin-3 -yl)-8-chloro-3 -methylbenzofuro [3 ,2-b]pyridin-2( 1 H)-one (5 mg, 13.3 ⁇ ) as a yellow solid.
  • Example 288 was prepared with substitution of 8-chloro-4-(3- iodophenyl)-3-methyl-lH-pyrido[3,2-b]indol-2(5H)-one in Example 285 by 4-(2-bromopyridin- 4-yl)-8-chloro-3-methylbenzofuro[3,2-b]pyridin-2(lH)-one.
  • Example 298 was prepared with substitution of pyrrolidin-2-one in Example 286 by oxazolidin-2-one.
  • Example 304 Preparation of ethyl 4-(3-(4H-l,2,4-triazol-3-yl)phenyl)-2-oxo-l,2- dihydrobenzofuro [3 ,2-b]pyridine-3 -carboxylate
  • Step 1 Preparation of ethyl 4-(3-(ethoxy(imino)methyl)phenyl)-2-oxo-l,2- dihydrobenzofuro [3 ,2-b]pyridine-3 -carboxylate hydrochloride
  • Step 1 Preparation of 3-(8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indol-4-yl)benzonitrile
  • Step 2 Preparation of 3-(8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indol-4-yl)-N'- hydrox benzimidamide
  • Step 3 Preparation of 4-(3-(l,2,4-oxadiazol-3-yl)phenyl)-8-chloro-lH-pyrido[3,2-b]indol- 2(5H)-one
  • Example 308 was prepared by using the procedure described in Example 307 with substitution of ethyl 5-chloro-2-(3-cyanobenzoyl)-3-(2-(diethoxyphosphoryl)acetamido)-lH- indole-l-carboxylate in Example 307 by ethyl 2-(3-cyanobenzoyl)-3-(2-
  • Step 1 Preparation of ethyl 8-chloro-4-(3-cyanophenyl)-3-(diethoxyphosphoryl)-2- pyrido[3,2-b]indole-5(2H)-carboxylate
  • Step 2 Preparation of 3-(8-chloro-2-oxo-2 5-dihydro-lH-pyrido[3,2-b]indol-4-yl)benzoic acid
  • Step 4 Preparation of (Z)-3-(8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indol-4-yl)-N- ((dimethylamino)methylene)benzamide
  • Example 310 was prepared with substitution of ethyl 5-chloro-2-(3- cyanobenzoyl)-3-(2-(diethoxyphosphoryl)acetamido)-lH-indole-l-carboxylate in Example 309 for ethyl 2-(3-cyanobenzoyl)-3-(2-(diethoxyphosphoryl)propanamido)-lH-indole-l-carboxylate and excluding step 2.
  • reaction mixture was cooled, saturated aqueous NH 4 C1 (20 mL) and EtOAc (50 mL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was washed with EtOAc/MeOH (10/1, 3 x 50 mL). The combined organics were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo.
  • Example 314 was prepared by using the procedure described in Example 313 with substitution of 8-chloro-4-(3-iodophenyl)-lH-pyrido[3,2-b]indol-2(5H)-one in Example 313 by 4-(3-iodophenyl)-3-methyl-lH-pyrido[3,2-b]indol-2(5H)-one.
  • Example 315 was prepared by using the procedure described in Example 313 with substitution of 8-chloro-4-(3-iodophenyl)-lH-pyrido[3,2-b]indol-2(5H)-one in Example 313 by 4-(3-iodophenyl)-lH-pyrido[3,2-b]indol-2(5H)-one.
  • Step 1 Preparation of (E)-3-(3-(8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indol-4- yl)phenyl)acrylaldehyde
  • reaction mixture was heated to 90 °C and stirred at that temperature overnight.
  • the reaction mixture was cooled to rt and 2 M HCl (5 mL) was added.
  • the mixture was stirred for an additional 40 min.
  • Water (50 mL) was added and the mixture was washed with DCM (4 x 50 mL).
  • the combined organics were washed with brine, dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • Step 2 Preparation of 8-chloro-4- 3-(isoxazol-3-yl)phenyl)-lH-pyrido[3,2-b]indol-2(5H)-one
  • Example 317 Preparation of 4-(3-(isoxazol-3-yl)phenyl)-3 -methyl- lH-pyrido [3, 2-b]indol- 2(5H)-one
  • Example 317 was prepared by using the procedure described in Example 316 with substitution of ethyl 8-chloro-4-(3-iodophenyl)-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-l- carboxylate in Example 316 by ethyl 4-(3-iodophenyl)-3-methyl-2-oxo-2,5-dihydro-lH- pyrido[3,2-b]indole-l-carboxylate
  • Step 1 Preparation of 3-(8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indol-4-yl)-N-methoxy- N-methylbenzamide
  • Step 3 Preparation of ethyl 4-(3-acetylphenyl)-8-chloro-2-oxo-2,5-dihydro-lH-pyrido[3,2- b]indole- 1 -carboxyl

Abstract

L'invention concerne des composés modulateurs du récepteur P2S4, leurs procédés de synthèse, des compositions pharmaceutiques comprenant lesdits composés et leurs procédés d'utilisation. Les composés selon l'invention sont utiles pour le traitement, la prévention et/ou la gestion de divers troubles, y compris, mais pas exclusivement, la douleur chronique, la neuropathie, les maladies inflammatoires et les troubles du système nerveux central.
PCT/US2013/075118 2013-12-13 2013-12-13 Composés modulateurs du récepteur p2x4 WO2015088564A1 (fr)

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WO2017191000A1 (fr) 2016-05-03 2017-11-09 Bayer Pharma Aktiengesellschaft Dérivés sulfonamides aromatiques
WO2018104307A1 (fr) 2016-12-09 2018-06-14 Bayer Pharma Aktiengesellschaft Dérivés de sulfonamide aromatiques et leur utilisation en tant qu'anatagon i sts ou des modulateurs allostériques négatifs de p2x4
WO2018104305A1 (fr) 2016-12-09 2018-06-14 Bayer Pharma Aktiengesellschaft Sulfamoylbenzamides
WO2018210729A1 (fr) 2017-05-18 2018-11-22 Bayer Pharma Aktiengesellschaft Dérivés de sulfonamide aromatiques utilisés en tant qu'antagonistes ou modulateurs allostériques négatifs du récepteur p2x4
CN108864089A (zh) * 2018-08-01 2018-11-23 河南湾流生物科技有限公司 一种新型吲哚并吡啶酮药物分子及其制备方法和应用
CN109232366A (zh) * 2018-09-29 2019-01-18 华中师范大学 2-酰基-3-氨基吲哚类化合物的制备方法及其应用
WO2019081573A1 (fr) 2017-10-29 2019-05-02 Bayer Aktiengesellschaft Dérivés sulfonamides aromatiques pour le traitement d'un accident cérébral ischémique
CN111777613A (zh) * 2019-04-03 2020-10-16 中国药科大学 嘧啶二酮并吲哚和吡啶酮并吲哚类化合物的制备及用途
CN113666906A (zh) * 2021-09-23 2021-11-19 安徽有吉医药科技有限公司 2-氯-1-(2,2-二甲基-4h-苯并[1,3]二噁英-6-基)乙酮的合成方法
WO2022002859A1 (fr) 2020-06-30 2022-01-06 Bayer Aktiengesellschaft N-phénylacétamides substitués ayant une activité antagoniste du récepteur p2x4
CN113943281A (zh) * 2021-10-15 2022-01-18 深圳湾实验室 异恶唑嘧啶衍生物的合成方法及其应用
WO2022049253A1 (fr) 2020-09-07 2022-03-10 Bayer Aktiengesellschaft N-hétéroaryl-n-pyridinylacétamides substitués en tant que modulateurs de p2x4
CN115335380A (zh) * 2020-02-03 2022-11-11 百时美施贵宝公司 可用作irak4抑制剂的三环杂芳基化合物
US11918589B2 (en) 2016-04-28 2024-03-05 Nippon Chemiphar Co., Ltd. Medicament for treatment of multiple sclerosis

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US11918589B2 (en) 2016-04-28 2024-03-05 Nippon Chemiphar Co., Ltd. Medicament for treatment of multiple sclerosis
EP3763704A1 (fr) 2016-05-03 2021-01-13 Bayer Pharma Aktiengesellschaft Derives sulfonamides aromatiques
WO2017191000A1 (fr) 2016-05-03 2017-11-09 Bayer Pharma Aktiengesellschaft Dérivés sulfonamides aromatiques
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WO2018210729A1 (fr) 2017-05-18 2018-11-22 Bayer Pharma Aktiengesellschaft Dérivés de sulfonamide aromatiques utilisés en tant qu'antagonistes ou modulateurs allostériques négatifs du récepteur p2x4
WO2019081573A1 (fr) 2017-10-29 2019-05-02 Bayer Aktiengesellschaft Dérivés sulfonamides aromatiques pour le traitement d'un accident cérébral ischémique
CN108864089A (zh) * 2018-08-01 2018-11-23 河南湾流生物科技有限公司 一种新型吲哚并吡啶酮药物分子及其制备方法和应用
CN108864089B (zh) * 2018-08-01 2020-01-10 日照巴洛特药业有限公司 一种吲哚并吡啶酮药物分子及其制备方法和应用
CN109232366A (zh) * 2018-09-29 2019-01-18 华中师范大学 2-酰基-3-氨基吲哚类化合物的制备方法及其应用
CN109232366B (zh) * 2018-09-29 2020-08-21 华中师范大学 2-酰基-3-氨基吲哚类化合物的制备方法及其应用
CN111777613A (zh) * 2019-04-03 2020-10-16 中国药科大学 嘧啶二酮并吲哚和吡啶酮并吲哚类化合物的制备及用途
CN115335380A (zh) * 2020-02-03 2022-11-11 百时美施贵宝公司 可用作irak4抑制剂的三环杂芳基化合物
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WO2022049253A1 (fr) 2020-09-07 2022-03-10 Bayer Aktiengesellschaft N-hétéroaryl-n-pyridinylacétamides substitués en tant que modulateurs de p2x4
CN113666906A (zh) * 2021-09-23 2021-11-19 安徽有吉医药科技有限公司 2-氯-1-(2,2-二甲基-4h-苯并[1,3]二噁英-6-基)乙酮的合成方法
CN113943281A (zh) * 2021-10-15 2022-01-18 深圳湾实验室 异恶唑嘧啶衍生物的合成方法及其应用
CN113943281B (zh) * 2021-10-15 2023-08-15 深圳湾实验室 异恶唑嘧啶衍生物的合成方法及其应用

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