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WO2015088565A1 - P2x4 receptor modulating compounds and methods of use thereof - Google Patents

P2x4 receptor modulating compounds and methods of use thereof Download PDF

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Publication number
WO2015088565A1
WO2015088565A1 PCT/US2013/075119 US2013075119W WO2015088565A1 WO 2015088565 A1 WO2015088565 A1 WO 2015088565A1 US 2013075119 W US2013075119 W US 2013075119W WO 2015088565 A1 WO2015088565 A1 WO 2015088565A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkyl
pain
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PCT/US2013/075119
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French (fr)
Inventor
Jason S. Newcom
Kerry L. Spear
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Sunovion Pharmaceuticals Inc.
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Priority to PCT/US2013/075119 priority Critical patent/WO2015088565A1/en
Publication of WO2015088565A1 publication Critical patent/WO2015088565A1/en

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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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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.
  • 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 HIV/AIDS.
  • AIDP and CIDP acute or chronic inflammatory demyelinating neuropathy
  • 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 N, N-oxide and CR 2 ;
  • L 1 is selected from a bond, Ci-C 6 alkyl, and Ci-C 6 haloalkyl;
  • R 1 is selected from C 3 -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 6 substituents;
  • R 2 is selected from hydrogen, halogen, CN, NR 7 R 8 , OR 9 , S0 2 R 9 , S0 3 R 9 , C(0)R 9 , C(0)OR 9 , C(0)NR 7 R 8 , Ci-C 6 haloalkyl and Ci-C 6 alkyl optionally substituted with one or more R 10 substituents; each R 3 is independently selected from halogen, CN, OR 11 , NR 12 R 13 , Ci-C 6 haloalkyl, and Ci-C 6 alkyl optionally substituted with one or more R 14 substituents;
  • R 4 and R 5 are each independently selected from hydrogen, OH, NH 2 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, C 3 -C 8 cycloalkyl, and 3- to 10-membered heterocyclyl; each R 6 is independently selected from halogen, CN, N0 2 , oxo, OR 15 , NR 16 R 17 , S0 2 R 15 , S0 3 R 15 , S0 2 NR 16 R 17 , NR 16 S0 2 R 15 , C(0)R 15 , OC(0)R 15 , C(0)OR 15 , C(0)NR 16 R 17 ,
  • 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 18 substituents;
  • R 7 and R 8 are each independently selected from hydrogen, S0 2 R 19 , S0 3 R 19 , SO 2 NR 20 R 21 , C(0)R 19 , C(0)OR 19 , C(0)C(0)R 19 , C(0)C(0)OR 19 , C(O)NR 20 R 21 , 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 22 substituents; or alternatively R 7 and R 8 taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, optionally
  • R 9 is 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 -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
  • each R 10 is independently selected from halogen, CN, OR 24 , NR 25 R 26 , S0 2 R 24 , S0 3 R 24 , S0 2 NR 25 R 26 , C(0)R 24 , C(0)OR 24 , C(0)NR 25 R 26 , and NHC(0)R 24 ;
  • each R 11 , R 15 , R 19 , and R 24 is independently 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 substituents independently selected from halogen, CN, OR 27 , NR 27 R 28 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, and phenyl;
  • each R 12 , R 13 , R 16 , R 17 , R 20 , R 21 , R 25 , and R 26 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-membered heterocyclyl groups are optionally substituted with one or substituents
  • each R 14 is independently selected from halogen, CN, OR 27 , NR 27 R 28 , C 3 -C 8 cycloalkyl,
  • each R 18 , R 22 , and R 23 is independently selected from halogen, CN, oxo, thione, OR 27 , NR 27 R 28 , C(0)R 27 , C(0)OR 27 , C(0)NR 27 R 28 , C C 6 haloalkyl, C C 6 alkyl, and C 3 -C 8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; each R 27 and R 28 is independently selected from hydrogen, C(0)Ci-C 6 alkyl, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; n is 0, 1, 2, 3 or 4; and m is 1, 2 or 3. [0081] In some embodimetns, A is N. In further embodimetns, A is N-oxide. In still further
  • R2 is C1-C6 optionally substituted with one or more R 10 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. In still further embodiments, R 2 is halogen. In still further embodiments,
  • R 2 is CI.
  • R 2 is C(0)OR 9 , and R 9 is selected from hydrogen and Ci-C 6 alkyl.
  • R 2 is hydrogen.
  • R 2 is NR 7 R 8 .
  • R is C(0)R , R is hydrogen, and R is 5- to 10-membered heteroaryl.
  • R 7 is selected from C(0)C(0)R 19 and C(0)C(0)OR 19
  • R 8 is hydrogen
  • R 19 is Ci-C 6 alkyl.
  • R 7 and R 8 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.
  • Li is a bond. In further embodiments, Li is Ci-C 6 alkyl.
  • R 1 is selected from 6- to 14 membered aryl and 5- to 10- membered heteroaryl, each optionally substituted with one or more R 6 substituents.
  • R 1 is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, each optionally substituted with one or more R 6 substituents.
  • R 1 is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with one or more R 6 substituents.
  • R 1 is unsubstituted 6- to 14-membered aryl.
  • R 1 is phenyl substituted with one or more R 6 substituents, and each R 6 is independently selected from halogen, CN, OR 15 , NR 16 R 17 , S0 2 R 15 , S0 2 NR 16 R 17 , C(0)OR 15 , C(0)NR 16 R 17 , C C 6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.
  • R 6 is independently selected from fluoro, chloro, bromo, methoxy, methyl, CF 3 , and C(0)OCH 3 .
  • R 1 is an unsubstituted 5- to 10-membered heteroaryl.
  • R 1 is pyridyl.
  • R 1 is 2-pyridyl.
  • R 1 is 3-pyridyl.
  • R 1 is 4-pyridyl.
  • R 1 is pyridyl substituted with one or more R 6 substituents, and each R 6 is independently selected from halogen, CN, OR 15 , NR 16 R 17 , S0 2 R 15 , S0 2 NR 16 R 17 , C(0)OR 15 , C(0)NR 16 R 17 , Ci-C 6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10- membered heterocyclyl.
  • R 6 is independently selected from fluoro, chloro, bromo, methoxy, methyl, CF 3 , and C(0)OCH 3 .
  • each R 3 is independently selected from halogen, CN, Ci-C 6 haloalkyl, and Ci-C 6 alkyl optionally substituted with one or more R 14 substituents.
  • n is 1.
  • R 3 is selected from F, CI, Ci-
  • R 3 is CI.
  • n 0.
  • At least one of R 4 and R 5 is selected from OH, Ci-C 6 alkyl, and Ci-C 6 alkoxy. In further embodiments, at least one of R 4 and R 5 is selected from the group consisting of OH and Ci-C 6 alkoxy. In still further embodiments, R 4 and R 5 are each hydrogen.
  • the compound is a compound of formula (II), or a
  • R 3 is selected from the group consisting of F, CI, methyl, and methoxy.
  • the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof:
  • the compound is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:
  • R 3 , R 4 , R 5 , and n are as defined herein;
  • each R 29 is independently selected from halogen, CN, OR 15 , NR 16 R 17 , S0 2 R 15 , S0 2 NR 16 R 17 , C(0)OR 15 , C(0)NR 16 R 17 , Ci-C 6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; and
  • p 0, 1 , 2, 3, 4 or 5.
  • R is ;
  • Y is S or O
  • R 30 is selected from hydrogen and Ci-C 6 alkyl.
  • the compound is a compound of formula (Va), or a pharmaceutically acceptable salt thereof:
  • the compound is a compound of formula (Vb), or a pharmaceutically acceptable salt thereof:
  • the compound is a compound of formula (Vc), or a pharmaceutically acceptable salt thereof:
  • 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 can be synthesized from commercially available 2-cyanno anilines 1-1 by first converting 1-1 into the corresponding ethyl carbamate by treatment with ethyl chloro formate in pyridine. Subsequent addition of an a-halogenated ketone 1-2 in the presence of a base (such as an inorganic carbonate, alkoxide, or basic tertiary amine) in an aprotic solvent (for example THF) affords intermediate 1-3 . From intermediate 1-3 compounds 1-5 and 1-7 can be synthesized as shown in Scheme 1.
  • a base such as an inorganic carbonate, alkoxide, or basic tertiary amine
  • Compounds having the formula 1-5 can be synthesized by coupling of intermediate 1-3, according to Method A, with 2-bromoacetyl bromide in the presence of an inorganic base, such as potassium carbonate in an aprotic solvent, such as acetonitrile. Addition of ammonia in a protic solvent (such as MeOH) results in the cyclization and concomitant deprotection to provide compounds of the structure 1-5.
  • a protic solvent such as MeOH
  • compounds having the formula 1-7 can be synthesized by from intermediate 1-3 in a two-step procedure described by Method B.
  • compounds of the structure 1-5 can be synthesized from intermediate 2-6 according to Scheme 2.
  • Treatment of ethyl carbamate-protected 2-cyanno anilines with ethyl 2-bromoacetate in the presence of a base (such as inorganic carbonate) in an aprotic solvent (for example ACN) at elevated temperatures (for instance 50 °C) provides intermediate 2-2. Protection of amino indole 2-2 can be accomplished by addition of /?-methoxybenzyl chloride in the presence of a base (for example inorganic carbonate) in an aprotic solvent (such as DCM) at elevated temperatures (for instance 60 °C).
  • Intermediate 2-4 can be synthesized by coupling of intermediate 2-3 with 2-bromoacetyl bromide in the presence of an inorganic base, such as potassium carbonate in an aprotic solvent, such as acetonitrile. Addition of ammonia in a protic solvent (such as MeOH) results in the cyclization and concomitant deprotection to provide intermediate 2-4. Treatment of intermediate 2-4 with phosphoryl tribromide at elevated temperatures (for example 120 °C) provides coupling partner 2-5.
  • an inorganic base such as potassium carbonate
  • an aprotic solvent such as acetonitrile
  • Coupling of intermediates 2- 5 and 2-6 can be accomplished under palladium mediated conditions with a palladium catalyst (such as Pd(OAc) 2 ) in the presence of an appropriate ligand (for instance triphenylphosphine) and inorganic carbonate (such as sodium carbonate) in a water/ 1,4-dioxane mixture to provide compound 2-7.
  • a palladium catalyst such as Pd(OAc) 2
  • an appropriate ligand for instance triphenylphosphine
  • inorganic carbonate such as sodium carbonate
  • Scheme 3 outlines the synthesis alcohol and methyl derivatives 3-1 and 3-2 respectively.
  • a reducing agent such as LAH or DIBAL
  • an ethereal solvent such as Et 2 0 or THF
  • Further reduction of compound 3-1 can be accomplished by treatment with triethyl silane in TFA to afford compounds of the formula 3-2.
  • Scheme 4 outlines the synthesis of sulfones 4-3, sulfonamides 4-6 and sulfonates 4- 8; wherein Cyl is defined as either an aryl, heteroaryl or heterocylcoalkyl 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 N,N- 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).
  • the resulting thioester is treated with a chlorinating agent (such as TCAA), phase transfer catalyst (for example BnNMesCl) and aqueous carbonate in acetonitrile to afford intermediate 4-4.
  • Intermediate 4-4 is treated immediately with either amine 4-5 or alcohol 4-7 to provide 4-6 and 4-8 respectively.
  • Scheme 5 outlines the synthesis of compounds of the formula 5-4.
  • the synthesis of 5-4 begins with the hydrolysis of 5-1 (wherein Cyl can be either an aryl or heteroaryl ring and R 6 is defined as CN or C0 2 Et) using aqueous hydroxide in a protic from activation of acid 5-2 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 5-3.
  • 5-1 wherein Cyl can be either an aryl or heteroaryl ring and R 6 is defined as CN or C0 2 Et
  • 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 6 outlines the synthesis of heterocycles 6-3.
  • Compound 6-2 can be synthesized by treating nitrile 6-1 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.
  • inorganic carbonate such as sodium or potassium carbonate
  • alcoholic solvent for instance EtOH
  • Scheme 7 outlines the synthesis of compounds of the formulas 7-6 and 7-8.
  • the synthesis of 7-6 and 7-8 can be derived from the common intermediate 7-3, which can be obtained in two steps from ester 7-1.
  • a reducing agent such as LAH or DIBAL
  • an aprotic solvent such as THF
  • alcohol 7-2 Treatment of compound 7-1 with a reducing agent (such as LAH or DIBAL) in an aprotic solvent (such as THF) provides alcohol 7-2.
  • Activation of alcohol 7-2 with regents such as MsCl or SOCl 2 in the presence of a tertiary amine (for example triethyl amine) in an aprotic solvent (such as DCM) affords intermediate 7-3 (wherein LG is OMs or CI).
  • a tertiary amine for example triethyl amine
  • aprotic solvent such as DCM
  • Scheme 8 describes derivatization of compounds 8-1.
  • Treatment of 8-1 with acid chloride 8-2 in the presence of a tertiary amine (for example TEA) in an aprotic solvent (such as DCM) affords compounds of the structure 8-3.
  • a tertiary amine for example TEA
  • an aprotic solvent such as DCM
  • Scheme 9 outlines the synthesis of substituted amines (9-4) and amides (9-6).
  • Reduction of nitro group in compound 9-1 can be accomplished by treatment with iron in the presence of aqueous ammonium chloride in a protic solvent (such as EtOH) at elevated temperatures (for example 100 °C).
  • Amine 9-2 can then be treated with aldehyde 9-3 under reductive aminiation conditions (for example NaBH 3 CN with catalytic acetic acid) in a protic solvent (such as MeOH), followed by removal of the indole carbamate with ammonia in methanol affords compounds of the structure 9-4.
  • amine 9-2 can be treated with acid chloride 9-5 in the presence of a tertiary amine (for example TEA) in an aprotic solvent (such as DCM), followed by removal of the indole carbamate with ammonia in methanol affords compounds of the structure 9-6.
  • a tertiary amine for example TEA
  • an aprotic solvent such as DCM
  • Scheme 11 describes the synthesis of compounds of the structure 11-2 and 11-4.
  • Boc-protected intermediate 11-1 can be treated with an acid (such as TFA) in an aprotic solvent (for example DCM) to provide compounds of the structure 11-2.
  • aprotic solvent for example DCM
  • Compounds 11-2 can be further elaborated under reductive aminiation conditions (for example NaBH 3 CN with acetic acid) in the presence of aldehyde 11-3 in a protic solvent (such as MeOH) to provide compounds of the structure 11-4.
  • reductive aminiation conditions for example NaBH 3 CN with acetic acid
  • aldehyde 11-3 such as MeOH
  • Scheme 12 outlines the synthesis of ethers 12-3 (wherein R is aryl or 5-6 membered heteroaryl).
  • Demethyaltion of compound 12-1 can be achieved by treatment with BBr3 in an aprotic solvent (such as DCM).
  • Alcohol 12-2 may then be treated with a copper(I) salt (such as Cul or CuBr), inorganic carbonate (for example cesium carbonate ), a ligand (such as 1,10-phenanthroline) and aromatic halide (for instance iodobenze or 3-bromopyridine) in an aprotic solvent (such as DMSO) at elevated temperatures (for instance 90 °C) to afford the corresponding ethers.
  • aprotic solvent such as DMSO
  • Scheme 13 details the synthesis of compound 13-4 and 13-5.
  • Treatment of intermediate 13-1 with an oxidizing agent (such as mCPBA) in an aprotic solvent (such as DCM) provides intermediate 13-2.
  • an oxidizing agent such as mCPBA
  • an aprotic solvent such as DCM
  • intermediate 13-2 may be stirred acetic anhydride at elevated temperatures (for example 100 °C) to afford intermediate 13-3.
  • Subsequent removal of the indole carbamate with ammonia in methanol affords compounds of the structure 13-5.
  • Scheme 14 describes the synthesis of tetrazole compounds 14-1.
  • Treatment of compound 6-1 with sodium azide, ammonium chloride and lithium chloride in a polar aprotic solvent (such as DMF) at elevated temperatures (for example 120 °C) affords compounds of the structure 14-1.
  • a polar aprotic solvent such as DMF
  • Scheme 15 describes the selective addition of amine 7-7 to compound 15-1.
  • Scheme 16 outlines the synthesis of alpha-halogenated ketones (intermediate 1-2).
  • Alpha-chloro keto derivatives of 1-2 can be generated from ester 16-1 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 16-2, 16-6 and 16-7.
  • Acid 16-2 can be purchased or obtained by hydrolysis of ester 16-1 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 16-2 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 16-6. The synthesis of intermediate 16-6 starts from nitrile 16- 3 or alcohol 16-4. Nitrile 16-3 can be treated with a reducing agent (such as DIBAL) an ethereal sovent (such as THF) to afford aldehyde 16-5.
  • a chlorinating agent such as thionyl chloride
  • alcohol 16-4 can be treated with an oxidizing agent (such as Dess-Martin Periodinane) in an aprotic solvent (such as DCM) to afford aldehyde 16-5.
  • an oxidizing agent such as Dess-Martin Periodinane
  • an aprotic solvent such as DCM
  • Addition of methyl magnesium bromide to Aldehyde 16-5 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 16-6.
  • Treatment of 16-6 under brominating conditions for example CuBr 2 in EtO Ac or Br 2 in the presence of catalytic HO Ac in DCM affords intermediate 1-2.
  • 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
  • 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 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. For example, 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.
  • Pharmaceutical compositions and dosage forms provided herein can also comprise one or more 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., flavored 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.
  • 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; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
  • Such 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.
  • 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.
  • 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 NaHC0 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 2 Preparation of l-bromo-3-phenylpropan-2-one
  • Step 1 Preparation of ethyl 2-((2-cyano henyl)(ethoxycarbonyl)amino)acetate
  • Step 5 Preparation of l-(4-methoxybenzyl)-3,4-dihydro-[l,4]diazepino[6,5-b]indole- 2,5(lH,6H)-dione
  • Step 6 Preparation of 5-bromo-l-(4-methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
  • Step 1 Preparation of tert-butyl (2-h droxyethyl)carbamate
  • Step 3 Preparation of tert-butyl (2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)amino)ethyl)carb
  • Step 1 Preparation of ethyl 3-amino- -nicotinoyl-lH-indole-l-carboxylate
  • Step 2 Preparation of ethyl 3-(2-bromoacetamido -2-nicotinoyl-lH-indole-l-carboxylate
  • Example 2 was prepared with substitution of 2-bromo-l-(pyridin-3- yl)ethanone hydrobromide
  • Example 1 Step 1 by 2-bromo-l-(3-bromophenyl)ethanone.
  • Step 1 Preparation of ethyl 3-(4-ethoxy-4-oxobutanamido)-2-nicotinoyl-lH-indole-l- carboxylate [00231] To a solution of ethyl 3-amino-2-nicotinoyl-lH-indole-l-carboxylate (600 mg, 1.94 mmol) and pyridine (1.23 g, 15.52 mmol) in DCM (50 mL) was added and ethyl 4-chloro-4- oxobutanoate (0.64 g, 3.88 mmol) in DCM (lOmL) dropwise at 0 °C.
  • the resulting oil was purified by flash column chromatography with a gradient elution of hexanes (25%) and EtOAc(75%) to hexanes (50%) and EtOAc (50%) to provide ethyl 3-(4-ethoxy-4- oxobutanamido)-2-isonicotinoyl-lH-indole-l-carboxylate (500mg, 1.14 mmol) as a white solid.
  • Step 2 Preparation of ethyl 2-oxo-5-(pyridin-3-yl)-l,2,3,6-tetrahydroazepino[3,2-b]indole-4- carboxylate
  • Example 47 was prepared by substitution of ethyl 3-amino-2- nicotinoyl-lH-indole-l-carboxylate in Example 46: Step 1 by ethyl 3-amino-5-fluoro-2- nicotinoyl- 1 H-indole- 1 -carboxylate.
  • Example 56 was prepared by substitution of Example 46 by Example 47.
  • Example 61 was prepared by substitution of Example 60 by Example 61. Table 4
  • Step 1 Preparation of 5-(2-fluoro-4-methoxyphenyl)-l-(4-methoxybenzyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
  • Example 66 was prepared by substitution of (2-fluoro-4- methoxyphenyl)boronic acid in Example 65 : Step 1 by m-tolylboronic acid.
  • Step 1 Prearation of methyl 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoate
  • Methyl 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoate was prepared according to the procedure described in Example 65 : Step 1 with substitution of (2-fluoro-4-methoxyphenyl)boronic acid by (2-fluoro- 4-(methoxycarbonyl)phenyl)boronic acid.
  • Step 2 Prearation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoic acid
  • Step 3 Preparation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzo l chloride
  • Step 4 Preparation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [ 1 ,4]diazepino[6,5-b]indol-5-yl)-N- 2-methoxyethyl)benzamide
  • Step 5 Preparation of 3-fluoro-N-(2-methoxyethyl)-4-(2-oxo-l ,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide
  • Step 1 Preparation of 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-l-(4-methoxybi dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 2 Preparation of 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 1 Preparation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide
  • Step 1 Preparation of tert-butyl 4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)piperidine- 1 -carboxylate
  • Step 5 Preparation of 5-(piperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 1 Preparation of ethyl 5-(3-methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
  • Ethyl 5-(3-methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)- carboxylate was prepared according to Example 1 : Steps 1 and 2 with substation of 2-bromo-l- (pyridin-3-yl)ethanone hydrobromide in Example 1 : Step 1 by 2-bromo-l-(3- methoxyphenyl)ethanone.
  • Step 2 Preparation of ethyl 5-(3-hydroxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
  • Step 3 Preparation of ethyl 2-oxo-5-(3-phenoxyphenyl)-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
  • Step 4 Preparation of 5-(3-phenoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 1 Preparation of ethyl 5-(3-aminophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole- 6(1 H)-carboxylate
  • Step 2 Preparation of ethyl 2-oxo-5-(3-(N-(phenylsulfonyl)phenylsulfonamido)phi dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate
  • Step 3 Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)phenyl)- N-(phenylsulfonyl)benzenesulfonamide
  • Step 4 Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)benzenesulfonamide
  • Step 1 Preparation of ethyl 5-(3-benzamidophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
  • Step 2 Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)benzamide
  • N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)phenyl)benzamide was prepared according to the procedure described in Example 81 : Step 3 with substitution of ethyl 2-oxo-5-(3-(N-(phenylsulfonyl)phenylsulfonamido)phenyl)-2,3-dihydro- [l,4]diazepino[6,5-b]indole-6(lH)-carboxylate by ethyl 5-(3-benzamidophenyl)-2-oxo-2,3- dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate.
  • Step 1 Preparation of ethyl 5-(3-(benzylamino)phenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
  • Step 2 Preparation of 5-(3-(benzylamino)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
  • the resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (25%) and hexanes (75%) to EtOAc (40%) and hexanes (60%) to provide 5-(3-(phenylsulfonyl)phenyl)-3,6- dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (4.2 mg, 0.01 mmol) as a yellow solid.
  • Step 1 Preparation of 5-(3-(chloromethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one and 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzyl
  • Step 2 Preparation of 5-(3-(methoxymethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
  • Example 91 was prepared with substitution of morpholine by imidazole.
  • Step 1 Preparation of (E)-N'-hydroxy-3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol- 5 -yl)benzimidamide
  • Step 2 Preparation of 5-(3-(5-thioxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 1 Preparation of tert-butyl (2-((3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-;
  • the reaction was degassed and purged with N 2 three times, then heated to 100 °C via MW irritation for 50 min.
  • Water (10 mL) and EtOAc (20 mL) were added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organics were dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo. The resulting oil was purified by flash column
  • Step 2 Preparation of 5-(4-((2-aminoethyl)amino)-2-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 2 Preparation of 2-oxo-5-phenyl-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indole 4-oxide
  • Step 1 Preparation of ethyl 3-acetoxy-2-oxo-5-phenyl-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
  • Step 2 Preparation of 3-hydroxy-5-phenyl-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 1 Preparation of 5-(2,4-difluorophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)- one
  • Step 2 Preparation of 5-(2-((2-aminoethyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
  • Step 1 Preparation of 5-(2-((3-aminopropyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
  • Example 104 Preparation of 5-(3-(lH-tetrazol-5-yl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
  • Example 105 In Vitro Cell-Based Assay For Modulation of the Activation of the P2X4 Purinergic Receptor
  • HEK-293 cells stably expressing human P2X4 purinergic receptor were grown in EMEM Minimum Essential Medium with Earle's Balanced Salt Solution (Lonza),
  • Plated cells were incubated for 24 hours at 37 °C under 5% C0 2 , 95% humidity, followed by a 30 min pre- incubated at room-temperature (RT).
  • the components of the Fluo-8 No Wash Calcium Assay kit (ABD Bioquest) were dissolved according to the instructions of the dye kit's manufacturer in the Tyrode's buffer (5 mM KC1, 130 mM NaCl, 2 mM CaCl 2 , 5 mM NaHC0 3 , 1 mM MgCl 2 , 20 mM HEPES, pH7.4).
  • test compound For measurement of the IC 50 value of test compound as a negative modulator of P2X4, the test compound was typically tested at 8 concentrations (30.00 ⁇ , 9.49 ⁇ , 3.00 ⁇ , 0.95 ⁇ , 0.30 ⁇ , 0.10 ⁇ , 0.03 ⁇ and 0.01 ⁇ ), and follow-up testing run at 8 concentrations (3.00 ⁇ , 0.95 ⁇ , 0.30 ⁇ , 0.10 ⁇ , 0.03 ⁇ , 0.01, ⁇ , 0.003 ⁇ , and 0.001 ⁇ ), in quadruplicate with intra-plate dose response curves.
  • a 96-well "master" plate with each compound in a single well (row A) was created, with a maximum of 10 compounds in the location of columns 2-11.
  • Test compound was typically added in a volume of 10 microliters as a dilution (in assay buffer) of a stock solution of test compound in
  • DMSO dimethylsulfoxide
  • the concentration response curve of a reference compound typically TNP-ATP
  • Table 7 shows biological data generated according to the assay disclosed herein.
  • Activity refers to a scale whereby “+” is an IC 50 of less than 1000 nM, "++” is 1000-10,000 nM, and "+++”is greater than 10,000 nM.

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Abstract

Provided herein are P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.

Description

P2X4 RECEPTOR MODULATING COMPOUNDS AND
METHODS OF USE THEREOF
I. FIELD
[0001] Provided herein are 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.
II. BACKGROUND
[0002] Chronic pain, neuropathy, inflammatory disorders and central nervous system (CNS) disorders are debilitating illnesses and remain a significant unmet medical need. Existing medications for the treatment of these conditions often do not provide complete relief, or do not provide relief in all patients.
[0003] Therefore, there is a great need for effective treatments of chronic pain, neuropathy, inflammatory diseases, and CNS disorders.
III. SUMMARY
[0004] Adenosine 5 '-triphosphate (ATP) 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). In addition, ATP may be released upon cell damage and from non-neural cells during mechanical deformation. Extracellular ATP signals through 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. Currently, 7 subtypes of P2X and 8 subtypes of P2Y receptors have been identified.
[0005] 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. Of note, 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.
[0006] Recent preclinical research suggests that P2X4R may be involved in neuropathic and inflammatory pain, including neuropathy-related hypersensitivity states (Trang, T.; Salter, M. Purinergic Signaling 2012, 8(3), 621). For neuropathic pain, the mechanism is believed to involve the consequences of activated microglia in the spinal cord, as P2X4R activation has been shown to result in calcium-mediated synthesis and release of brain-derived neurotrophic factor (BDNF), a key facilitator of nociceptive transmission (Inoue, K.; Tsuda, M. P2X4 Receptors of Microglia in Neuropathic Pain in CNS & Neurological Disorders - Drug Targets (2012), Vol. 11, p. 699-704). For example, in naive rats, intrathecal administration of ATP- stimulated microglia induced tactile hypersensitivity, which was reversed by a non-selective P2X1-4 antagonist. In addition, in nerve -injured rats, inhibition of P2X4R function by antisense oligodeoxynucleotides or non-selective pharmacological antagonism attenuated tactile hypersensitivity (Tsuda, M. et al. Nature 2003, 424, 778-783). In P2X4R knock-out mice, development of nerve injury- or inflammation-induced tactile hypersensitivity was reduced compared to wild-type animals (Ulmann et al. Neurosci. 2008, 28, 11263-11268; Tsuda, M. et al. Molecular Pain 2009, 5, 28). In addition, spinal BDNF signaling was impaired in knock-out versus wild-type mice (Ulmann et al. Neurosci. 2008, 28, 11263-11268). Furthermore, in a rat Spinal Nerve Ligation/Chung model, intrathecal administration of a reportedly selective P2X4R antagonist, NCP-308, attenuated tactile hypersensitivity (Nakata et al. J. Pharmacol. Sci. 2012, iiS(Suppl. 1), 146P). For inflammatory pain, the mechanism is believed to involve peripheral macrophages, on which P2X4R activation results in calcium-mediated synthesis and release of prostaglandin E2 (PGE2), a key inflammatory mediator. In P2X4R knock-out mice, 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). In addition, local PGE2 concentrations were reduced in knock-out versus wild- type mice (Ulmann et al. EMBO J. 2010, 29, 2290-2300).
[0007] Thus, inhibition of 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.
[0008] Thus, inhibition of 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. Further, 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. See Guo, L. H.; Schluesener, H. J. Neurosci. 2005, 134(1), 199-205; Zhang, Z. et al. Exp. Neurol. 2006, 197(1), 252-257; Cavaliere, F. et al. Neurosci. 2003, 120(1), 85-98; Guo, L. -H. et al. J. Neuroimmunol. 2004, 152(1-2), 67-72; Schwab, J. M. et al. J.
Neuroimmunol. 2005, 163(1-2), 185-189; Varma, R. et al. NueroMolecular Med. 2009, 11(2), 63-75.
[0009] Based on the foregoing, the inventors have discovered purinergic 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. In addition, the disclosed compounds have therapeutic benefit for a broad range of inflammatory disorders.
[0010] Provided herein are compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof:
[0011] In one aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
(I)
wherein A, L1, R1, R3, R4, R5, and n are defined as described herein.
[0012] In another aspect, disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0013] In another aspect, a method of treating a condition in a subject in need thereof is disclosed herein, the method 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, cardiac ischemia, allodynia, causalgia, post-herpetic neuralgia, hyperesthesia, hyperpathia, dysesthesia, fibromyalgia, causalgia, hyperalgesia, central nervous system disorders, sensory loss, arthritis and rheumatoid arthritis.
[0014] In another aspect, a method of inhibiting or modulating a purinergic P2X4 ion channel receptor (P2X4R) in a subject is disclosed herein, the method 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.
[0015] Disclosed herein are compounds that inhibit the function of a purinergic P2X4 ion channel receptor (P2X4R). In some embodiments, the compounds are purinergic P2X4R antagonists. In further embodiments, the compounds disclosed herein are purinergic P2X4R negative allosteric modulators. In some embodiments, the compounds disclosed herein are selective purinergic P2X4 ion channel receptor (P2X4R) antagonists. In further embodiments, the compounds disclosed herein are selective purinergic P2X4R negative allosteric modulators.
[0016] Also provided herein are 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.
[0017] Also provided herein are methods for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, and inflammatory diseases, using the compounds and compositions provided herein. In one embodiment, provided herein is a method of treating a condition selected from the group consisting of pain, central pain, peripheral inflammatory pain, neuropathic pain, neuropathy, inflammatory pain, inflammatory diseases, peripheral inflammatory conditions, multiple sclerosis, stroke, traumatic brain injury, asthma and diabetic neuropathy. In one embodiment, provided herein is a method of treating 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.
[0018] Also provided herein are methods of inhibiting or modulating a purinergic P2X4 ion channel receptor (P2X4R) in a subject by administering to the subject a compound or pharmaceutical composition provided herein. In some embodiments, the compound is a P2X4R antagonist. In some embodiments, the compound is a P2X4R negative allosteric modulator. In some embodiments, the compound or pharmaceutical composition is administered in combination with another agent or therapy. IV. DETAILED DESCRIPTION
[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art. In certain embodiments, abbreviations are as defined in J. Org. Chem. 2007, 72, 23 A. All publications and patents referred to herein are incorporated by reference herein in their entireties.
A. Definitions
[0020] As used in the specification and the accompanying claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.
[0021] As used herein, and unless otherwise indicated, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 12 (C1-12), 1 to 10 (Ci_io), or 1 to 6 (C1-6) 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 (C3_6) carbon atoms. As used herein, linear Ci_6 and branched C3-6 alkyl groups are also referred as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl
(including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, and t-butyl), pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, Ci_6 alkyl refers to a linear saturated monovalent
hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is optionally substituted as described herein elsewhere.
[0022] As used herein, and unless otherwise specified, the term "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. The term "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. For example, C2-6 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. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2_i5), 2 to 12 (C2-12), 2 to 10 (C2_io), or 2 to 6 (C2_6) carbon atoms, or a branched 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 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-l-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl. In certain embodiments, the alkenyl is optionally substituted as described herein elsewhere.
[0023] As used herein, and unless otherwise specified, the term "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. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C2_i5), 2 to 12 (C2_i2), 2 to 10 (C2_io), or 2 to 6 (C2_6) carbon atoms, or a branched 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 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH2C≡CH). For example, C2-6 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. In certain embodiments, the alkynyl is optionally substituted as described herein elsewhere.
[0024] As used herein, and unless otherwise specified, the term "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. In certain embodiments, 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 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl. In certain embodiments, the cycloalkyl is optionally substituted as described herein elsewhere.
[0025] As used herein, and unless otherwise specified, the term "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. In one embodiment, the heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. In one embodiment, 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. Examples include, but are not limited to, -CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2- CH3, -CH2-CH2-S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N- OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-O-CH3 and -CH2-0-Si(CH3)3. In certain embodiments, the heteroalkyl is optionally substituted as described herein elsewhere.
[0026] As used herein, and unless otherwise specified, the term "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. Examples of alkoxyl include, but are not limited to, -O-CH3, -O-CF3, -0-CH2-CH3, -O- CH2-CH2-CH3, -0-CH-(CH3)2, and -0-CH2-CH2-0-CH3. In one embodiment, the alkoxyl is optionally substituted as described herein elsewhere.
[0027] As used herein, and unless otherwise specified, the term "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-CH3, -N(CH3)2, -NH-CH2-CH3, -N(CH3)-CH2-CH3, -NH-CH-(CH3)2, -CH2-CH2-NH-CH3, and -CH2-CH2- N(CH3)2. In one embodiment, the aminoalkyl is optionally substituted as described herein elsewhere. In some embodiments, the aminoalkyl is optionally substituted with one or more halo.
[0028] As used herein, and unless otherwise specified, the term "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. In certain embodiments, 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). In certain embodiments, 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. In certain embodiments, the aryl is optionally substituted with one or more substituents as described herein elsewhere.
[0029] As used herein, and unless otherwise specified, the term "arylalkyl" or "aralkyl" refers to a monovalent alkyl group substituted with aryl. Example of aralkyl includes, but is not limited to, benzyl. In certain embodiments, both alkyl and aryl may be optionally substituted with one or more substituents as described herein elsewhere. [0030] As used herein, and unless otherwise specified, the term "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.
[0031] As used herein, and unless otherwise specified, the term "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. In one embodiment, 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. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In certain embodiments, 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. Examples of 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. Examples of bicyclic heteroaryl groups include, but are not limited to, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,
benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydroisoindolyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, β-carbolinyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents as described herein elsewhere. [0032] As used herein, and unless otherwise specified, the term "heterocycloalkyl" or "heterocyclyl" 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. In certain embodiments, 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. In certain embodiments, 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,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, when the heterocyclyl or heterocycloalkyl ring contains one or more O, the heterocyclyl or heterocycloalkyl may also be referred to as
"cycloalkoxyl." In certain embodiments, the heterocyclyl or heterocycloalkyl is optionally substituted with one or more substituents as described herein elsewhere.
[0033] As used herein, and unless otherwise specified, the term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and iodine.
[0034] As used herein, and unless otherwise specified, the term "hydrogen" encompasses proton (1H), deuterium (2H), tritium (3H), and/or mixtures thereof. In a compound described herein, one or more positions occupied by hydrogen may be enriched with deuterium and/or tritium. Such isotopically enriched analogs may be prepared from suitable isotopically labeled starting material obtained from a commercial source or prepared using known literature procedures.
[0035] As used herein, and unless otherwise specified, 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, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (b) halo, cyano (-CN), nitro (-N02), -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbRc, -ORa, - OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc, -OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, - OS(0)NRbRc, -OS(0)2NRbRc, -NRbRc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, - NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, - S(0)Ra, -S(0)2Ra, -S(0)NRbRc, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1. As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.
[0036] In one embodiment, each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)Re, -C(0)ORe, -C(0)NRfRg, - C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg, -OS(0)Re, - OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(0)ORh, - NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, - NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NRfRg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.
[0037] As used herein, and unless otherwise specified, 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 /?-toluenesulfonic.
[0038] As used herein, and unless otherwise specified, the term "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.
[0039] As used herein, and unless otherwise specified, the term "stereoisomer"
encompasses all enantiomerically/diastereomerically/stereomerically pure and enantiomerically/ diastereomerically/stereomerically enriched compounds provided herein.
[0040] As used herein and unless otherwise specified, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, 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.
[0041] As used herein and unless otherwise indicated, the term "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.
[0042] As used herein, and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having one chiral center.
[0043] In certain embodiments, as used herein, and unless otherwise specified, "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%. In certain embodiments, 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..
[0044] In describing an optically active compound, the prefixes 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
counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.
[0045] As used herein, and unless otherwise specified, the terms "selective purinergic P2X4R antagonists" and "selective purinergic P2X4R negative allosteric modulators" mean selective for the indicated target over other P2X isoforms. In certain embodiments, 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.
[0046] As used herein, and unless otherwise specified, 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
embodiments, 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.
[0047] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or
encapsulating material. In one embodiment, 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. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al. Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.
[0048] As used herein, and unless otherwise specified, the terms "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. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.
[0049] As used herein, and unless otherwise specified, the terms "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.
[0050] As used herein, and unless otherwise indicated, 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.
[0051] As used herein, and unless otherwise indicated, 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."
[0052] As used herein, and unless otherwise specified, 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.
[0053] As used herein, and unless otherwise specified, 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. The term
"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.
[0054] As used herein, and unless otherwise specified, 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.
[0055] As used herein, and unless otherwise specified, 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. [0056] As used herein, and unless otherwise specified, 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) and 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; and 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. 93-98 (Wilson et al. eds., 12th ed. 1991); Williams et al. J. Med. Chem. 1999, 42, 1481-1485, herein each incorporated by reference in their entirety). "Pain" is also meant to include mixed etiology pain, dual mechanism pain, allodynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia. In one embodiment, the term "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.
[0057] Unless otherwise specified, 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).
[0058] Unless otherwise specified, the term "neuropathic pain," as used herein, 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. Common types of peripheral neuropathic pain include diabetic neuropathy (also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP), post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Central 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.
[0059] As used herein, and unless otherwise specified, the term "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.
[0060] As used herein, and unless otherwise specified, the term "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.
[0061] As used herein, and unless otherwise specified, the term "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 PGE2 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.
[0062] As used herein, and unless otherwise specified, the term "visceral pain" refers to pain which is located in an internal organ.
[0063] As used herein, and unless otherwise specified, the term "mixed etiology pain" refers to pain that contains both inflammatory and neuropathic components.
[0064] As used herein, and unless otherwise specified, the term "dual mechanism pain" refers to pain that is amplified and maintained by both peripheral and central sensitization.
[0065] As used herein, and unless otherwise specified, the term "causalgia" refers to a syndrome of sustained burning, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes. [0066] As used herein, and unless otherwise specified, the term "central pain" refers to pain initiated by a primary lesion or dysfunction in the central nervous system.
[0067] As used herein, and unless otherwise specified, the term "hyperesthesia" refers to increased sensitivity to stimulation, excluding the special senses.
[0068] As used herein, and unless otherwise specified, the term "hyperpathia" 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, hyperalgesia, or dysesthesia.
[0069] As used herein, and unless otherwise specified, the term "dysesthesia" refers to an unpleasant abnormal sensation, whether spontaneous or evoked. In certain embodiments, dysesthesia include hyperalgesia and allodynia.
[0070] As used herein, and unless otherwise specified, the term "hyperalgesia" refers to an increased response to a stimulus that is normally painful. It reflects increased pain on suprathreshold stimulation.
[0071] As used herein, and unless otherwise specified, the term "allodynia" refers to pain due to a stimulus that does not normally provoke pain.
[0072] As used herein, and unless otherwise specified, the term "diabetic peripheral neuropathic pain" (DPNP), also called diabetic neuropathy, DN or diabetic peripheral neuropathy, refers to chronic pain caused by neuropathy associated with diabetes mellitus. The classic presentation of DPNP is pain or tingling in the feet that can be described not only as "burning" or "shooting" but also as severe aching pain. Less commonly, patients may describe the pain as itching, tearing, or like a toothache. The pain may be accompanied by allodynia and hyperalgesia and an absence of symptoms, such as numbness.
[0073] As used herein, and unless otherwise specified, the term "post-herpetic neuralgia", also called "postherpetic neuralgia" (PHN), refers to a painful condition affecting nerve fibers and skin. Without being limited by a particular theory, it is a complication of shingles, a second outbreak of the varicella zoster virus (VZV), which initially causes chickenpox.
[0074] As used herein, and unless otherwise specified, the term "neuropathic cancer 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).
[0075] As used herein, and unless otherwise specified, the term "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 HIV/AIDS.
[0076] As used herein, and unless otherwise specified, the term "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.
[0077] As used herein, and unless otherwise specified, the term "trigeminal neuralgia" (TN) refers to 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".
[0078] As used herein, and unless otherwise specified, the term "complex regional pain syndrome" (CRPS), formerly known as "reflex sympathetic dystrophy" (RSD), refers to a chronic pain condition whose key symptom is continuous, intense pain out of proportion to the severity of the injury, which gets worse rather than better over time. The term encompasses type 1 CRPS, which includes conditions caused by tissue injury other than peripheral nerve, and type 2 CRPS, in which the syndrome is provoked by major nerve injury, and is sometimes called causalgia.
[0079] As used herein, and unless otherwise specified, the term "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.
B. Compounds
[0080] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof is disclosed herein:
Figure imgf000019_0001
(I)
wherein: A is selected from N, N-oxide and CR2;
L1 is selected from a bond, Ci-C6 alkyl, and Ci-C6 haloalkyl;
R1 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 R6 substituents;
R2 is selected from hydrogen, halogen, CN, NR7R8, OR9, S02R9, S03R9, C(0)R9, C(0)OR9, C(0)NR7R8, Ci-C6 haloalkyl and Ci-C6 alkyl optionally substituted with one or more R10 substituents; each R3 is independently selected from halogen, CN, OR11, NR12R13, Ci-C6 haloalkyl, and Ci-C6 alkyl optionally substituted with one or more R14 substituents;
R4 and R5 are each independently selected from hydrogen, OH, NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, C3-C8 cycloalkyl, and 3- to 10-membered heterocyclyl; each R6 is independently selected from halogen, CN, N02, oxo, OR15, NR16R17, S02R15, S03R15, S02NR16R17, NR16S02R15, C(0)R15, OC(0)R15, C(0)OR15, C(0)NR16R17,
NR16C(0)R15, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C6 alkyl, C3-C8 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 R18 substituents;
R7 and R8 are each independently selected from hydrogen, S02R19, S03R19, SO2NR20R21, C(0)R19, C(0)OR19, C(0)C(0)R19, C(0)C(0)OR19, C(O)NR20R21, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-Cg cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10- membered heterocyclyl, wherein the Ci-C6 alkyl, C3-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 R22 substituents; or alternatively R7 and R8 taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, optionally substituted with one or more substituents each independently selected from halogen, oxo, Ci-C6 alkyl, and Ci-C6 haloalkyl;
R9 is selected from hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-C8 cycloalkyl, 6- to 14- membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C6 alkyl, C3-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
substituents; each R10 is independently selected from halogen, CN, OR24, NR25R26, S02R24, S03R24, S02NR25R26, C(0)R24, C(0)OR24, C(0)NR25R26, and NHC(0)R24; each R11, R15, R19, and R24 is independently selected from hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-Cg cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C6 alkyl, C3-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 substituents independently selected from halogen, CN, OR27, NR27R28, Ci-C6 alkyl, Ci-C6 haloalkyl, and phenyl;
each R12, R13, R16, R17, R20, R21, R25, and R26 is independently selected from hydrogen, C(0)Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the C(0)Ci-C6 alkyl, Ci-C6 alkyl, C3-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 substituents
independently selected from halogen, CN, OR27, NR27R28, Ci-C6 alkyl, C C6 haloalkyl, and phenyl; or alternatively any R12 and R13, R16 and R17, R20 and R21, or R25 and R26, taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with one or more substituents each independently selected from halogen, oxo, CN, OR27, NR27R28, C C6 haloalkyl, and C C6 alkyl; each R14 is independently selected from halogen, CN, OR27, NR27R28, C3-C8 cycloalkyl,
6- to 14-membered aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; each R 18 , R 22 , and R 23 is independently selected from halogen, CN, oxo, thione, OR 27 , NR27R28, C(0)R27, C(0)OR27, C(0)NR27R28, C C6 haloalkyl, C C6 alkyl, and C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; each R27 and R28 is independently selected from hydrogen, C(0)Ci-C6 alkyl, Ci-C6 alkyl, and Ci-C6 haloalkyl; n is 0, 1, 2, 3 or 4; and m is 1, 2 or 3. [0081] In some embodimetns, A is N. In further embodimetns, A is N-oxide. In still further embodimetns, A is CR2.
[0082] In some embodimetns, R2 is C1-C6 optionally substituted with one or more R10 substituents. In further embodiments, R2 is selected from methyl, ethyl, propyl, and isopropyl. In still further embodiments, R2 is Ci-C6 alkyl substituted with OH. In still further
embodiments, R2 is CN. In still further embodiments, R2 is halogen. In still further
embodiments, R2 is CI.
[0083] In some embodimetns, R2 is C(0)OR9, and R9 is selected from hydrogen and Ci-C6 alkyl. In further embodiments, R2 is hydrogen. In still further embodiments, R2 is NR7R8.
7 19 8 19
[0084] In some embodimetns, R is C(0)R , R is hydrogen, and R is 5- to 10-membered heteroaryl. In further embodimetns, R7 is selected from C(0)C(0)R19 and C(0)C(0)OR19, R8 is hydrogen, and R19 is Ci-C6 alkyl. In still further embodiments, R7 and R8 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-C6 alkyl.
[0085] In some embodimetns, Li is a bond. In further embodiments, Li is Ci-C6 alkyl.
[0086] In some embodimetns, R1 is selected from 6- to 14 membered aryl and 5- to 10- membered heteroaryl, each optionally substituted with one or more R6 substituents. In further embodiments, R1 is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, each optionally substituted with one or more R6 substituents. In still further embodimetns, R1 is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with one or more R6 substituents. In still further embodimetns, R1 is unsubstituted 6- to 14-membered aryl. In still further embodimetns, R1 is phenyl substituted with one or more R6 substituents, and each R6 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, C C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.
[0087] In some embodimetns, R6 is independently selected from fluoro, chloro, bromo, methoxy, methyl, CF3, and C(0)OCH3.
[0088] In some embodimetns, R1 is an unsubstituted 5- to 10-membered heteroaryl. In further embodiments, R1 is pyridyl. In still further embodiments, R1 is 2-pyridyl. In still further embodiments, R1 is 3-pyridyl. In still further embodimetns, R1 is 4-pyridyl.
[0089] In some embodimetns, R1 is pyridyl substituted with one or more R6 substituents, and each R6 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10- membered heterocyclyl. In further embodimetns, R6 is independently selected from fluoro, chloro, bromo, methoxy, methyl, CF3, and C(0)OCH3.
[0090] In some embodimetns, each R3 is independently selected from halogen, CN, Ci-C6 haloalkyl, and Ci-C6 alkyl optionally substituted with one or more R14 substituents.
[0091] In some embodimetns, n is 1. In further embodimetns, R3 is selected from F, CI, Ci-
C6 haloalkyl, and Ci-C6 alkyl. In still further embodiments, R3 is CI.
[0092] In some embodimetns, n is 0.
[0093] In some embodimetns, at least one of R4 and R5 is selected from OH, Ci-C6 alkyl, and Ci-C6 alkoxy. In further embodiments, at least one of R4 and R5 is selected from the group consisting of OH and Ci-C6 alkoxy. In still further embodiments, R4 and R5 are each hydrogen.
[0094] In some embodiments, the compound is a compound of formula (II), or a
pharmaceutically acceptable salt thereof:
Figure imgf000023_0001
[0095] In some embodiments, R3 is selected from the group consisting of F, CI, methyl, and methoxy.
[0096] In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000023_0002
[0097] In some embodiments, the compound is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:
Figure imgf000024_0001
(IV)
wherein
A, R3, R4, R5, and n are as defined herein;
each R29 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; and
p is 0, 1 , 2, 3, 4 or 5.
[0098] In some embodiments, R is
Figure imgf000024_0002
;
wherein
Y is S or O; and
R30 is selected from hydrogen and Ci-C6 alkyl.
[0099] In some embodiments, the compound is a compound of formula (Va), or a pharmaceutically acceptable salt thereof:
Figure imgf000024_0003
(Va)
wherein A, R3, R4, R5, R29, n, and p are as defined herein. [00100] In some embodiments, the compound is a compound of formula (Vb), or a pharmaceutically acceptable salt thereof:
Figure imgf000025_0001
wherein A, R3, R4, R5, R29, n, and p are as defined herein.
[00101] In some embodiments, the compound is a compound of formula (Vc), or a pharmaceutically acceptable salt thereof:
Figure imgf000025_0002
(Vc)
wherein A, R3, R4, R5, R29, n, and p are as defined herein.
[00102] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000026_0001
[00103] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000026_0002
[00104] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000026_0003
[00105] In another aspect, disclosed herein is the compound
Figure imgf000027_0001
pharmaceutically acceptable salt thereof.
[00106] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000027_0002
Figure imgf000028_0001
[00107] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000028_0002
[00108] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000029_0001
[00109] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000029_0002
Figure imgf000029_0003
[00111] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000030_0001
and 0 0 .
[00112] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000030_0002
Figure imgf000031_0001
[00113] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000031_0002
[00114] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000032_0001
[00115] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000032_0002
[00116] It should be noted that if there is a discrepancy between a depicted structure and a chemical name given that structure, the depicted structure is to be accorded more weight. In addition, if 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. Where 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. Where structural isomers are inter-convertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contains, for example, an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[00117] 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. In some instances, for compounds that undergo epimerization in vivo, one of skill in the art will recognize that administration of 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.
[00118] When 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).
[00119] 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, lauric acid, maleic acid, malic acid, (-)-L- malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene- 1, 5 -disulfonic acid, l-hydroxy-2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, pyroglutamic acid, pyroglutamic acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4- amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.
[00120] 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; and 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.
[00121] Unless otherwise specified, 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. In certain embodiments, the term "compound" referred to herein is intended to encompass a
pharmaceutical acceptable form of the compound, including but not limited to, a free base, a pharmaceutically acceptable salt, 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, a solvate {e.g., a hydrate), or a cocrystal thereof. In one embodiment, 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.
[00122] 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. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al. Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al. Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al. Pharm. Biotech. 1998, 11, 345-365; Gaignault et al. Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al. Ed., Marcell Dekker, 185-218, 2000; Balant et al. Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183- 209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, A dv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al. Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al. Methods Enzymol. 1985, 112, 360-381; Farquhar et al. J. Pharm. Sci. 1983, 72, 324-325; Freeman et al. J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al. Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al. Drugs 1985, 29, 455-73; Tan et al. Adv. Drug Delivery Rev. 1999, 39, 117-151; l&y\ox, Adv. Drug Delivery Rev. 1996, 19, 131-148;
Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; and Waller et al. Br. J. Clin. Pharmac. 1989, 28, 497-507.
C. Synthetic Schemes
[00123] Schemes below provide exemplary synthetic methods for the preparation of the compounds provided herein. One of ordinary skill in the art will understand that similar methods may be employed to prepare the compounds provided herein. In other words, one of ordinary skills in the art will recognize that suitable adjustments to reagents, protecting groups, reaction conditions, and reaction sequences may be employed to prepare a desired embodiment. The reactions may be scaled upwards or downwards to suit the amount of material to be prepared.
[00124] Compounds disclosed herein can be prepared according to Schemes 1-16. Scheme 1
Figure imgf000036_0001
[00125] Compounds can be prepared from intermediate 1-3 depicted in Scheme 1.
Intermediate 1-3 can be synthesized from commercially available 2-cyanno anilines 1-1 by first converting 1-1 into the corresponding ethyl carbamate by treatment with ethyl chloro formate in pyridine. Subsequent addition of an a-halogenated ketone 1-2 in the presence of a base (such as an inorganic carbonate, alkoxide, or basic tertiary amine) in an aprotic solvent (for example THF) affords intermediate 1-3 . From intermediate 1-3 compounds 1-5 and 1-7 can be synthesized as shown in Scheme 1. Compounds having the formula 1-5 can be synthesized by coupling of intermediate 1-3, according to Method A, with 2-bromoacetyl bromide in the presence of an inorganic base, such as potassium carbonate in an aprotic solvent, such as acetonitrile. Addition of ammonia in a protic solvent (such as MeOH) results in the cyclization and concomitant deprotection to provide compounds of the structure 1-5. Alternatively, compounds having the formula 1-7 can be synthesized by from intermediate 1-3 in a two-step procedure described by Method B. Treatment of intermediate 1-3 with ethyl 4-chloro-4- oxobutanoate in an aprotic solvent (such as DCM), followed by cyclization of the resulting amide using LiHMDS in THF affords compounds of the formula 1-7.
Scheme 2
Figure imgf000037_0001
Figure imgf000037_0002
2-7
[00126] Additionally, compounds of the structure 1-5 can be synthesized from intermediate 2-6 according to Scheme 2. Treatment of ethyl carbamate-protected 2-cyanno anilines with ethyl 2-bromoacetate in the presence of a base (such as inorganic carbonate) in an aprotic solvent (for example ACN) at elevated temperatures (for instance 50 °C) provides intermediate 2-2. Protection of amino indole 2-2 can be accomplished by addition of /?-methoxybenzyl chloride in the presence of a base (for example inorganic carbonate) in an aprotic solvent (such as DCM) at elevated temperatures (for instance 60 °C). Intermediate 2-4 can be synthesized by coupling of intermediate 2-3 with 2-bromoacetyl bromide in the presence of an inorganic base, such as potassium carbonate in an aprotic solvent, such as acetonitrile. Addition of ammonia in a protic solvent (such as MeOH) results in the cyclization and concomitant deprotection to provide intermediate 2-4. Treatment of intermediate 2-4 with phosphoryl tribromide at elevated temperatures (for example 120 °C) provides coupling partner 2-5. Coupling of intermediates 2- 5 and 2-6 can be accomplished under palladium mediated conditions with a palladium catalyst (such as Pd(OAc)2) in the presence of an appropriate ligand (for instance triphenylphosphine) and inorganic carbonate (such as sodium carbonate) in a water/ 1,4-dioxane mixture to provide compound 2-7. Compound 1-7 can be obtained by removal of the PMB group, which can be accomplished by stirring compound 2-7 in TFA at elevated temperatures (for example 120 °C).
Scheme 3
Figure imgf000038_0001
3-2
[00127] Scheme 3 outlines the synthesis alcohol and methyl derivatives 3-1 and 3-2 respectively. Treatment of compound 1-7 with a reducing agent (such as LAH or DIBAL) in an ethereal solvent (such as Et20 or THF) provides compounds of formula 3-1. Further reduction of compound 3-1 can be accomplished by treatment with triethyl silane in TFA to afford compounds of the formula 3-2.
Scheme 4
Figure imgf000038_0002
[00128] Scheme 4 outlines the synthesis of sulfones 4-3, sulfonamides 4-6 and sulfonates 4- 8; wherein Cyl is defined as either an aryl, heteroaryl or heterocylcoalkyl ring. Synthesis of compounds of structure 4-3 (wherein R8 is alkyl or aryl) can be derived from compound 4-1 (X = Br, I) by treatment of compound 4-1 with sodium sulfmate 4-2 in the presence of a copper(I) salt (such as Cul or CuBr), inorganic carbonate (for example CS2CO3) and a ligand (such as L- proline) in DMSO at elevated temperatures (for instance 80 °C). Alternatively, 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 N,N- 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). The resulting thioester is treated with a chlorinating agent (such as TCAA), phase transfer catalyst (for example BnNMesCl) and aqueous carbonate in acetonitrile to afford intermediate 4-4. Intermediate 4-4 is treated immediately with either amine 4-5 or alcohol 4-7 to provide 4-6 and 4-8 respectively.
Scheme 5
Figure imgf000039_0001
[00129] Scheme 5 outlines the synthesis of compounds of the formula 5-4. The synthesis of 5-4 begins with the hydrolysis of 5-1 (wherein Cyl can be either an aryl or heteroaryl ring and R6 is defined as CN or C02Et) using aqueous hydroxide in a protic from activation of acid 5-2 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 5-3. Scheme 6
Figure imgf000040_0001
[00130] Scheme 6 outlines the synthesis of heterocycles 6-3. Compound 6-2, can be synthesized by treating nitrile 6-1 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 6-2 with a reagent such as CDI or TCDI in an aprotic solvent (such as THF or ACN) at elevated temperatures (for instance 70 °C) affords compounds of the structure 6-4 (wherein Y = O or S).
Scheme 7
Figure imgf000041_0001
[00131] Scheme 7 outlines the synthesis of compounds of the formulas 7-6 and 7-8. The synthesis of 7-6 and 7-8 can be derived from the common intermediate 7-3, which can be obtained in two steps from ester 7-1. Treatment of compound 7-1 with a reducing agent (such as LAH or DIBAL) in an aprotic solvent (such as THF) provides alcohol 7-2. Activation of alcohol 7-2 with regents such as MsCl or SOCl2 in the presence of a tertiary amine (for example triethyl amine) in an aprotic solvent (such as DCM) affords intermediate 7-3 (wherein LG is OMs or CI). Treatment of intermediate 7-3 with alcohol 7-5 in the presence of the
corresponding alkoxide 7-4 provides compounds of the structure 7-6. Similarly, treatment of intermediate 7-3 with amine 7-7 in the presence of a tertiary amine (such as TEA) in an aprotic solvent (for example ACN) at elevated temperatures (for instance 80 °C) provides compounds of the structure 7-8. Scheme 8
Figure imgf000042_0001
8-1 8-3
[00132] Scheme 8 describes derivatization of compounds 8-1. Treatment of 8-1 with acid chloride 8-2 in the presence of a tertiary amine (for example TEA) in an aprotic solvent (such as DCM) affords compounds of the structure 8-3.
Scheme 9
Figure imgf000042_0002
[00133] Scheme 9 outlines the synthesis of substituted amines (9-4) and amides (9-6).
Reduction of nitro group in compound 9-1 can be accomplished by treatment with iron in the presence of aqueous ammonium chloride in a protic solvent (such as EtOH) at elevated temperatures (for example 100 °C). Amine 9-2 can then be treated with aldehyde 9-3 under reductive aminiation conditions (for example NaBH3CN with catalytic acetic acid) in a protic solvent (such as MeOH), followed by removal of the indole carbamate with ammonia in methanol affords compounds of the structure 9-4. Alternatively, amine 9-2 can be treated with acid chloride 9-5 in the presence of a tertiary amine (for example TEA) in an aprotic solvent (such as DCM), followed by removal of the indole carbamate with ammonia in methanol affords compounds of the structure 9-6.
heme 10
Figure imgf000043_0001
[00134] In a similar fashion, Scheme 10 outlines the synthesis of sulfonamides (10-3).
Treatment of amine 9-2 with sulfonyl chloride 10-1 in the presence of a tertiary amine (for example TEA) in an aprotic solvent (such as DCM), followed by removal of the indole carbamate with ammonia in methanol affords intermediate 10-2. Treatment of 10-2 with TBAF in an aprotic solvent (such as THF) provides compounds of the structure 10-3.
Scheme 11
Figure imgf000043_0002
[00135] Scheme 11 describes the synthesis of compounds of the structure 11-2 and 11-4. Boc-protected intermediate 11-1 can be treated with an acid (such as TFA) in an aprotic solvent (for example DCM) to provide compounds of the structure 11-2. Compounds 11-2 can be further elaborated under reductive aminiation conditions (for example NaBH3CN with acetic acid) in the presence of aldehyde 11-3 in a protic solvent (such as MeOH) to provide compounds of the structure 11-4.
Scheme 12
Figure imgf000043_0003
[00136] Scheme 12 outlines the synthesis of ethers 12-3 (wherein R is aryl or 5-6 membered heteroaryl). Demethyaltion of compound 12-1 can be achieved by treatment with BBr3 in an aprotic solvent (such as DCM). Alcohol 12-2 may then be treated with a copper(I) salt (such as Cul or CuBr), inorganic carbonate (for example cesium carbonate ), a ligand (such as 1,10-phenanthroline) and aromatic halide (for instance iodobenze or 3-bromopyridine) in an aprotic solvent (such as DMSO) at elevated temperatures (for instance 90 °C) to afford the corresponding ethers. Subsequent removal of the indole carbamate with ammonia in methanol affords compounds of the structure 12-3.
Scheme 13
Figure imgf000044_0001
13-4 13-5
[00137] Scheme 13 details the synthesis of compound 13-4 and 13-5. Treatment of intermediate 13-1 with an oxidizing agent (such as mCPBA) in an aprotic solvent (such as DCM) provides intermediate 13-2. Subsequent removal of the indole carbamate with ammonia in methanol affords compounds of the structure 13-4. Alternatively, intermediate 13-2 may be stirred acetic anhydride at elevated temperatures (for example 100 °C) to afford intermediate 13-3. Subsequent removal of the indole carbamate with ammonia in methanol affords compounds of the structure 13-5. Scheme 14
Figure imgf000045_0001
6-1 14-1
[00138] Scheme 14 describes the synthesis of tetrazole compounds 14-1. Treatment of compound 6-1 with sodium azide, ammonium chloride and lithium chloride in a polar aprotic solvent (such as DMF) at elevated temperatures (for example 120 °C) affords compounds of the structure 14-1.
Scheme 15
Figure imgf000045_0002
15-1 15-2
[00139] Scheme 15 describes the selective addition of amine 7-7 to compound 15-1.
Treatment of compound 15-1 with amine 7-7 in the presence of a base (for example TEA or potassium carbonate) in a aprotic solvent (such as ACN or 1 ,4-dioxane) at elevated
temperatures (for example 60 °C) affords compounds of the structure 15-2.
Scheme 16
oride Formation
Red
Figure imgf000046_0001
2) Oxidation
16-5 16-6
,Rn
HO
16-4
[00140] Scheme 16 outlines the synthesis of alpha-halogenated ketones (intermediate 1-2). Alpha-chloro keto derivatives of 1-2 can be generated from ester 16-1 by treatment with a strong base (such as LDA) in the presence of chloroiodomethane in an aprotic solvent (for example THF). Alternatively, alpha-bromo keto derivatives of 1-2 can be synthesized from intermediates 16-2, 16-6 and 16-7. Acid 16-2 can be purchased or obtained by hydrolysis of ester 16-1 using aqueous hydroxide in a protic solvent (for example ethanol). Formation of the acid chloride can be achieved by treatment of 16-2 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 16-6. The synthesis of intermediate 16-6 starts from nitrile 16- 3 or alcohol 16-4. Nitrile 16-3 can be treated with a reducing agent (such as DIBAL) an ethereal sovent (such as THF) to afford aldehyde 16-5. Furthermore, alcohol 16-4 can be treated with an oxidizing agent (such as Dess-Martin Periodinane) in an aprotic solvent (such as DCM) to afford aldehyde 16-5. Addition of methyl magnesium bromide to Aldehyde 16-5 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 16-6. Treatment of 16-6 under brominating conditions (for example CuBr2 in EtO Ac or Br2 in the presence of catalytic HO Ac in DCM) affords intermediate 1-2. D. Methods of Treatment, Prevention, and/or Management
1. Treatment, Prevention, and/or Management
[00141] In one aspect, a method of treating a condition in a subject in need thereof is disclosed herein, the method 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, cardiac ischemia, allodynia, causalgia, post-herpetic neuralgia, hyperesthesia, hyperpathia, dysesthesia, fibromyalgia, causalgia, hyperalgesia, central nervous system disorders, sensory loss, arthritis and rheumatoid arthritis.
[00142] In some embodiments, the condition is selected from the group consisting of pain; central pain; and peripheral pain.
[00143] In another aspect, a method of inhibiting or modulating a purinergic P2X4 ion channel receptor (P2X4R) in a subject is disclosed herien, the method 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.
[00144] In some embodiments, the compound is a P2X4R antagonist. In further
embodmients, the compound is a P2X4R negative allosteric modulator.
[00145] In some embodiments, the compound is administered in combination with another agent or therapy.
[00146] In some embodiments, 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. In one embodiment, provided herein is a method of treating, preventing, and/or managing one or more symptoms of chronic pain, neuropathy, inflammatory diseases and central nervous system disorders. In one embodiment, the method 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. In one embodiment, the subject is a human. In one embodiment, the subject is an animal. In one embodiment, the compounds provided herein are highly brain penetrable in the subject. In certain embodiments, the efficacious concentration of a compound provided herein is less than 10 nM, less than 100 nM, less than 1 μΜ, less than 10 μΜ, less than 100 μΜ, or less than 1 mM. In one embodiment, a compound's activity may be assessed in various art-recognized animal models as described herein elsewhere or known in the literature.
[00147] In some embodiments, without being limited by a particular theory, 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. For example, 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.
[00148] In some embodiments, 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. Non-limiting examples of such 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.
[00149] P2X4R antagonists or negative allosteric modulators are useful for mitigation of pain in neuropathic and/or inflammatory pain states.
[00150] Further, without being limited by a particular theory, 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.
[00151] In other embodiments, provided herein is a method of effecting a therapeutic effect as described herein elsewhere. The method comprises administering to a subject (e.g. , a mammal) a therapeutically effective amount of a compound or composition provided herein. 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.
[00152] 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).
[00153] In one embodiment, the compounds described herein treat, prevent, and/or manage a neurological disorder of the central nervous system, without causing addiction to said compounds.
[00154] Any suitable route of administration can be employed for providing the patient with a therapeutically or prophylactically effective dose of an active ingredient. For example, oral, mucosal (e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral (e.g. , intravenous, intramuscular), transdermal, and subcutaneous routes can be employed. Exemplary 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.
[00155] 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.
[00156] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount required. For example, 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.
[00157] In general, 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.
Generally, 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. In one embodiment, the oral dose of a compound provided herein will range from about 10 mg to about 300 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 20 mg to about 250 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 100 mg to about 300 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 10 mg to about 100 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 25 mg to about 50 mg per day. In another embodiment, 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.
[00158] In some embodiments, 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.
[00159] In some embodiments, the second active agent is an analgesic. In some
embodiments, the second active agent is an opioid analgesic, a non-opioid analgesic or an adjuvant analgesic.
[00160] In some embodiments, 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). In some embodiments, 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. [00161] In some embodiments, the second agent is an opioid analgesic. In some
embodiments, the second agent is morphine or a derivative thereof. In some embodiments, the second agent is selected from morphine, codeine, thebaine, hydrocodone, oxycodone, hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine,
benzylmorphine, ethylmorphine, dipropanoylmorphine, buprenorphine, pethidine, tramadol, methadone, fentanyl, alfentanil sufentanil, meperidine, dextropropoxyphene, tramadol, tapentadol, Hydrocodone/ Acetaminophen (Vicodin) and oxycodone/acetaminophen (Percoset), or a combination thereof.
[00162] In some embodiments, the second agent is an adjuvant analgesic. In some embodiments, 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. In some embodiments, 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, cannabidiol, nabilone, mexiletine, lidocaine, diclofenac, capsacin, doxepin, carisoprodol, cyclobenzaprine, metaxolone, calcitonin, and bisphosphonates (e.g., pamidronate, clodronate), or a combination thereof.
2. Pharmaceutical Compositions and Dosage Forms
[00163] In one aspect, a pharmaceutical composition is disclosed herein, comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[00164] Pharmaceutical 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. [00165] Pharmaceutical compositions and dosage forms provided herein can also comprise one or more additional active ingredients. Examples of optional second, or additional, active ingredients are also disclosed herein.
[00166] 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. Examples of 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.
[00167] The composition, shape, and type of dosage forms will typically vary depending on their use. For example, 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. Similarly, 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. These and other ways in which specific dosage forms are used will vary from one another and will be readily apparent to those skilled in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18th Ed., Mack Publishing, Easton PA (1990).
[00168] In one embodiment, pharmaceutical 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. For example, 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.
Consequently, provided are pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or disaccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
[00169] 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). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In one embodiment, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre- gelatinized starch, and/or magnesium stearate.
[00170] Also provided are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water {e.g., 5%) 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. In effect, water and heat accelerate the decomposition of some compounds. Thus, 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.
[00171] 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.
[00172] An 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.
[00173] Also provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
[00174] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. In one embodiment, 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.
[00175] In other embodiments, 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. Of course, 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,
(a) Oral Dosage Forms
[00176] Pharmaceutical 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., flavored syrups). Such 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).
[00177] 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. For example, 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. Examples of excipients suitable for use in solid oral dosage forms {e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[00178] In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another embodiment, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, 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.
[00179] For example, 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.
[00180] Examples of 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.
[00181] 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-103™ and Starch 1500 LM.
[00182] Examples of 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.
[00183] 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.
[00184] 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.
[00185] 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.
[00186] In one embodiment, 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.
(b) Controlled Release Dosage Forms
[00187] 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; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such 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. In one embodiment, provided are single unit dosage forms suitable for oral
administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
[00188] In one embodiment, controlled-release pharmaceutical products improve drug therapy over that achieved by their non-controlled counterparts. In another embodiment, the 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. In addition, 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.
[00189] In another embodiment, 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. In one embodiment, 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
physiological conditions or compounds,
(c) Parenteral Dosage Forms
[00190] 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. In some embodiments, 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.
Examples of 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.
[00191] 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
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 non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[00192] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. For example, 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,
(d) Topical and Mucosal Dosage Forms
[00193] Topical and mucosal dosage forms provided herein 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
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
[00194] Suitable excipients {e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. In one embodiment, 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).
[00195] The pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Also, 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. In other embodiments, 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. In other embodiments, salts, solvates, prodrugs, clathrates, or stereoisomers of the active ingredients can be used to further adjust the properties of the resulting composition.
3. Kits
[00196] In one embodiment, active ingredients provided herein are not administered to a patient at the same time or by the same route of administration. In another embodiment, provided are kits which can simplify the administration of appropriate amounts of active ingredients.
[00197] In one embodiment, a kit 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.
[00198] In other embodiments, 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.
[00199] Kits can further comprise cells or blood for transplantation as well as
pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, 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.
V. EXAMPLES
[00200] Certain embodiments are illustrated by the following non-limiting examples.
A. General Procedures for Compound Synthesis
[00201] In the examples below, unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents may be purchased from commercial suppliers, such as Sigma- Aldrich® Chemical Company, and may be used without further purification unless otherwise indicated. Reagents may also be prepared following standard literature procedures known to those skilled in the art. Solvents may be purchased from Sigma-Aldrich® in Sure-Seal® bottles and used as received. All solvents may be purified using standard methods known to those skilled in the art, unless otherwise indicated.
[00202] The reactions set forth below were done generally at ambient temperature, unless otherwise indicated. Unless otherwise specified, generally the reaction flasks were fitted with rubber septa for introduction of substrates and reagents via syringe. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel pre-coated plates and eluted with appropriate solvent ratios (v/v). Reactions were assayed by TLC or LC/MS, and terminated as judged by the consumption of starting material. Visualization of the TLC plates was done with UV light (254 wavelength) or with an appropriate TLC visualizing solvent, such as basic aqueous KMn04 solution activated with heat. Flash column chromatography (see, e.g., Still et al. J. Org. Chem., 43: 2923 (1978)) was performed using, for example, silica gel 60 or various MPLC systems (such as Biotage® or ISCO® separation systems).
[00203] The compound structures in the examples below were confirmed by one or more of the following methods: proton nuclear magnetic resonance spectroscopy, mass spectroscopy, elemental microanalysis, and melting point. Proton nuclear magnetic resonance (1H NMR) spectra were determined using a NMR spectrometer operating at 300 MHz field strength.
Chemical shifts are reported in parts per million (ppm, δ) downfield from an internal standard, such as TMS. Alternatively, 1H NMR spectra were referenced to signals from residual protons in deuterated solvents, for example, as follows: CDCI3 = 7.26 ppm; DMSO-d6 = 2.50 ppm; C6D6 = 7.16 ppm; CD3OD = 3.30 ppm. Peak multiplicities are designated, for example, as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using a mass spectrometer with APCI or ESI ionization.
Intermediate A: Preparation of ethyl 2-cyanophenyl)carbamate
Figure imgf000060_0001
[00204] To a solution of 2-aminobenzonitrile (10 g, 0.08 mol) in pyridine (50 mL) under ice bath was added ethyl chloroformate (13.7 g, 0.13 mol). The reaction mixture was stirred at rt for 50 min. Diluted hydrochloric acid (100 mL, 2 M) was added in dropwise until a pH of 5 was obtained. The solid was collected after filtration and dried to provide ethyl (2- cyanophenyl)carbamate (16 g, 51.9 mmol) as a white solid. GCMS [M]: 190. [00205] Alpha-halo ketone (1-2) coupling intermediates described in general Scheme 1 and Scheme 16 were either purchased or synthesized according to reaction conditions detailed below (Intermediates B-G).
Intermediate B: Preparation of 2-bromo-l-(2-fluoro-3-methoxyphenyl)ethanone
Step 1: Preparation of l-(2-fluoro-3-methox henyl)ethanol
Figure imgf000061_0001
[00206] Under N2 to a solution of 2-fluoro-3-methoxybenzaldehyde (2.0 g, 13 mmol) in anhydrous THF (30 mL) at 0 °C was added CH3MgBr (18 mL, 3M). The reaction was stirred at 0 °C for 3 h. Saturated NH4C1 solution (100 mL) was added to the reaction vessel and the mixture was washed with EtOAc (3 x 100 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide of l-(2-fluoro-3- methoxyphenyl)ethanol (2.58 g, 15.2 mmol) as a brown oil, which was used without further purification. GCMS [M]: 170.
Step 2: Preparation of l-(2-fluoro-3-methoxyphenyl)ethanone
Figure imgf000061_0002
[00207] To a solution of l-(2-fluoro-3-methoxyphenyl)ethanol (2.58 g, 15.2 mmol) in DCM (150 mL) was added Dess-Martin reagent (13 g, 30.5 mmol). The reaction was stirred at rt for 90 min. A saturated aqueous Na2C03 solution (100 mL) was added to the reaction mixture and the layers were separated. The aqueous phase was washed with DCM (3 x 100 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide l-(2-fluoro-3-methoxyphenyl)ethanone (2.2 g, 13.1 mmol) as a yellow solid, which was used without further purification. GCMS [M]: 168.
Step 3: Preparation of 2-bromo-l-(2-fluoro-3-methoxyphenyl)ethanone
Figure imgf000061_0003
[00208] To a solution of l-(2-fluoro-3-methoxyphenyl)ethanone (4.25 g, 25.27 mmol) in DCM (100 mL) was added Br2 (4.04 g, 25.27 mmol) and acetic acid (10 drops). The reaction mixture was cooled to 0 °C and stirred at that temperature for 4 h. Saturated aqueous Na2S203 (50 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 phase was washed with DCM (2 x 30 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (9%) and Hex (91%) to provide 2-bromo-l-(2-fluoro-3- methoxyphenyl)ethanone (6 g, 24.29 mmol) as a yellow oil . GCMS [M] = 246
Intermediate C: Preparation of 2-bromo-l-(pyridin-4-yl)ethanone hydrobromide
Figure imgf000062_0001
[00209] To a solution of l-(pyridin-4-yl)ethanone (1.0 g, 8.25 mmol) in HO Ac (60 mL) under ice bath was added aqueous HBr (1 mL, 48%) and Br2 (1.45 g, 9.1 mmol) in HO Ac (20 mL). The mixture was stirred at rt for 4 h during which time a precipitate formed. Filtration of the solid provided 2-bromo-l-(pyridin-4-yl)ethanone hydrobromide (0.72 g, 3.6 mmol) as a yellow solid. LCMS [M+H]+ = 200.1.
Intermediate D: Preparation of 2-bromo-l-(3-iodophenyl)ethanone
Figure imgf000062_0002
Step 1: Preparation of 3-iodobenzoyl chloride
Figure imgf000062_0003
[00210] To a solution of 3-iodobenzoic acid (10.0 g, 40.32 mmol) in was added thionyl chloride (57.56 g, 483.84 mmol). The reaction mixture was heated to reflux and stirred at that temperature for 1.5 h. The reaction was concentrated in vacuo to provide 3-iodobenzoyl chloride (5.2g, 19.5 mmol), which was used without further purification.
Step 2: Preparation of 2-bromo-l-(3-iodophenyl)ethanone
Figure imgf000062_0004
[00211] 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. In a separate vessel 3-iodobenzoyl chloride (5.2g, 19.5 mmol) was dissolved in anhydrous THF (30 mL). The diazomethane solution was introduced into the above 3-iodobenzoyl chloride solution via cannulation under positive N2 pressure at 0 °C. The 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 NaHC03 (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). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 2-bromo-l-(3- iodophenyl)ethanone (13.3 g, 40.93 mmol) as yellow solid. GCMS [M]: 324.
Intermediate E: Preparation of l-bro -3-phenylpropan-2-one
Step 1: Preparation of l-phenylpropan-
Figure imgf000063_0001
[00212] To a solution of iodobenzene (10.00 g, 49.02 mmol) in DMSO (150 mL) was added pentane-2,4-dione (14.72 g, 147.1 mmol), potassium phosphate (31.22 g, 147.1 mmol), water (7.95 g, 441.2 mmol) and copper(I) iodide (0.93 g, 4.90 mmol). The reaction then heated and kept at 90 °C overnight. After cooled to room temperature, 2 M aqueous HC1 (100 mL) was added into the reaction. The water phase was extracted with EtOAc (3 x 80 mL). The combined organics was washed with saturated aqueous NaCl (2 x 100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column
chromatography to provide l-phenylpropan-2-one (1.8 g, 13.42 mmol) as light yellow oil. GCMS [M] = 134
Step 2: Preparation of l-bromo-3-phenylpropan-2-one
Figure imgf000063_0002
[00213] To a solution of l-phenylpropan-2-one (2.60 g, 19.38 mmol) in AcOH (6.5 mL) was added Br2 (2.2 mL, 42.9 mmol) and a solution of hydrogen bromide (3.2 mL) in AcOH (10.6 mL). The reaction was stirred at ambient temperature for 6 h. After that acetone (34.3 mL) was added into the reaction. The reaction was stirred at ambient temperature for another 16 h. The reaction mixture was concentrated in vacuo. Then the reaction mixture was concentrated in vacuo. Water (50 mL) was added into the resulting oil. The water phase was extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography to provide l-bromo-3-phenylpropan-2-one (3.0 g, 14.08 mmol) as yellow oil. GCMS [M] = 212.
Intermediate F: Preparation of tert-butyl 4- 2-bromoacetyl)piperidine-l-carboxylate
Figure imgf000064_0001
[00214] To a solution of tert-butyl 4-acetylpiperidine-l-carboxylate (2.0 g, 8.8 mmol) in THF (50 mL) was added LHMDS (10.5 mL, 10.5 mmol) at -78 °C. The reaction was stirred at that temperature for 1 h. Then trimethyl chlorosilane (1.45 mL, 11.4 mmol) was added. The mixture was warmed to 0 °C and stirred at that room temperature for 30 min, then cooled to -78 °C again. Br2 (0.45 mL, 8.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred at that room temperature for 30 min. Saturated Na2S03 aqueous solution (30 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil (3.2 g) was directly used for the next step without further purification. LCMS [M+H]+ =306.1.
Intermediate G: Preparation of 2-chloro-l-(3-iodophenyl)ethanone
Figure imgf000064_0002
[00215] Under N2 at 0 °C to a solution of diisopropylamine (60.82 g, 601.05 mmol) in THF (400 mL) was added n-BuLi (206.08 mL, 515.19 mmol) in dropwise. The mixture was stirred at 0 °C for 1.5 h at which time it was added, dropwise, into a solution of methyl 3-iodobenzoate (45 g, 171.73 mmol) and chloroiodomethane (90.87 g, 515.19 mmol) in THF (300 mL) at -78 °C. The reaction was stirred at -78 °C for 3 h. The reaction mixture was poured into saturated aqueous NH4C1. The layers were separated and the aqueous layer was washed with EtOAc (3 x 80 mL). The combined organic layers were dried over Na2S04, concentrated and purified by flash column chromatography to provide 2-chloro-l-(3-iodophenyl)ethanone (25 g, 89.3 mmol) as yellow solid. GCMS [M]: 280.
[00216] For any intermediates B-G wherein a suitable precursor (aldehyde, ketone or ester) was not commercially available, aldehyde precursors were synthesized as detailed below (Intermediate H) Intermediate H: Preparation of 2-methylisonicotinaldehyde
Figure imgf000065_0001
[00217] Under a nitrogen atmosphere, to a solution of 4-bromo-2-methylpyridine (2.00 g, 11.63 mmol) in anhydrous Et20 (150 mL) was added t-butyllithium (0.82 g, 12.79 mmol) at -78 °C. The reaction was kept at that temperature for 30 min. Anhydrous DMF (0.85 g, 11.63 mmol) was added and the mixture was stirred at -78 °C for an additional 30 min. Saturated aqueous NH4C1 (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were washed with Et20 (6 x 50 mL). The combined organics were washed with saturated NaCl (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide 2-methylisonicotinaldehyde (lg, 8.3 mmol). GCMS [M] = 121
Intermediate I: Preparation of 5-bromo-l-(4-methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000065_0002
Step 1: Preparation of ethyl 2-((2-cyano henyl)(ethoxycarbonyl)amino)acetate
Figure imgf000065_0003
[00218] To a solution of ethyl 2-cyanophenylcarbamate (250 g, 1.32mol) and K2CO3 (1100 g, 7.92 mol) in ACN (2.5 L) which were placed in a 5L three-necked flask equipped with a mechanical stirrer was added ethyl 2-bromoacetate (242 g, 1.45 mol) in dropwise at r.t. over a period of lhr. The mixture was then stirred at 50 °C for 2 days. After cooled to room
temperature, the mixture was filtered. The filtrate was concentrated, re-dissolved in EtOAc, washed with brine (300 mL x 3), dried over anhydrous Na2S04 and concentrated. The resulting oil was purified by silica gel column to afford the desired product (283 g, 1.02 mol) as colorless oil. LCMS: [M+Na]+ =299.2 Step 2: Preparation of diethyl 3-amino-lH-indole-l,2-dicarboxylate
Figure imgf000066_0001
[00219] To a solution of ethyl 2-((2-cyanophenyl)(ethoxycarbonyl)amino)acetate (200 g, 0.725 mol) in ACN (2 L) which were placed in a 5L three-necked flask equipped with a mechanical stirrer was added K2CO3 (300 g, 2.17mol) in one portion at r.t. The mixture was stirred at 50 °C for 72 hrs. The reaction mixture was cooled to r.t., filtered and the filter cake was washed with DCM (1 x 500mL). The filtrate was concentrated, the resulting residue was dissolved in DCM (1 L), washed with brine (500mL x 2). The organic phase was dried over Na2S04 and concentrated to afford the desired product as a yellow solid (153 g, 0.513 mol). [M+Na]+ =299.2
Step 3: Preparation of diethyl 3-(4-methoxybenzylamino)-lH-indole-l,2-dicarboxylate
Figure imgf000066_0002
[00220] To a solution of diethyl 3-amino-lH-indole-l,2-dicarboxylate (300 g, 1.09 mol) and K2C03 (450 g, 3.27 mol, 3eq) in DCM(2 L) which were placed in a 5L three necked flask equipped with a mechanical stirrer was added l-(chloromethyl)-4-methoxybenzene (153 g, 0.98mol) in one portion at r.t. The mixture was then heated to 60 °C and stirred at that temperature for 3 days. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated and purified by silica-gel column to afford the desired product (40 g, 0.10 mol) as a white solid. LCMS: [M+Na]+ = 419.2. Step 4: Preparation of diethyl 3 -(2 -bromo-N-(4-methoxybenzyl)acetamido)-lH-indole- 1,2- dicarboxylate
Figure imgf000067_0001
[00221] To a solution of diethyl 3 -(4-methoxybenzylamino)-lH-indole- 1,2-dicarboxylate (7.5 g, 18.9 mmol) and K2C03 (7.8 g, 56.7mmol) in ACN (150mL) was added 2-bromoacetyl bromide (7.6 g, 37.8 mmol) via syringe at r.t. over a period of lmin. The reaction mixture was then filtered. The filtrate was concentrated, re-dissolved in DCM (200 mL) and washed with brine (100 mL x 2). The organic phase was dried over Na2S04, concentrated and the resulting residue was washed with MTBE (20mL) to afford the desired product (8.2 g, 15.9 mmol) as a white solid. LCMS: [M+H]+ =517.2.
Step 5: Preparation of l-(4-methoxybenzyl)-3,4-dihydro-[l,4]diazepino[6,5-b]indole- 2,5(lH,6H)-dione
Figure imgf000067_0002
[00222] To a solution of DCM/MEOH (1/2, 360 mL) placed in a 1L three necked flask was bubbled with NH3 for 3 hrs. Then diethyl 3-(2-bromo-N-(4-methoxybenzyl)acetamido)-lH- indole- 1,2-dicarboxylate (8.2 g, 15.8 mmol) was added in one portion. The reaction mixture was stirred for 3 days. After the solvent was removed until 1/10 volume, white solid was precipitated. After filtration, l-(4-methoxybenzyl)-3,4-dihydro-[l,4]diazepino[6,5-b]indole- 2,5(lH,6H)-dione (2.5 g, 7.5 mmol) was obtained as white solid. LCMS: [M+H]+ =336.2.
Step 6: Preparation of 5-bromo-l-(4-methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000067_0003
[00223] To a solution of l-(4-methoxybenzyl)-3,4-dihydro-[l,4]diazepino[6,5-b]indole- 2,5(lH,6H)-dione (500 mg, 1.49 mmol) in DCM (100 mL) was added phosphoryl tribromide (1.28 g, 4.47 mmol). The reaction mixture was heated to 120 °C and stirred at that temperature for 3 h. Saturated aqueous Na2C03 (100 mL) and MTBE (50mL) was added to the reaction vessel at 0°C and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was washed with MTBE (1 x 50mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo at 5°C to provide 5-bromo-l-(4-methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)- one (591 mg, 1.49 mmol) as a yellow solid, which was used immediately without further purification. TLC EtOAc : Hex (1 : 1) Rf = 0.85
Intermediate J: Preparation of tert-butyl (2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)amino)ethyl)carbamate
Figure imgf000068_0001
Step 1: Preparation of tert-butyl (2-h droxyethyl)carbamate
Figure imgf000068_0002
[00224] To a solution of 2-aminoethanol (3.00 g, 49.11 mmol) in DCM (200 mL) was added di-tert-butyl dicarbonate (12.86 g, 58.93 mmol) and triethylamine (14.91 g, 147.33 mmol). The reaction was stirred at ambient temperature for 16 h. Water (100 mL) was added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (5 x 100 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo to give tert- butyl (2-hydroxyethyl)carbamate (7.74 g, 48.10 mmol )as colorless oil, which was directly used for the next step without further purification. LCMS [M+H]+ = 162.1.
Step 2: Preparation of tert-butyl (2-oxoeth l)carbamate
Figure imgf000068_0003
[00225] To a solution of tert-butyl (2-hydroxyethyl)carbamate (4 g, 24.81 mmol) in DCM (200 mL) was added Dess-Martin reagent (12.62 g, 29.77 mmol) at 0 °C. The reaction was stirred at ambient temperature for 16 h. Saturated aqueous Na2C03 (80 mL) and Na2S203 (80 mL) were added to the reaction and stirred for lh. The resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (3 x 200 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and hexanes (90 %) to provide tert-butyl (2- oxoethyl)carbamate (2 g, 12.56 mmol) as a colorless oil. LCMS [M+H]+ = 160.1.
Step 3: Preparation of tert-butyl (2-((3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)amino)ethyl)carb
Figure imgf000069_0001
[00226] To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.00 g, 4.22 mmol) in DCM (50 mL) was added tert-butyl (2-oxoethyl)carbamate (1.34 g, 8.44 mmol), sodium triacetoborohydride (3.58 g, 16.88 mmol) and AcOH (0.4 mL). The reaction was stirred at ambient temperature for 24 h. Saturated aqueous NaHC03 (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the organic phase was extracted with DCM (3 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc (10%) and hexanes (90 %) to EtOAc (15%) and hexanes (85 %) to provide tert-butyl (2-((3- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)carbamate (620 mg, 1.63 mmol) as a colorless oil.
Example 1: Preparation of 5-(pyridin-3-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000069_0002
Step 1: Preparation of ethyl 3-amino- -nicotinoyl-lH-indole-l-carboxylate
Figure imgf000070_0001
[00227] To a solution of ethyl (2-cyanophenyl)carbamate (400 mg, 2.1 mmol) in DMF (30 mL) was added K2CO3 (0.87 g, 6.3 mmol). The mixture was stirred at r.t. for 30mins. To the stirred solution 2-bromo-l-(pyridin-3-yl)ethanone hydrobromide (0.65 g, 2.31 mmol) in DMF (5mL) was added dropwise at r.t. The reaction mixture was stirred at ambient temperature for 16 h. Saturated aqueous NaCl (45 mL) and EtOAc (lOOmL) were added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (2 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with an isocratic elution of hexanes (50%) and EtOAc (50%) to provide ethyl 3-amino-2-nicotinoyl-lH-indole-l- carboxylate (400 mg, 1.29 mmol) as a yellow solid.
Step 2: Preparation of ethyl 3-(2-bromoacetamido -2-nicotinoyl-lH-indole-l-carboxylate
Figure imgf000070_0002
[00228] To a solution of ethyl 3-amino-2-nicotinoyl-lH-indole-l-carboxylate (200 mg, 0.65 mmol) and K2CO3 (269 mg, 1.95 mmol) in ACN (30mL) was added 2-bromoacetyl bromide (263 mg, 1.3 mmol) via syringe at r.t. over a period of lmin. The reaction mixture was diluted with water (150 mL) and washed with EtOAc (3 x 50 ml). The combined organics were washed with brine (100 mL x 2), dried over Na2S04, concentrated in vacuo to afford ethyl 3-(2- bromoacetamido)-2-nicotinoyl-lH-indole-l-carboxylate (90 mg, 0.21 mmol) as a yellow oil. LCMS: [M+H]+ = 430.2. Step 3: Preparation of 5-(pyridin-3-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000071_0001
[00229] To a solution of ethyl 3-(2-bromoacetamido)-2-nicotinoyl-lH-indole-l-carboxylate (90 mg, 0.21 mmol) in methanol (50 mL) was bubbled with NH3 gas for 30 min at 0 °C. The reaction was stirred at ambient temperature for 16 h. The solvent was removed in vacuo. The resulting oil was purified by flash column chromatography to provide 5-(pyridin-3-yl)-3,6- dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (9 mg, 0.032 mmol) as an orange solid. 1H NMR (300 MHz, Methanol-d4) δ 8.82 (d, J = 1.6 Hz, 1H), 8.73 - 8.70 (m, 1H), 8.16 - 8.10 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.60 (dd, J = 5.1, 4.5 Hz, 1H), 7.40 (d, J = 0.6 Hz, 2H), 7.22 - 7.17 (m, 1H), 4.46 (s, 2H). LCMS [M+H]+ = 277.3.
[00230] The compounds listed in Table 1 were prepared according to procedure described in Example 1. For instance Example 2 was prepared with substitution of 2-bromo-l-(pyridin-3- yl)ethanone hydrobromide Example 1 : Step 1 by 2-bromo-l-(3-bromophenyl)ethanone.
Table 1
Figure imgf000072_0001
Figure imgf000073_0001
one IH), 4.25 (s, 2H), 2.39 (s, 3H).
Figure imgf000074_0001
one
Figure imgf000075_0001
one
Figure imgf000076_0001
one
Figure imgf000077_0001
one
Figure imgf000078_0001
Figure imgf000079_0001
one
Figure imgf000080_0001
Example : Preparaton o et y -oxo-5-pyr n- -y - , , , -tetra y roazepno , - b]indole-4-carboxylate
Figure imgf000080_0002
Step 1: Preparation of ethyl 3-(4-ethoxy-4-oxobutanamido)-2-nicotinoyl-lH-indole-l- carboxylate
Figure imgf000080_0003
[00231] To a solution of ethyl 3-amino-2-nicotinoyl-lH-indole-l-carboxylate (600 mg, 1.94 mmol) and pyridine (1.23 g, 15.52 mmol) in DCM (50 mL) was added and ethyl 4-chloro-4- oxobutanoate (0.64 g, 3.88 mmol) in DCM (lOmL) dropwise at 0 °C. The reaction was stirred at that temperature for 10 min. Saturated aqueous NaCl (20 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (3 x 20 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hexanes (25%) and EtOAc(75%) to hexanes (50%) and EtOAc (50%) to provide ethyl 3-(4-ethoxy-4- oxobutanamido)-2-isonicotinoyl-lH-indole-l-carboxylate (500mg, 1.14 mmol) as a white solid.
Step 2: Preparation of ethyl 2-oxo-5-(pyridin-3-yl)-l,2,3,6-tetrahydroazepino[3,2-b]indole-4- carboxylate
Figure imgf000081_0001
[00232] To a solution of ethyl 3-(4-ethoxy-4-oxobutanamido)-2-nicotinoyl-lH-indole-l- carboxylate (500 mg, 1.14 mmol) in anhydrous THF (50 mL) was added lithium
bis(trimethylsilyl)amide (4.56 mL, 4.56 mmol) at 0 °C under N2 atmosphere. The reaction was stirred at 0 °C for 5 min. Saturated aqueous NH4C1 (20 mL) and EtOAc (25 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 phase was extracted with EtOAc (3 x 25 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was washed with EtOAc (5 mL) and ether (2 x 5 mL) to provide ethyl 2-oxo-5- (pyridin-3-yl)-l,2,3,6-tetrahydroazepino[3,2-b]indole-4-carboxylate (100 mg, 0.29 mmol) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 8.61 (d, J = 3.5 Hz, 1H), 8.45 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.56 - 7.52 (m, 1H), 7.28 (d, J = 3.6 Hz, 2H), 7.16 - 7.12 (m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.46 (s, 2H), 0.94 (t, J = 7.1 Hz, 3H).LCMS [M+H]+ = 348.2.
[00233] The compounds listed in Table 2 were prepared according to procedure described in Example 46. For instance Example 47 was prepared by substitution of ethyl 3-amino-2- nicotinoyl-lH-indole-l-carboxylate in Example 46: Step 1 by ethyl 3-amino-5-fluoro-2- nicotinoyl- 1 H-indole- 1 -carboxylate. Table 2
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Example 55: Preparation of 4-(hydroxymethyl)-5-(pyridin-3-yl)-3,6-dihydroazepino[3,2- b]indol-2(lH)-one
Figure imgf000084_0002
[00234] To a solution of ethyl 2-oxo-5-(pyridin-3-yl)-l,2,3,6-tetrahydroazepino[3,2- b]indole-4-carboxylate (100 mg, 0.29 mmol) in anhydrous THF (20 mL) was added Lithium aluminum hydride (0.04 g, 1.16 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h. Water (5 mL) and NaOH (10% aq, 2 mL) were added to the reaction mixture. After filtration, the filtrate was transferred to a separatory funnel. The layers were separated with EtOAc (3 x 10 mL). The combined organics were washed with water, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of THF (30%) and hexane (70%) to THF (50%) and hexane (50%) to provide 4-(hydroxymethyl)-5-(pyridin-3-yl)-3,6-dihydroazepino[3,2-b]indol-2(lH)-one (20 mg, 0.07 mmol) as a white solid. 1H NMR (300 MHz, Methanol-d4) δ 8.60 - 8.54 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.27 - 7.21 (m, 2H), 7.13 - 7.10 (m, 1H), 4.13 (s, 2H), 3.21 (s, 2H). LCMS [M+H]+ = 306.3.
[00235] The compounds listed in Table 3 were prepared according to procedure described in Example 55. For instance Example 56 was prepared by substitution of Example 46 by Example 47.
Table 3
Figure imgf000085_0001
Figure imgf000086_0001
Example : Preparat on o -met y -5- pyr n- -y - , - y roazep no , - n o - H - one
Figure imgf000086_0002
[00236] To a solution of 4-(hydroxymethyl)-5-(pyridin-3-yl)-3,6-dihydroazepino[3,2- b]indol-2(lH)-one (20 mg, 0.07 mmol) in TFA (5 mL) was added triethylsilane (1 mL).The reaction was stirred at ambient temperature for 1 h. Saturated aqueous Na2CC"3 (20 mL) was added to the reaction vessel, which resulted in the formation of a precipitate. The solid was filtered, washed with water and diethyl ether to provide 4-methyl-5-(pyridin-3-yl)-3,6- dihydroazepino[3,2-b]indol-2(lH)-one (10 mg, 0.03 mmol) as a purple solid. 1H NMR (300 MHz, Methanol-d4) δ 8.55 (d, J = 3.6 Hz, 1H), 8.46 (s, 1H), 7.75 - 7.67 (m, 2H), 7.55 - 7.51 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 3.08 (s, 2H), 2.06 (s, 3H). LCMS [M+H]+ = 290.2.
[00237] The compounds listed in Table 4 were prepared according to procedure described in Example 60. For instance Example 61 was prepared by substitution of Example 60 by Example 61. Table 4
Figure imgf000087_0001
Example 65: Preparation of 5-(2-fluoro-4-methoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000088_0001
Step 1: Preparation of 5-(2-fluoro-4-methoxyphenyl)-l-(4-methoxybenzyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000088_0002
[00238] To a solution of 5-bromo-l-(4-methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one (100 mg, 0.25 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added (2-fluoro-4-methoxyphenyl)boronic acid (85 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (33 mg, 0.125 mmol) and Na2C03 (106 mg, 1 mmol) at rt under N2 atmosphere. The reaction was heated to 80°C and stirred at that temperature overnight. Water (20 mL) and EtOAc (25 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 phase was extracted with EtOAc (3 x 25 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hexanes (100 %) to EtOAc (25%) and hexanes (75 %) to provide 5-(2-fluoro-4-methoxyphenyl)-l-(4-methoxybenzyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (20 mg, 0.045 mmol) as a tan solid. LCMS [M+H]+ = 444.2. Step 2: Preparation of 5-(2-fluoro-4-methoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000089_0001
[00239] A solution of 5-(2-fluoro-4-methoxyphenyl)-l-(4-methoxybenzyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (20 mg, 0.045 mmol) in TFA (10 mL) was heated and kept under reflux in sealed tube for 6 h. Saturated aqueous Na2C03 (50 mL) and EtOAc (25 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 phase was extracted with EtOAc (3 x 25 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hexanes (100%) to EtOAc (40%>) and hexanes (60%>) to provide 5-(2-fluoro- 4-methoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (4.9 mg, 0.015 mmol) as a brown solid. 1H NMR (300 MHz, Methanol-d4) δ 7.79 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 8.5 Hz, 1H), 7.35 (d, J = 4.2 Hz, 2H), 7.18 - 7.12 (m, 1H), 6.91 (dd, J = 8.4, 2.1 Hz, 1H), 6.81 (dd, J = 9.6, 2.4 Hz, 1H), 4.39 (s, 2H), 3.88 (s, 3H). LCMS [M+H]+ = 324.3.
[00240] The compounds listed in Table 5 were prepared according to procedure described in Example 65. For instance Example 66 was prepared by substitution of (2-fluoro-4- methoxyphenyl)boronic acid in Example 65 : Step 1 by m-tolylboronic acid.
Table 5
Figure imgf000089_0002
Figure imgf000090_0001
V-o 6,5-b]indol- (s, 2H), 4.34 (s, 2H). 2(lH)-one
Example 72: Preparation of 3-fluoro-N-(2-methoxyethyl)-4-(2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide
Figure imgf000091_0001
Step 1: Prearation of methyl 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoate
Figure imgf000091_0002
[00241] Methyl 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoate was prepared according to the procedure described in Example 65 : Step 1 with substitution of (2-fluoro-4-methoxyphenyl)boronic acid by (2-fluoro- 4-(methoxycarbonyl)phenyl)boronic acid.
Step 2: Prearation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoic acid
Figure imgf000091_0003
[00242] To a solution of methyl 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoate (380 mg, 0.81 mmol) in THF (6 mL) was added an aqueous solution of KOH (1 N, 6 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was washed with DCM (20 mL) and the aqueous phase was acidified with 6N HC1 until a pH of 5 was achieved. The mixture was washed with DCM(5 x 25 mL) and the combined the organic layers were dried over Na2S04, filtered and concentrated to provide 3- fluoro-4-(l -(4-methoxybenzyl)-2-oxo- 1 ,2,3,6-tetrahydro-[ 1 ,4]diazepino[6,5-b]indol-5- yl)benzoic acid (250 mg, 0.54 mmol), which was used without further purification.
Step 3: Preparation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzo l chloride
Figure imgf000092_0001
[00243] To a solution of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoic acid (0.10 g, 0.22 mmol) in DCM (10 mL) was added thionyl chloride (3 ml, 41.6 mmol). The reaction mixture was heated to 80 °C and stirred at that temperature for 3 h. The reaction mixture was concentrated in vacuo to provide 3-fluoro-4-(l- (4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzoyl chloride (100 mg, 0.21 mmol), which was used immediately without purification.
Step 4: Preparation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [ 1 ,4]diazepino[6,5-b]indol-5-yl)-N- 2-methoxyethyl)benzamide
Figure imgf000092_0002
[00244] To a solution of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoyl chloride (0.21 g, 0.44 mmol) in DCM (10 mL) was added 2-methoxyethanamine (0.07 g, 0.88 mmol). The reaction was stirred at ambient temperature for 16 h. saturated aqueous Na2C03 (2 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaCl (1 x 2 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (50%) and hexanes(50%) to EtOAc (100%) to provide 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6- tetrahydro-[ 1 ,4]diazepino[6,5-b]indol-5-yl)-N-(2-methoxyethyl)benzamide (50mg, 0.09mmol) as a yellow solid.
Step 5: Preparation of 3-fluoro-N-(2-methoxyethyl)-4-(2-oxo-l ,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide
Figure imgf000093_0001
[00245] To a solution of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)-N-(2-methoxyethyl)benzamide (0.05 g, 0.10 mmol) in DCM (2ml) was added trifluoroacetic acid (2ml), trifluoromethanesulfomc acid (0.1ml) .The reaction mixture was heated to 50 °C and stirred at that temperature for 2 days. Saturated aqueous Na2C03 (20 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 phase was washed with EtOAc (3 x 20 mL) . The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by preparative thin layer chromatography with an isocratic elution of DCM (90%) and MeOH(10%) to provide 3-fluoro- N-(2-methoxyethyl)-4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzamide
(6mg, 0.02mmol) as a yellow solid . 1H NMR (300 MHz, Methanol-d4) δ 7.81 - 7.77 (m, 2H), 7.73 - 7.66 (m, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 4.38 (s, 2H), 3.50 (s, 4H), 3.30 (s, 3H). LCMS [M+H]+ = 395.2.
Example 73: Preparation of 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000094_0001
Step 1: Preparation of 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-l-(4-methoxybi dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000094_0002
[00246] To a solution of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoic acid (60 mg, 0.131 mmol) in DMF (lmL) was added pyrrolidine (0.019 g, 0.262 mmol), lH-benzo[d][l,2,3]triazol-l-ol (0.018 g, 0.131 mmol), triethylamine (0.040 g, 0.939 mmol) and EDCI (0.050 g, 0.262 mmol). The mixture was stirred at 40 °C for 16 h. Sat. NaCl (4 mL) was added to the reaction vessel and the mixture was washed with EtOAc (3 x 10 mL). The combined the organic layers were washed with sat. NaCl (5 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting solid was washed with Hex/EtOAc=30/l (15 mL) to provide 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-l-(4- methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (67 mg, 0.131), which was used without further purification. LCMS [M+H]+ = 511.4. Step 2: Preparation of 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000095_0001
[00247] To a solution of 5-(2-fluoro-4-(pyrrolidine-l-carbonyl)phenyl)-l-(4- methoxybenzyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (67 mg, 0.131 mmol) in TFA (2 mL) was added trifluoromethanesulfonic acid (0.024 g, 0.157 mmol). The reaction mixture was stirred at 35 °C for 48 h. The reaction mixture was concentrated in vacuo and water (8 mL) was added. The aqueous phase was washed with DCM (12 mL), and then treated with sat. Na2C03 until a pH of 8 was achieved. The mixture was washed with DCM (3 x 10 mL). The combined the organic layers were dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC to provide 5-(2-fluoro-4- (pyrrolidine-l-carbonyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (16 mg, 0.04 mmol). 1H NMR (300 MHz, CDC13) δ 8.72 (s, 1H), 8.22 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.49 - 7.31 (m, 4H), 7.27 - 7.23 (m, 1H), 4.61 (s, 2H), 3.66 (t, J = 6.7 Hz, 2H), 3.43 (t, J = 6.7 Hz, 2H), 2.03 - 1.91 (m, 4H). LCMS [M+H]+ = 391.1.
Example 74: Preparation of 3-fluoro-N,N-dimethyl-4-(2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide
Figure imgf000095_0002
[00248] Compound 74 was prepared according to the procedure outlined in 73 with substitution of pyrrolidine in Example 73: Step 1 by dimethyl amine. 1H NMR (300 MHz, DMSO-d6) 5 11.21 (s, 1H), 11.14 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.37 - 7.27 (m, 4H), 7.09 (td, J = 7.8, 1.8 Hz, 1H), 4.32 (s, 2H), 3.01 (s, 3H), 2.96 (s, 3H). LCMS [M+H]+ = 365.3.
Example 75: Preparation of 3-fluoro-4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzamide
Figure imgf000096_0001
Step 1: Preparation of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide
Figure imgf000096_0002
[00249] To a solution of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzoic acid (90 mg, 0.197 mmol) in DCM (2 mL) was added ethyl chloroformate (0.064 g, 0.591 mmol) and triethylamine (0.100 g, 0.985 mmol) under N2. The reaction mixture was stirred at rt for 3 h. Ammonium hydroxide (0.021 g, 0.591 mmol) was added and the reaction mixture was stirred at rt for an additional 16 h. The reaction mixture was concentrated in vacuo and the resulting solid was purified by flash column chromatography eluted with DCM: MeOH (50: 1) to DCM: MeOH 20: 1 to provide 3-fluoro-4-(l-(4- methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzamide (20 mg, 0.04 mmol). Step 2: Preparation of 3-fluoro-4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzamide
Figure imgf000097_0001
[00250] A solution of 3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide (20 mg, 0.04 mmol) in TFA (5 mL) was stirred at 110 °C for 72 h. The reaction mixture was concentrated in vacuo and water (lOmL) was added. The aqueous mixture was washed with DCM (9 mL). Saturated aqueous Na2C03 was added until a pH of 8 was achieved. The resulting mixture was washed with DCM/MeOH(20/l)(5 x 10 mL). The Combined the organic layers were dried over Na2S04, filtered and concentrated in vacuo to provide 3-fluoro-4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzamide (3 mg, 8.9 μιηοΐ). 1H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 11.15 (s, 1H), 8.18 (s, 1H), 7.87 - 7.83 (m, 2H), 7.76 (d, J = 11.1 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.30 (d, J = 5.7 Hz, 2H), 7.12 - 7.06 (m, 1H), 4.33 (s, 2H). LCMS [M+H]+ = 337.2.
Example 76: Preparation of 5-(piperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)- one
Figure imgf000097_0002
Step 1: Preparation of tert-butyl 4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)piperidine- 1 -carboxylate
Figure imgf000097_0003
[00251] Tert-butyl 4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)piperidine-l- carboxylate was prepared according to the procedure outlined in Example 1 with substitution of 2-bromo-l-(pyridin-3-yl)ethanone hydrobromidein example 1 : Step 1 by Intermediate F.
Step 5: Preparation of 5-(piperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000098_0001
[00252] To a solution of tert-butyl 4-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)piperidine-l -carboxylate (150 mg, 0.39 mmol) in DCM (8 mL) was added TFA (3 mL). The reaction was stirred at room temperature overnight. Saturated Na2C03 aqueous solution (30 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide 5-(piperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one (105 mg, 0.37 mmol). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J = 7.8 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.31 - 7.26 (m, 1H), 4.70 (s, 2H), 3.41 - 3.34 (m, 1H), 3.14 - 3.07 (m, 2H), 2.69 (t, J = 6.9 Hz, 2H), 1.96 - 1.77 (m, 4H). LCMS [M+H]+ = 283.3.
Example 77: Preparation of 5-(l-methylpiperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000098_0002
[00253] To a solution of 5-(piperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)- one (35 mg, 0.12 mmol) in CH3OH (5 mL) was added formaldehyde aqueous solution (37%, 39 mg, 0.48 mmol), NaBH3CN (15 mg, 0.24 mmol) and AcOH (11 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h. Saturated Na2C03 aqueous solution (20 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of DCM (100%) to DCM (98%) and CH30H (2%) to provide 5-(l- methylpiperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (13 mg, 0.044 mmol) as a solid. 1H NMR (300 MHz, Methanol-d4) δ 8.36 (d, J = 8.1 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.32 (t, J = 7.8 Hz, 1H), 4.94 (s, 2H), 3.56 - 3.44 (m, 3H), 3.03 - 2.87 (m, 2H), 2.86 (s, 3H), 2.71 - 2.58 (m, 2H), 2.08 - 1.98 (m, 2H). LCMS [M+H]+ = 297.3.
Example 78: Preparation of 5-(l-benzylpiperidin-4-yl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000099_0001
[00254] Compound 78 was prepared according to the procedure outlined in 77 with substitution of formaldehyde by benzaldehyde. 1H NMR (300 MHz, Methanol-d4) δ 8.35 (d, J = 7.9 Hz, 1H), 7.74 - 7.58 (m, 2H), 7.43 - 7.27 (m, 6H), 4.89 (s, 2H), 3.70 (s, 2H), 3.40 - 3.37 (m, 1H), 3.17 (d, J = 11.1 Hz, 2H), 2.42 - 2.20 (m, 4H), 2.00 - 1.96 (m, 2H). LCMS [M+H]+ = 373.3.
Example 79: Preparation of 5-(3-phenoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-
2(lH)-one
Figure imgf000099_0002
Step 1: Preparation of ethyl 5-(3-methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
Figure imgf000099_0003
[00255] Ethyl 5-(3-methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)- carboxylate was prepared according to Example 1 : Steps 1 and 2 with substation of 2-bromo-l- (pyridin-3-yl)ethanone hydrobromide in Example 1 : Step 1 by 2-bromo-l-(3- methoxyphenyl)ethanone.
Step 2: Preparation of ethyl 5-(3-hydroxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
Figure imgf000100_0001
[00256] To a solution of ethyl 5-(3-methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (150 mg, 0.4 mmol) in DCM (20 mL) was added BBr3 (1 mL, 10.6 mmol) in dropwise. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was treated with saturated aqueous Na2C03 until a pH of 8 was obtained. The biphasic solution was washed with DCM (3 x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo under reduced pressure to provide ethyl 5-(3- hydroxyphenyl)-2-oxo-2,3-dihydro-[l ,4]diazepino[6,5-b]indole-6(lH)-carboxylate (50 mg, 0.14 mmol) as green solid, which was used without further purification. LCMS: [M+H]+ = 364.2.
Step 3: Preparation of ethyl 2-oxo-5-(3-phenoxyphenyl)-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
Figure imgf000100_0002
[00257] To a solution of ethyl 5-(3-hydroxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (50 mg, 0.14 mmol) in DMSO (5 mL) was added iodobenzene (55 mg, 0.27 mmol), 1,10-phenanthroline (4 mg, 0.02 mmol), copper(I) iodide (4 mg, 0.02 mmol) and Cs2C03 (23 mg, 0.07 mmol). The reaction was stirred at 90 °C under nitrogen atmosphere overnight. Water (2 x 30 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography to provide ethyl 2-oxo- 5-(3-phenoxyphenyl)-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (9 mg, 0.02 mmol) as a white solid. LCMS: [M+H]+ = 440.2.
Step 4: Preparation of 5-(3-phenoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000101_0001
[00258] To a solution of ethyl 2-oxo-5-(3-phenoxyphenyl)-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (9 mg, 0.02 mmol) in MeOH (100 mL) was bubbled with NH3 gas for 30 min at 0 °C. The reaction mixture was then stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo. The resulting solid was purified by preparative TLC to provide 5-(3-phenoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (2.5 mg, 0.007 mmol) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 7.79 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.39 - 7.34 (m, 5H), 7.24 - 7.07 (m, 6H), 4.37 (s, 2H). LCMS [M+H]+ = 368.3
Example 80: Preparation of 5-(3-aminophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)- one
Figure imgf000101_0002
[00259] A solution of 5-(3-nitrophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (50 mg, 0.156 mmol; Example 36), Fe powder (222 mg, 3.96 mmol) and NH4Cl (5 mg, 0.094 mmol) in EtOH (2 mL) and H20 (2 mL) was stirred at 100 °C for 3 h. The reaction mixture was cooled to rt and diluted with water (60 mL), and filtered. The filtrate was washed with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2S04, concentrated and purified by flash column chromatography to provide 5-(3-aminophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (24 mg, 0.083 mmol). 1H NMR (300 MHz, Methanol-d4) δ 7.80 (d, J = 8.1 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.25 - 7.13 (m, 2H), 6.96 - 6.88 (m, 3H), 4.35 (s, 2H). LCMS [M+H]+ = 291.3.
Example 81: Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)benzenesulfonamide
Figure imgf000102_0001
Step 1: Preparation of ethyl 5-(3-aminophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole- 6(1 H)-carboxylate
Figure imgf000102_0002
[00260] A solution of ethyl 5-(3-nitrophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (140 mg, 0.357 mmol), Fe powder (600 mg, 10.7 mmol) and NH4Cl (15 mg, 0.214 mmol) in EtOH (10 mL) and H20 (10 mL) was stirred at 100 °C for 3 h. After cooled to room temperature, the reaction mixture was diluted with water (60 mL), filtered and the filtration was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2S04, concentrated and purified by silica-gel column chromatography to provide ethyl 5-(3-aminophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (115 mg, 0.318 mmol). LCMS [M+H]+ = 363.2. Step 2: Preparation of ethyl 2-oxo-5-(3-(N-(phenylsulfonyl)phenylsulfonamido)phi dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate
Figure imgf000103_0001
[00261] To a solution of ethyl 5-(3-aminophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (115 mg, 0.318 mmol) and Et3N (0.7 mL) in DCM (15 mL) at rt was added benzenesulfonyl chloride (62 mg, 0.349 mmol) in dropwise. The reaction mixture was then stirred at ambient temperature overnight, diluted with water (20 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were dried over Na2S04, concentrated and purified by silica-gel column to provide ethyl 2-oxo-5-(3-(N-
(phenylsulfonyl)phenylsulfonamido)phenyl)-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)- carboxylate (80 mg, 0.125 mmol). LCMS [M+H]+ = 643.2.
Step 3: Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)phenyl)- N-(phenylsulfonyl)benzenesulfonamide
Figure imgf000103_0002
[00262] To a solution of ethyl 2-oxo-5-(3-(N-(phenylsulfonyl)phenylsulfonamido)phenyl)- 2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (80 mg, 0.125 mmol) in MeOH (100 mL) was bubbled with NH3 gas at 0 °C for 30 min. The reaction mixture was then stirred at ambient temperature for 24 h. The reaction mixture was concentrated in vacuo. The resulting oil was diluted with water (20 mL), extracted with EtOAc (3 x 20 mL), dried over Na2S04 and concentrated to provide N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (63 mg, 0.11 mmol). LCMS [M+H] = 571.2.
Step 4: Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)benzenesulfonamide
Figure imgf000104_0001
[00263] To a solution of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide (63 mg, 0.11 mmol) in THF (12 mL) was added TBAF (433 mg, 1.65 mmol) at rt. The reaction mixture was then stirred at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na2S04 and purified by silica-gel column chromatography with a gradient elution of EtOAc (40%) and hexane (60%) to EtOAc (50%)) and hexane (50%>) to provide N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5- b]indol-5-yl)phenyl)benzenesulfonamide (17 mg, 0.039 mmol). 1H NMR (300 MHz, Methanol- d4) δ 7.82 - 7.77 (m, 3H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 - 7.33 (m, 8H), 7.20 - 7.15 (m, 1H), 4.36 (s, 2H). LCMS [M+H]+ = 431.3.
Example 82: Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)benzamide
Figure imgf000104_0002
Step 1: Preparation of ethyl 5-(3-benzamidophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
Figure imgf000105_0001
[00264] To a solution of ethyl 5-(3-aminophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (80 mg, 0.211 mmol) and Et3N (0.5 mL) in DCM (10 mL) at rt was added benzoyl chloride (0.03 mL, 0.232 mmol) in dropwise. The reaction mixture was then stirred at ambient temperature for 2 h, diluted with water (20 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were dried over Na2S04, concentrated to provide crude ethyl 5-(3-benzamidophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (93.2 mg, 0.20 mmol), which was used for the next step without further purification. LCMS [M+H]+ = 467.2.
Step 2: Preparation of N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)benzamide
Figure imgf000105_0002
[00265] N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)phenyl)benzamide was prepared according to the procedure described in Example 81 : Step 3 with substitution of ethyl 2-oxo-5-(3-(N-(phenylsulfonyl)phenylsulfonamido)phenyl)-2,3-dihydro- [l,4]diazepino[6,5-b]indole-6(lH)-carboxylate by ethyl 5-(3-benzamidophenyl)-2-oxo-2,3- dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate. 1H NMR (300 MHz, Methanol-d4) δ 8.00 - 7.92 (m, 3H), 7.82 (d, J = 8.2 Hz, 1H), 7.69 - 7.34 (m, 8H), 7.19 (dt, J = 6.6, 1.5 Hz, 1H), 4.41 (s, 2H). LCMS [M+H]+ = 395.4. Example 83: Preparation of 5-(3-(benzylamino)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000106_0001
Step 1: Preparation of ethyl 5-(3-(benzylamino)phenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
Figure imgf000106_0002
[00266] To a solution of ethyl 5-(3-aminophenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6(lH)-carboxylate (60 mg, 0.17 mmol) in CH3OH (10 mL) was added benzaldehyde (21 mg, 0.20 mmol), HO Ac (3 drops) and NaBH3CN (10.4 mg, 0.17 mmol). The reaction mixture was stirred at rt for 10 min. Na2C03 solution (30 mL) was added to the reaction vessel and the mixture was washed with EtOAc (3 x 30 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide crude ethyl 5-(3- (benzylamino)phenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (75 mg, 0.17 mmol). LCMS [M+H]+ = 453.3.
Step 2: Preparation of 5-(3-(benzylamino)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000106_0003
[00267] 5-(3-(benzylamino)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one was prepared according to the procedure described in Example 81 : Step 3 with substitution of ethyl 2-0X0-5 -(3 -(N-(phenylsulfonyl)phenylsulfo
b]indole-6(lH)-carboxylate by ethyl 5-(3-(benzylamino)phenyl)-2-oxo-2,3-dihydro- [l,4]diazepino[6,5-b]indole-6(lH)-carboxylate. 1H NMR (300 MHz, Methanol-d4) δ 7.78 (d, J = 8.2 Hz, 1H), 7.36 - 7.33 (m, 4H), 7.28 - 7.13 (m, 5H), 6.90 - 6.78 (m, 3H), 4.57 (s, 1H), 4.33 (s, 3H). LCMS [M+H]+ = 381.4.
Example 84: Preparation of 5-(3-(phenylsulfonyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000107_0001
[00268] To a solution of 5-(3-iodophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (100 mg, 0.25 mmol) in DMSO (3 mL) was added sodium benzenesulfmate (82 mg, 0.5 mmol), copper(I) iodide (9.5 mg, 0.05 mmol), L-proline (5.75 mg, 0.05 mmol) and cesiumcarbonate (162.9 mg, 0.5 mmol) under N2 atmosphere. The reaction mixture was heated to 150 °C and stirred at that temperature for 16 h. Saturated aqueous NaCl (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous was extracted with EtOAc/MeOH=10: l (4 x 25 mL). The organic phase was washed with saturated aqueous NaCl (1 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (25%) and hexanes (75%) to EtOAc (40%) and hexanes (60%) to provide 5-(3-(phenylsulfonyl)phenyl)-3,6- dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (4.2 mg, 0.01 mmol) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 8.26 (d, J = 1.8 Hz, 1H), 8.14 (dd, J = 7.8, 0.9 Hz, 1H), 8.02 - 7.99 (m, 2H), 7.90 - 7.89 (m, 1H), 7.84 - 7.81 (m, 1H), 7.74 - 7.71 (m, 1H), 7.69 - 7.64 (m, 1H), 7.61 - 7.56 (m, 2H), 7.39 - 7.35 (m, 2H), 7.22 - 7.16 (m, 1H), 4.43 (s, 2H). LCMS [M+H]+ = 416.4. Example 85: Preparation of 9-chloro-5-(3-(methylsulfonyl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000108_0001
[00269] To a solution of 9-chloro-5-(3-iodophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one (0.05 g, 0.11 mmol) in DMSO (2 mL) was added sodium methanesulfmate (0.02 g, 0.22 mmol), Cuprous Iodide (3.8mg, 0.02mmol) and L-Proline (2.6mg, 0.02mmol). The reaction was irritated by microwave at 80°C for 30 min. Water (20 mL) was added to the reaction vessel. The resulting mixture was extracted with EtOAc (4 x 25 mL), the combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with an gradient elution of hexanes (85%) and EtOAc(15%) to hexanes (40%) and EtOAc (60%) to provide 9-chloro-5-(3- (methylsulfonyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (8.2 mg, 0.02 mmol) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 11.06 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.35 - 7.31 (m, 1H), 4.34 (s, 2H), 3.25 (s, 3H). LCMS [M+H]+ = 388.2.
Example 86: Preparation of 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzoic acid
Figure imgf000108_0002
[00270] To a solution of methyl 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzoate (100 mg, 0.3 mmol) in THF (5 mL) and H20 (2 mL) was added LiOH. H20 (76 mg, 1.8 mmol). The reaction was stirred at room temperature overnight. Water (20 mL) was added. The mixture was adjusted to pH 2 using 2M HCl and then extracted with EtOAc (3 x 50 mL). The aqueous layers were concentrated to 5 mL in vacuo and the yellow solid was precipitated. After filtration, the filter cake was washed with H20 (2 x 5 mL) and then dried to provide 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzoic acid (58 mg, 0.18 mmol) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 12.18 (s, 1H), 11.80 (s, 1H), 8.35 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.22 (t, J = 7.5 Hz, 1H), 4.94 (s, 2H). LCMS
[M+H]+ = 320.3.
Example 87: Preparation of 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzamide
Figure imgf000109_0001
[00271] To a solution of 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzoic acid (35 mg, 0.11 mmol) in DCM (5 mL) was added Et3N (0.3 mL, 2.1 mmol). Then ethyl chloroformate (48 mg, 0.44 mmol) was added. The reaction was stirred at room temperature for 30 min. After cooled to 0 °C, the reaction mixture was bubbled with NH3 for 10 min. Then the reaction was stirred at room temperature overnight. After filtration, a pale yellow solid was obtained, which was purified by flash column chromatography with a gradient elution of EtOAc (100%) to EtOAc (99%) and CH30H (1%) to provide 3-(2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzamide (11 mg, 0.035 mmol) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.27 (s, 1H), 11.03 (s, 1H), 8.15 (s, 1H), 8.07 - 8.01 (m, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 6.9 Hz, 1H), 7.11 (t, J = 7.1 Hz, 1H), 4.30 (s, 2H). LCMS [M+H]+ = 319.3.
Example 88: Preparation of 5-(3-(hydroxymethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000109_0002
[00272] To a solution of methyl 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzoate (1.0 g, 3.0 mmol) in anhydrous THF (20 mL) was added Lithium aluminum hydride (0.22 g, 6.0 mmol) at 0 °C in three portions. After the reaction was kept for 30 min, additional Lithium aluminum hydride (500 mg, 13.6 mmol) was added. The reaction was then stirred at 0 °C for another 2 h. Saturated NH4C1 aqueous was added to the reaction mixture. After filtration, the filtrate was transferred to a separatory funnel. The layers were separated with EtOAc (4 x 100 mL). The combined organics were washed with water, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (30%) and hexane (70%) to EtOAc (99%) and MeOH (1%) to provide 5-(3-(hydroxymethyl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (400 mg, 1.31 mmol) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 11.26 (s, 1H), 10.96 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.52 - 7.27 (m, 5H), 7.10 (t, J = 7.2 Hz, 1H), 5.25 (t, J = 5.7 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.26 (s, 2H). LCMS[M+H]+ = 306.3.
Example 89: Preparation of 5-(3-(methoxymethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000110_0001
Step 1: Preparation of 5-(3-(chloromethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one and 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzyl
methanesulfonate
Figure imgf000110_0002
[00273] To a solution of 5-(3-(hydroxymethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one (350 mg, 1.15 mmol) in DCM (150 mL) was added Et3N (0.24 mL, 1.73 mmol). The reaction was cooled to 0°C and stirred at that temperature for 5 min. Then methanesulfonyl chloride (158 mg, 1.38 mmol) in DCM (1 mL) was added. The reaction was warmed to room temperature and stirred for 4 h. Water (50 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 extracted with DCM (3 x 100 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc (50%) and Hex (50%) to EtOAc to provide 5-(3-(chloromethyl)-phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (60 mg, 0.19 mmol) as a white solid and 3-(2-oxo- 1,2,3, 6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzyl methanesulfonate (30 mg, 0.078 mmol) as a white solid.
Step 2: Preparation of 5-(3-(methoxymethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000111_0001
[00274] To a solution of 5-(3-(chloromethyl)-phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one (60 mg, 0.19 mmol) in CH30H (5 mL) was added CH30Na (31 mg, 0.57 mmol). The reaction was stirred at reflux for 1 h. Water (20 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting pale yellow solid was washed with EtOAc to provide 5-(3- (methoxymethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (4 mg, 0.013 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.52 (m, 1H), 7.47 - 7.45 (m, 2H), 7.39 - 7.37 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.45 (s, 2H), 4.25 (s, 2H), 3.28 (s, 3H). LCMS [M+H]+ = 320.3.
Example 90: Preparation of 5-(3-(morpholinomethyl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000112_0001
[00275] To a solution of 3-(2-oxo- ,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzyl methanesulfonate (20 mg, 0.052 mmol) in ACN (5 mL) was added Et3N (20 mg, 0.198 mmol) and morpholine (14 mg, 0.156 mmol). The reaction was heated to 80°C and stirred at that temperature for 1 h. Water (30 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (4 x 30 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc (50%) and Hex (50%) to EtOAc to provide 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzyl methanesulfonate (4 mg, 0.011 mmol) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.98 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.46 - 7.28 (m, 5H), 7.08 (t, J = 7.2 Hz, 1H), 4.27 (s, 2H), 3.54 - 3.47 (m, 6H), 2.43 - 2.38 (m, 4H). LCMS [M+H]+ = 375.2.
[00276] The compounds listed in Table 6 were prepared according to the procedure described in Examples 90. For instance Example 91 was prepared with substitution of morpholine by imidazole.
Table 6
Figure imgf000112_0002
Figure imgf000113_0001
Example : Preparat on o N-met y -N- - -oxo- , , , -tetra y ro- , azep no ,5- b]indol-5-yl)benzyl)acetamide
Figure imgf000113_0002
[00277] To a solution of 5-(3-((methylamino)methyl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (15 mg, 0.047 mmol; Example 93) in DCM (10 mL) and N,N-Dimethylacetamide (2 mL) was added Et3N (20 mg, 0.198 mmol) and acetyl chloride (7.4 mg, 0.094 mmol). The reaction was stirred at room temperature for 20 min. Water (20 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (4 x 30 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc (50%) and Hex (50%) to EtOAc (99%) and CH30H (1%) to provide N-methyl-N-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)benzyl)acetamide (8 mg, 0.022 mmol) as a white solid. 1H NMR (300 MHz, Methanol-d4) δ 7.82 (d, J = 8.1 Hz, 1H), 7.62 - 7.45 (m, 4H), 7.38 - 7.37 (m, 2H), 7.20 - 7.15 (m, 1H), 4.70 - 4.66 (m, 2H), 4.41 - 4.40 (m, 2H), 3.04 - 2.75 (m, 3H), 2.20 - 2.13 (m, 3H). LCMS [M+H]+ = 361.3.
Example 95: Preparation of 5-(3-(5-thioxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-3,6- dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000114_0001
Step 1: Preparation of (E)-N'-hydroxy-3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol- 5 -yl)benzimidamide
Figure imgf000114_0002
[00278] To a solution of 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzonitrile (120 mg, 0.4 mmol; Example 60) in 1,4-dioxane (9 mL) was added
hydroxylamine hydrochloride (28 mg, 0.4 mmol) and NaHC03 (33.6 mg, 0.4 mmol) which was dissolved in H20 (6 mL). The reaction mixture was stirred overnight. H20 (20 mL) and EtOAc (30 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 (3 x 30 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide crude (E)-N'-hydroxy-3-(2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)benzimidamide (133.6 mg, 0.4 mmol), which was directly used for the next step without purification. LCMS [M+H]+ = 334.3. Step 2: Preparation of 5-(3-(5-thioxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000115_0001
[00279] To a solution of (E)-N'-hydroxy-3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5- b]indol-5-yl)benzimidamide (85 mg, 0.26 mmol) in ACN (15 mL) and THF (10 mL) was added TCDI (190 mg, 1.07 mmol). The reaction mixture was stirred at 70 °C overnight. After concentration, the resulting oil was purified by preparative HPLC to provide 5-(3-(5-thioxo-4,5- dihydro-1 ,2,4-oxadiazol-3-yl)phenyl)-3,6-dihydro-[l ,4]diazepino[6,5-b]indol-2(lH)-one (38 mg, 0.10 mmol) as yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.85 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 4.48 (s, 2H). LCMS [M+H]+ = 376.2.
Example 96: Preparation of 3-(3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)phenyl)- 1 ,2,4-oxadiazol-5(4H)-one
Figure imgf000115_0002
[00280] To a solution of (E)-N'-hydroxy-3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5- b]indol-5-yl)benzimidamide (140 mg, 0.42 mmol) in DCM (25 mL) and THF (5 mL) was added CDI (136 mg, 0.84 mmol). The reaction mixture was stirred at 70 °C overnight. After concentration, the resulting oil was purified by silica-gel column to provide 3-(3-(2-oxo-l,2,3,6- tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)phenyl)-l,2,4-oxadiazol-5(4H)-one (27 mg, 0.075 mmol) as an orange solid. 1H NMR (300 MHz, Methanol-d4) δ 8.24 - 8.20 (m, 2H), 8.07 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 4.48 (s, 2H). LCMS [M+H]+ = 360.2. Example 97: Preparation of 5-(4-((2-aminoethyl)amino)-2-fluorophenyl)-3,6-dihydro- [l ,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000116_0001
Step 1: Preparation of tert-butyl (2-((3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-;
tetrahydro-[l ,4]diazepino[6,5-b]indol-5- l)phenyl)amino)ethyl)carbamate
Figure imgf000116_0002
[00281] To a solution of 5-bromo-l-(4-methoxybenzyl)-3,6-dihydro-[l ,4]diazepino[6,5- b]indol-2(lH)-one (0.32 g, 0.80 mmol, Intermediate I) in dioxane (6 mL) was added tert-butyl (2-((3-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)carbamate (0.30 g, 0.80 mmol, Intermediate J), sodium carbonate (0.17 g, 1.60 mmol) in H20 (lmL) and Tetrakis(triphenylphosphine)palladium (0.05 g, 0.04 mmol). The reaction was degassed and purged with N2 three times, then heated to 100 °C via MW irritation for 50 min. Water (10 mL) and EtOAc (20 mL) were added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column
chromatography with a gradient elution of EtOAc (50%) and hexanes (50%) to EtOAc and preparative HPLC to give tert-butyl (2-((3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l ,2,3,6- tetrahydro-[l,4]diazepino[6,5-b]indol-5-yl)phenyl)amino)ethyl)carbamate (35 mg, 0.06 mmol ) as a yellow solid. LCMS [M+H]+ = 572.2.
Step 2: Preparation of 5-(4-((2-aminoethyl)amino)-2-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000117_0001
[00282] To tert-butyl (2-((3-fluoro-4-(l-(4-methoxybenzyl)-2-oxo-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indol-5-yl)phenyl)amino)ethyl)carbamate (35 mg, 0.06 mmol) was added 2,2,2-trifluoroacetic acid (5 mL). The reaction mixture was heated to 100 °C in a sealed tube and stirred at that temperature for 4 days. The solution was concentrated in vacuo. To the resulting oil was added NaHC03 (50 mg, 0.59 mmol) and MeOH (10 mL). After concentration and removing the solid, the resulting mixture was purified by preparative HPLC to give 5-(4- ((2-aminoethyl)amino)-2-fluorophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (11 mg, 0.02 mmol) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 7.97 (d, J = 8.4 Hz, 1H), 7.60 - 7.48 (m, 3H), 7.26 (t, J = 7.5 Hz, 1H), 6.82- 6.69 (m, 2H), 4.36 (s, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H). LCMS [M+H]+ = 352.3.
Example 98: Preparation of 2-oxo-5-phenyl-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indole 4- oxide
Figure imgf000117_0002
Figure imgf000118_0001
[00283] To a solution of m-CPBA (318 mg, 1.84 mmol) in DCM (20 mL) was added ethyl 2- oxo-5-phenyl-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (640 mg, 1.84 mmol) in DCM (30 mL) over 10 min. The reaction was stirred at rt overnight. NH40H (2 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 was extracted with DCM (4 x 50 mL). The organic phase was washed with NaCl (1 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (25%) and hexanes (75%) to EtOAc (40%)) and hexanes (60%>) to provide 6-(ethoxycarbonyl)-2-oxo-5-phenyl-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indole 4-oxide (230 mg, 0.63 mmol) as a yellow solid. LCMS [M+H]+ = 364.2.
Step 2: Preparation of 2-oxo-5-phenyl-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indole 4-oxide
Figure imgf000118_0002
[00284] To a solution of 6-(ethoxycarbonyl)-2-oxo-5-phenyl-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indole 4-oxide (30 mg, 0.083 mmol) in MeOH (7.5 mL) and DCM (7.5 mL) was bubbled with NH3 gas for 30 min at 0 °C. The reaction mixture was then stirred at ambient temperature for 24 h. The reaction mixture was concentrated in vacuo. The resulting oil was quenched with saturated aqueous Na2C03 (50 mL). The water phase was extracted with EtOAc (3 x 100 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (25%) and hexanes (75%) to EtOAc (40%) and hexanes (60%) to provide 2-oxo-5-phenyl-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indole 4-oxide (10 mg, 0.034 mmol) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 11.02 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 6.9 Hz, 2H), 7.49 - 7.47 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 4.66 (s, 2H). LCMS [M+H]+ = 292.3.
Example 99: Preparation of 5-(3-methoxyphenyl)-2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5- b]indole 4-oxide
Figure imgf000119_0001
[00285] 5-(3-methoxyphenyl)-2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indole 4-oxide was prepared according to the procedure described in Example 98 with substitution of ethyl 2- oxo-5-phenyl-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate by ethyl 5-(3- methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate. 1H NMR (300 MHz, DMSO-d6) 5 11.32 (s, 1H), 11.01 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.33 - 7.18 (m, 4H), 7.11 - 7.04 (m, 2H), 4.65 (s, 2H), 3.76 (s, 3H). LCMS [M+H]+ = 322.3.
Example 100: Preparation of 3-hydroxy-5-phenyl-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one
Figure imgf000119_0002
Step 1: Preparation of ethyl 3-acetoxy-2-oxo-5-phenyl-2,3-dihydro-[l,4]diazepino[6,5- b]indole-6( 1 H)-carboxylate
Figure imgf000119_0003
[00286] A solution of 6-(ethoxycarbonyl)-2-oxo-5-phenyl-l,2,3,6-tetrahydro- [l,4]diazepino[6,5-b]indole 4-oxide (180 mg, 0.50 mmol; Example 70: Step 1) in acetic anhydride (10 mL) was heated to reflux for 1 h. Saturated aqueous Na2C03 (100 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 phase was extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo to provide crude ethyl 3-acetoxy-2-oxo-5-phenyl-2,3- dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate (202 mg, 0.5 mmol) as a oil, which was directly used for the next step without further purification. LCMS [M+H]+ = 406.2.
Step 2: Preparation of 3-hydroxy-5-phenyl-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000120_0001
[00287] To a solution of 3-acetoxy-2-oxo-5-phenyl-2,3-dihydro-[l,4]diazepino[6,5-b]indole- 6(lH)-carboxylate (202 mg, 0.5 mmol) in MeOH (5 mL) was added a solution of NaOH (80 mg, 2.0 mmol) in water (5 mL). The reaction mixture was stirred at rt for 3 h. Water (50 mL) was added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic phase was washed with brine (1 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting solid was purified by flash column chromatography with a gradient elution of EtOAc (25%) and hexanes (75%) to EtOAc (40%)) and hexanes (60%>) to provide 3-hydroxy-5-phenyl-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (116.5 mg, 0.4 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 11.15 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 6.6 Hz, 2H), 7.60 - 7.51 (m, 3H), 7.40 - 7.29 (m, 2H), 7.11 (t, J = 7.3 Hz, 1H), 6.14 (s, 1H), 4.84 (s, 1H). LCMS [M+H]+ = 292.3.
Example 101: Preparation of 3-hydroxy-5-(3-methoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000120_0002
[00288] 3-hydroxy-5-(3-methoxyphenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one was prepared according to the procedure described in Example 100 with substitution of ethyl 2- oxo-5-phenyl-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)-carboxylate in Example 98: Step 1 by ethyl 5-(3-methoxyphenyl)-2-oxo-2,3-dihydro-[l,4]diazepino[6,5-b]indole-6(lH)- carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 11.16 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.35 - 7.24 (m, 3H), 7.14 - 7.11 (m, 2H), 6.17 (brs, 1H), 4.84 (s, 1H), 3.79 (s, 3H). LCMS [M+H]+ = 322.3.
Example 102: Preparation of 5-(2-((2-aminoethyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000121_0001
Step 1: Preparation of 5-(2,4-difluorophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)- one
Figure imgf000121_0002
[00289] 5-(2,4-difluorophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one was prepared according to the procedure described in Example 1 with substitution of 2-bromo-l - (pyridin-3-yl)ethanone hydrobromide in Example 1 : Stepl by 2-bromo-l -(2,4- difluorophenyl)ethanone. LCMS [M+H]+ = 312.2. Step 2: Preparation of 5-(2-((2-aminoethyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000122_0001
[00290] To a solution of 5-(2,4-difluorophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one (100 mg, 0.32 mmol) in dioxane (30 mL) was added ethane- 1,2-diamine (0.3 mL) and triethylamine (0.3 mL). The reaction mixture was kept under reflux for 24 h. Water (30 mL) was added to the reaction vessel and the resulting biphasic mixture was transfered to a separatory funnel. The mixture was extracted with EtOAc (4 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc to MeOH (15%) and DCM (85 %) to provide 5-(2-((2-aminoethyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one (18 mg, 0.06 mmol) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 7.78 (d, J = 8.1 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.23 - 7.14 (m, 2H), 6.65 (dd, J = 11.7, 2.4 Hz, 1H), 6.45 (td, J = 8.4, 2.4 Hz, 1H), 4.40 (s, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.16 (t, J = 5.8 Hz, 2H). LCMS [M+H]+ = 352.3.
Example 103: Preparation of 5-(2-((3-aminopropyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000122_0002
Step 1: Preparation of 5-(2-((3-aminopropyl)amino)-4-fluorophenyl)-3,6-dihydro- [l,4]diazepino[6,5-b]indol-2(lH)-one
Figure imgf000123_0001
[00291] To a solution of 5-(2,4-difluorophenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol- 2(lH)-one (0.10 g, 0.32 mmol) in ACN (20 mL) was added propane- 1,3 -diamine (0.5 mL) and potassium carbonate (0.09 g, 0.64 mmol). The reaction mixture was refiuxed for 2 days. Water (20 mL) was added to the reaction. The mixture was extracted with EtOAc (4 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc to MeOH (15%) and DCM (85 %) to provide 5-(2-((3-aminopropyl)amino)-4-fluorophenyl)-3,6- dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (5 mg, 0.03 mmol) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 7.76 (d, J = 7.8 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.29 - 7.24 (m, 1H), 7.17 (t, J = 6.6 Hz, 1H), 6.60 - 6.56 (m, 1H), 6.40 (td, J = 8.4, 2.4 Hz, 1H), 4.39 (s, 2H), 3.37 - 3.32 (m, 2H), 3.06 (t, J = 7.7 Hz, 2H), 2.05 - 1.98 (m, 2H). LCMS [M+H]+ = 366.4.
Example 104: Preparation of 5-(3-(lH-tetrazol-5-yl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5- b]indol-2(lH)-one
Figure imgf000123_0002
[00292] To a solution of 3-(2-oxo-l,2,3,6-tetrahydro-[l,4]diazepino[6,5-b]indol-5- yl)benzonitrile (50 mg, 0.167 mmol) in DMF (20 mL) was added NaN3 (32.5 mg, 0.50 mmol), NH4C1 (26.8 mg, 0.50 mmol) and lithium chloride (21.0 mg, 0.50 mmol). The reaction mixture was heated to 120 °C and stirred at that temperature for 16 h. After cooled to ambient temperature, the reaction mixture was filtered, concentrated and purified by silica column chromatography with a gradient elution of EtOAc (50%) and Hex (50%) to EtOAc to provide 5- (3-(lH-tetrazol-5-yl)phenyl)-3,6-dihydro-[l,4]diazepino[6,5-b]indol-2(lH)-one (6 mg, 0.017 mmol) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.36 (s, 1H), 11.11 (s, 1H), 8.36 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.8 Hz, 2H), 7.74 (t, J = 7.8 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.13 (t, J = 7.5 Hz, 1H), 4.34 (s, 2H). LCMS [M+H]+ = 344.2.
Example 105: In Vitro Cell-Based Assay For Modulation of the Activation of the P2X4 Purinergic Receptor
[00293] HEK-293 cells stably expressing human P2X4 purinergic receptor were grown in EMEM Minimum Essential Medium with Earle's Balanced Salt Solution (Lonza),
supplemented with 10% fetal bovine serum (Euroclone), 1% Ultraglutamine (Lonza), 400 μg/mL G418 (InvivoGen), 0.2 μg/mL Puromycin (InvivoGen), and 1% Penicillin/Streptomycin. Cells were seeded at a density of lOxlO6 cells per one T-225 flask, grown in the culture medium at 37 °C under 5% C02, 95% humidity, and harvested three days later by trypsinization. Cells for assays were plated into 384-well sterile standard microliter plates (MATRIX, black/clear bottom) at a density of 10,000 cells per well in 25 microliters of medium. Plated cells were incubated for 24 hours at 37 °C under 5% C02, 95% humidity, followed by a 30 min pre- incubated at room-temperature (RT). The components of the Fluo-8 No Wash Calcium Assay kit (ABD Bioquest) were dissolved according to the instructions of the dye kit's manufacturer in the Tyrode's buffer (5 mM KC1, 130 mM NaCl, 2 mM CaCl2, 5 mM NaHC03, 1 mM MgCl2, 20 mM HEPES, pH7.4). After the 30 min of pre-incubation at RT, the cell medium was completely removed by BioTek ELx405 Select Microplate Washer instrument without disturbing the cellular monolayer and the calcium dye solution (30 μΕΛνεΙΙ) then added to the cells by the CyBi® drop. The cell plates were then incubated for 1 hour at room temperature before test compounds and / or controls (TNP-ATP or DMSO), at 4X-concentration in Tyrode's buffer, were added to the wells of an assay plate, in 10 iL volume by a FLIPR Tetra
(Fluorometric Imaging Plate Reader) (Molecular Devices). The kinetic response was monitored by the instrument over a period of 3 minutes. A second injection of 20 μΕΛνεΙΙ of CTP at EC50 concentration (determined daily by performing a pre-run test) at 3X-concentration in Tyrode's buffer was then executed by the FLIPR Tetra. The signal of the emitted fluorescence was recorded for a total time of 150 seconds.
[00294] For measurement of the IC50 value of test compound as a negative modulator of P2X4, the test compound was typically tested at 8 concentrations (30.00 μΜ, 9.49 μΜ, 3.00 μΜ, 0.95 μΜ, 0.30 μΜ, 0.10 μΜ, 0.03 μΜ and 0.01 μΜ), and follow-up testing run at 8 concentrations (3.00 μΜ, 0.95 μΜ, 0.30 μΜ, 0.10 μΜ, 0.03 μΜ, 0.01, μΜ, 0.003 μΜ, and 0.001 μΜ), in quadruplicate with intra-plate dose response curves. To prepare the test compounds, a 96-well "master" plate with each compound in a single well (row A) was created, with a maximum of 10 compounds in the location of columns 2-11. Serial dilutions were then performed starting from row A to row H of each 96-well Compound Dilution plate to form the other necessary concentration points. Each Compound Dilution plate was then transferred into one 384 microliter plates (Compound Dilution plate) obtaining the intra-plate quadruplicate data point for each concentration. The test compound was typically added in a volume of 10 microliters as a dilution (in assay buffer) of a stock solution of test compound in
dimethylsulfoxide (DMSO), such that the final concentration of DMSO was 0.5% (previously demonstrated to be well tolerated by HEK293/hP2X4 for the duration the assay). Addition to certain wells of the same buffer containing 0.5% DMSO, but without any test compound, provided a negative control. Addition to certain wells of a saturating concentration of CTP (typically a final concentration of 900 micromolar) provided a positive control. The maximal fluorescence signals from the second time interval, from wells containing varying concentration of test compound, were analyzed to determine the IC50 value for each test compound. The concentration response curve of a reference compound (typically TNP-ATP) provided a quality control measurement on each plate. Table 7 shows biological data generated according to the assay disclosed herein. "Activity" refers to a scale whereby "+" is an IC50 of less than 1000 nM, "++" is 1000-10,000 nM, and "+++"is greater than 10,000 nM.
Table 7
EXAMPLE # ACTIVITY EXAMPLE # ACTIVITY
1 ++ 31 +
2 + 32 +
3 + 33 ++
4 + 34 ++
5 ++ 35 +
6 +++ 36 +
7 ++ 37 +
8 +++ 38 +++
9 +++ 39 ++
10 +++ 40 +
11 + 41 +
12 ++ 42 +
13 +++ 43 ++
14 + 44 ++
15 + 45 +++
16 + 46 +
17 + 47 +
18 +++ 48 +
19 ++ 49 +
20 ++ 50 +
21 +++ 51 +
22 +++ 52 +
23 + 53 +
24 + 54 +
25 + 55 +++
26 +++ 56 +++
27 +++ 57 +++
28 + 58 ++
29 +++ 59 ++
30 +++ 60 +++ EXAMPLE # ACTIVITY EXAMPLE # ACTIVITY
61 ++ 83 +++
62 +++ 84 ++
63 +++ 85 ++
64 ++ 86 ++
65 + 87 ++
66 + 88 ++
67 ++ 89 +
68 + 90 +++
69 + 91 +++
70 ++ 92 ++
71 + 93 +++
72 ++ 94 ++
73 +++ 95 +
74 ++ 96 +
75 ++ 97 +++
76 +++ 98 +
77 +++ 99 +
78 +++ 100 ++
79 +++ 101 +
80 + 102 +++
81 +++ 103 +++
82 +++ 104 ++
[00295] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the disclosure and are encompassed by the appended claims.
[00296] All of the patents, patent applications and publications referred to herein are incorporated by reference herein in their entireties. Citation or identification of any reference in this application is not an admission that such reference is available as prior art to this application. The full scope of the disclosure is better understood with reference to the appended claims.

Claims

WHAT IS CLAIMED:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000129_0001
(I)
wherein:
A is selected from N, N-oxide and CR2;
L1 is selected from a bond, Ci-C6 alkyl, and Ci-C6 haloalkyl;
R1 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 R6 substituents;
R2 is selected from hydrogen, halogen, CN, NR7R8, OR9, S02R9, S03R9, C(0)R9, C(0)OR9, C(0)NR7R8, Ci-C6 haloalkyl and CrC6 alkyl optionally substituted with one or more R10 substituents; each R3 is independently selected from halogen, CN, OR11, NR12R13, Ci-C6 haloalkyl, and Ci-C6 alkyl optionally substituted with one or more R14 substituents;
R4 and R5 are each independently selected from hydrogen, OH, NH2, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, C3-Cg cycloalkyl, and 3- to 10-membered heterocyclyl; each R6 is independently selected from halogen, CN, N02, oxo, OR15, NR16R17, S02R15, S03R15, S02NR16R17, NR16S02R15, C(0)R15, OC(0)R15, C(0)OR15, C(0)NR16R17,
NR16C(0)R15, Ci-C6 haloalkyl, C C6 alkyl, C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C6 alkyl, C3-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 R18 substituents;
R7 and R8 are each independently selected from hydrogen, S02R19, S03R19, SO2NR20R21, C(0)R19, C(0)OR19, C(0)C(0)R19, C(0)C(0)OR19, C(O)NR20R21, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10- membered heterocyclyl, wherein the Ci-C6 alkyl, C3-C8 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 R22 substituents; or alternatively R7 and R8 taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, optionally substituted with one or more substituents each independently selected from halogen, oxo, Ci-C6 alkyl, and Ci-C6 haloalkyl;
R9 is selected from hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-C8 cycloalkyl, 6- to 14- membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C6 alkyl, C3-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 R23 substituents; each R10 is independently selected from halogen, CN, OR24, NR25R26, S02R24, S03R24, S02NR25R26, C(0)R24, C(0)OR24, C(0)NR25R26, and NHC(0)R24; each R11, R15, R19, and R24 is independently selected from hydrogen, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the Ci-C6 alkyl, C3-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 substituents independently selected from halogen, CN, OR27, NR27R28, Ci-C6 alkyl, Ci-C6 haloalkyl, and phenyl;
each R12, R13, R16, R17, R20, R21, R25, and R26 is independently selected from hydrogen, C(0)Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl, C3-Cg cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the C(0)Ci-C6 alkyl, Ci-C6 alkyl, C3-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 substituents independently selected from halogen, CN, OR27, NR27R28, Ci-C6 alkyl, Ci-C6 haloalkyl, and phenyl; or alternatively any R12 and R13, R16 and R17, R20 and R21, or R25 and R26, taken together with the nitrogen to which they are bound form a 3- to 10-membered heterocyclyl or 5- to 10- membered heteroaryl, optionally substituted with one or more substituents each independently selected from halogen, oxo, CN, OR27, NR27R28, Ci-C6 haloalkyl, and Ci-C6 alkyl; each R is independently selected from halogen, CN, OR , M R , C3-C8 cycloalkyl, 6- to 14-membered aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; each R 18 , R 22 , and R 23 is independently selected from halogen, CN, oxo, thione, OR 27 , NR27R28, C(0)R27, C(0)OR27, C(0)NR27R28, C C6 haloalkyl, C C6 alkyl, and C3-C8 cycloalkyl, 6- to 14-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; each R27 and R28 is independently selected from hydrogen, C(0)Ci-C6 alkyl, Ci-C6 alkyl, and Ci-C6 haloalkyl; n is 0, 1, 2, 3 or 4; and m is 1, 2 or 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is N.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is N-oxide.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is CR2.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is Ci-C6 alkyl optionally substituted with one or more R10 substituents.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from methyl, ethyl, propyl, and isopropyl.
7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is Ci-C6 alkyl substituted with OH.
8. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is CN.
9. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is halogen.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R2 is CI.
11. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: R2 is C(0)OR9; and R9 is selected from hydrogen and Ci-C6 alkyl.
12. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
13. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is NR7R8.
14. The compound of claim 13, wherein: R7 is C(0)R19;
R8 is hydrogen; and
R19 is 5- to 10-membered heteroaryl.
15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein: R7 is selected from C(0)C(0)R19 and C(0)C(0)OR19;
R8 is hydrogen; and R19 is Ci-C6 alkyl.
16. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R7 and R8 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-C6 alkyl.
17. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Li is a bond.
18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Li is Ci-C6 alkyl.
19. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from 6- to 14 membered aryl and 5- to 10-membered heteroaryl, each optionally substituted with one or more R6 substituents.
20. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, each optionally substituted with one or more R6 substituents.
21. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with one or more R6 substituents.
22. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted 6- to 14-membered aryl.
23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with one or more R6 substituents, and each R6 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.
24. The compound of claim 23, wherein each R6 is independently selected from fluoro, chloro, bromo, methoxy, methyl, CF3, and C(0)OCH3.
25. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted 5- to 10-membered heteroaryl.
26. The compound of claim 25, wherein R1 is pyridyl.
27. The compound of claim 26, wherein R1 is 2-pyridyl.
28. The compound of claim 26, wherein R1 is 3-pyridyl.
29. The compound of claim 26, wherein R1 is 4-pyridyl.
30. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1 is pyridyl substituted with one or more R6 substituents, and each R6 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.
31. The compound of claim 30, wherein each R6 is independently selected from fluoro, chloro, bromo, methoxy, methyl, CF3, and C(0)OCH3.
32. The compound of claim 30, wherein R1 is 2-pyridyl.
33. The compound of claim 30, wherein R1 is 3-pyridyl.
34. The compound of claim 30, wherein R1 is 4-pyridyl.
35. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from halogen, CN, Ci-C6 haloalkyl, and Ci-C6 alkyl optionally substituted with one or more R14 substituents.
36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein n is 1.
37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from F, CI, Ci-C6 haloalkyl, and Ci-C6 alkyl.
38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R3 is CI.
39. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 0.
40. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein at least one of R4 and R5 is selected from OH, Ci-C6 alkyl, and Ci-C6 alkoxy.
41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein at least one of R4 and R5 is selected from the group consisting of OH and Ci-C6 alkoxy.
42. The compound of any one of claims 1 to 39, wherein R4 and R5 are each hydrogen.
43. The compound of claim 1, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000134_0001
(II)
44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of F, CI, methyl, and methoxy.
45. The compound of claim 1, wherein the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000135_0001
(III)
46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of F, CI, methyl and methoxy.
47. The compound of claim 1, wherein the compound is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:
Figure imgf000135_0002
(IV) wherein: each R29 is independently selected from halogen, CN, OR15, NR16R17, S02R15,
S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; and p is 0, 1, 2, 3, 4 or 5.
48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R29 is
Figure imgf000135_0003
wherein
Y is S or O; and
R30 is selected from hydrogen and Ci-C6 alkyl.
49. The compound of claim 1, wherein the compound is a compound of formula (Va), or a pharmaceutically acceptable salt thereof:
Figure imgf000136_0001
(Va) wherein: each R29 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; and p is 0, 1, 2, 3 or 4.
50. The compound of claim 1, wherein the compound is a compound of formula (Vb), or a pharmaceutically acceptable salt thereof:
Figure imgf000136_0002
(Vb) wherein: each R29 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; and p is 0, 1, 2, 3 or 4.
51. The compound of claim 1 , wherein the compound is a compound of formula (Vc), or a pharmaceutically acceptable salt thereof:
Figure imgf000137_0001
(Vc) wherein: each R29 is independently selected from halogen, CN, OR15, NR16R17, S02R15, S02NR16R17, C(0)OR15, C(0)NR16R17, Ci-C6 haloalkyl,5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; and p is 0, 1, 2, 3 or 4.
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000137_0002
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000138_0001
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000138_0002
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000138_0003
Figure imgf000139_0001
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000140_0001
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000140_0002
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000140_0003
Figure imgf000141_0001
Figure imgf000141_0002
140 A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000142_0001
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000143_0001
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000143_0002
A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000144_0001
66. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any preceding claim or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
67. A method of treating a condition in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 65, or a pharmaceutical composition of claim 66; 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, cardiac ischemia, allodynia, causalgia, post-herpetic neuralgia, hyperesthesia, hyperpathia, dysesthesia, fibromyalgia, causalgia, hyperalgesia, central nervous system disorders, sensory loss, arthritis and rheumatoid arthritis.
68. The method of claim 67, wherein the condition is selected from the group consisting of pain; central pain; and peripheral pain.
69. A method of inhibiting or modulating a purinergic P2X4 ion channel receptor (P2X4R) in a subject, the method comprising: administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 65, or a pharmaceutical composition of claim 66.
70. The method of claim 69, wherein the compound is a P2X4R antagonist.
71. The method of claim 69, wherein the compound is a P2X4R negative allosteric modulator.
72. The method of any one of claims 67 to 71, wherein the compound is administered in combination with another agent or therapy.
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WO2022049253A1 (en) 2020-09-07 2022-03-10 Bayer Aktiengesellschaft Substituted n-heteroaryl-n-pyridinylacetamides as p2x4 modulators

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