WO2013170072A2 - Composés pour le traitement de troubles neurologiques - Google Patents

Composés pour le traitement de troubles neurologiques Download PDF

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Publication number
WO2013170072A2
WO2013170072A2 PCT/US2013/040408 US2013040408W WO2013170072A2 WO 2013170072 A2 WO2013170072 A2 WO 2013170072A2 US 2013040408 W US2013040408 W US 2013040408W WO 2013170072 A2 WO2013170072 A2 WO 2013170072A2
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alkyl
hydrogen
compound
halogen
polyhaloalkyl
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PCT/US2013/040408
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WO2013170072A3 (fr
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Kamalesh Babu Ruppa POORNACHARY
Scott J. MYERS
George Walter Koszalka
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Neurop, Inc.
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Publication of WO2013170072A3 publication Critical patent/WO2013170072A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • Neurological disorders are disorders that affect the nervous system. They can be categorized according to the structure or primary location affected, the nature of the dysfunction, or the primary cause (e.g., genetic disorder, injury, infection). Some neurologic disorders, like Parkinson's disease and stroke, are well-known, while others are very rare.
  • WHO World Health Organization
  • neurologic disorders account for almost 1 1% of total global disease burden worldwide. Collectively, the burden of neurologic disorders is hard to overstate, and include direct health care costs, disability, quality of life, and lost productivity. Alzheimer's disease alone drains more than $ 148 billion from the U.S. economy each year.
  • the burden of neurologic disorder is expected to increase on a global basis, as demographic changes in the world's most populous countries will result in a significant increase in the number of persons with neurodegenerative diseases over the next few decades.
  • Glutamate L-glutamic acid
  • the ionotropic glutamate receptors comprise three receptor families: NMDA (N-methyl-D- aspartate), AMPA (2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid), and kainate receptors.
  • NMDA N-methyl-D- aspartate
  • AMPA 2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid
  • kainate receptors Ionotropic glutamate receptors form ligand-gated ion channels in the plasma membranes of neuronal cells, and mediate excitatory synaptic transmission in the central nervous system.
  • a neurotransmitter or agonist ligand Upon binding, a neurotransmitter or agonist ligand induces activation of the receptor and opening of the ion channel, allowing the flow of ions across the cell membrane (Br. J. Pharmacol. 2009, 157: 1301, Pharmacol. Rev. 2010, 62:405, Nature 1987, 325:529).
  • the NMDA subtype of glutamate-gated ion channels comprise heterotetrametric assemblies composed of combinations of two or more of the three subunit subtypes, GluNl, GluN2 (A, B, C, and D), and GluN3 (A and B). Additionally, genes that encode for certain subunits of ionotropic glutamate receptors can undergo alternative splicing (e.g. GluNl-la, GluNl-lb, GluNl-2a, GluNl-2b, Glu l-3a, GluNl-3b, GluNl-4a, and GluNl-4b) to generate diverse subunit compositions, which are critical in determining biological and pharmacological properties of the NMDA receptor.
  • alternative splicing e.g. GluNl-la, GluNl-lb, GluNl-2a, GluNl-2b, Glu l-3a, GluNl-3b, GluNl-4a, and GluN
  • a functional channel requires the co-expression of at least one Glu l subunit and one or more GluN2 subunits.
  • cells express the GluN3 subunit, which co-assembles with GluNl or GluNl and GluN2 to form GluNl-GluN3 or GluNl -GluN2-GluN3 tetrameric complexes (Pharmacol. Rev. 2010, 62:405).
  • GluNl subunits are expressed virtually uniformally in all neurons and at all developmental stages, the GluN2 subunits exhibit different regional distribution and developmental patterns, and can provide a more selective therapeutic target (Neuron 1994, 12:529).
  • NMDA receptor subunits share a common modular design, each representing a functional unit, including: the extracellular area containing two large bi-lobed domains, the amino terminal domain (ATD) and the ligand binding domain (LBD), which binds glycine in GluNl and GluN3, and glutamate in GluN2, the membrane domain comprising three transmembrane segments and a re-entrant loop that forms the ion channel, and the C-terminal cytoplasmic domain.
  • ATD amino terminal domain
  • LBD ligand binding domain
  • the membrane domain comprising three transmembrane segments and a re-entrant loop that forms the ion channel
  • the C-terminal cytoplasmic domain the C-terminal cytoplasmic domain.
  • the NMDA receptor has multiple binding and regulatory sites in addition to an ion channel, which also contains several internal binding sites.
  • the NMDA receptor requires co-activation by the binding of a co-agonist, glycine or D-serine, at GluNl subunits, in addition to glutamate binding on GluN2 subunits.
  • a co-agonist glycine or D-serine
  • GluNl subunits in addition to glutamate binding on GluN2 subunits.
  • NMDA conductance is markedly reduced due to a voltage-dependent block of the channel pore by magnesium ions. Depolarization releases this channel block and permits passage of calcium and monovalent ions such as sodium ions (Curr. Opin.
  • NMDA receptors have been implicated in a myriad of biological functions in the nervous system, indicating a potential role for the NMDA receptor in a variety of disease processes in mammals (Trends).
  • ligands of NMDA receptors can be used for the treatment or prevention of acute and/or chronic neurological and/or psychiatric disorders associated with glutamate dysfunction, such as chronic pain and neuropathic pain
  • Neurotherapeutics J. Am. Soc. Exp. Neurotherapeutics 2009, 6:693
  • neurodegenerative disorders Exp. Opin. Drug Metab. Toxicol. 2007 ' , 3 : 135, Pharmacol. Ther. 2004, 102: 155
  • mood disorders ischemic or traumatic brain injury (Steroids 2011, 76:845), and the like.
  • NMDA receptors play an important role in lasting changes in synaptic transmission and synaptic plasticity, including an essential role in the induction of two forms of synaptic plasticity, such as long term potentiation (LTP) and long term depression (LTD) (Cell 1994, 78:535).
  • LTP long term potentiation
  • LTD long term depression
  • Selective noncompetitive allosteric modulators are compounds that do not directly act on receptors by themselves, but binding of these compounds modulates, positively or negatively, the response of the receptor to glutamate, glycine, or other orthosteric agonists by modulating the affinity of an orthosteric agonist at the orthosteric binding site, or by modifying other conformational states of the receptor affecting channel function. Selective noncompetitive allosteric modulators are thus an attractive mechanism for regulating appropriate physiological receptor activation (Curr. Opin. Pharmacol. 2007, 7:39, Mol. Pharm 2011, 80:782, J. Pharmacol. Exp. Ther. 2010, 335:614, J. Med. Chem. 2010, 53:5476).
  • the invention in one aspect, relates to compounds useful as modulators (i.e., inhibitors) of the NMDA receptor, methods of making same, pharmaceutical compositions comprising same, and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using same.
  • Ar 1 is selected from phenyl and heterocyclyl; and wherein Ar 1 is substituted with 0-2 groups independently selected from halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, Cl- C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein L is selected from:
  • each occurrence of R ia , R 1D , R 1C , and R 1Q when present, is independently selected from hydrogen, halogen,— H 2 ,—OH,— CN, and C1-C3 alkyl; wherein m is an integer from 1-3; wherein n is an integer from 1-4; wherein q is an integer from 0-1 ; wherein r is an integer from 0-1; wherein Y 1 , when present, is selected from— O— and— CR 2a R 2b — ; wherein each of R 2a and R 2b is independently selected from hydrogen, halogen,— H 2 ,—OH,— CN, and C1-C3 alkyl; wherein Z 1 , when present, is a 4- to 7-membered hetercycloalkyl selected fro
  • a 1 is N or CR 3 ; wherein R 3 is selected from hydrogen, halogen,—OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen, — NH 2 , -OH,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein Z 2 , when present, is a 3 - to 7- membered cycloalkyl substituted with 0-2 groups independently selected from halogen, — NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamin
  • each of R 9 when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • compositions comprising an effective amount of at least one disclosed compound, a product of a disclosed method of making, or pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.
  • Also disclosed are methods for manufacturing a medicament comprising combining at least one disclosed compound, or a product of a disclosed method of making, with a pharmaceutically acceptable carrier or diluent. Additionally, the invention relates to a compound as defined herein, or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, for use as a medicament, and to a compound as defined herein for use in the treatment or in the prevention of neurological and psychiatric disorders and diseases.
  • Also disclosed are methods for the treatment of a neurological and/or psychiatric disorder associated with NMDA receptor function in a mammal comprising the step of administering to the mammal an effective amount of at least one disclosed compound, a product of a disclosed method of making, or pharmaceutically acceptable salt, solvate, or polymorph thereof
  • Also disclosed are methods for inhibition of NMD A receptor activity in a mammal comprising the step of administering to the mammal an effective amount of at least one disclosed compound, a product of a disclosed method of making, or pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • Also disclosed are methods for inhibition of NMDA receptor activity in at least one cell comprising the step of contacting the cell with an effective amount of at least one disclosed compound, a product of a disclosed method of making, or pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • Also disclosed are methods for modulating NMDA activity in a mammal comprising the step of administering to the mammal an effective amount of at least one disclosed compound or pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • the invention also relates to a product comprising a compound as described herein and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of neurological and psychiatric disorders and diseases.
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about” that particular value in addition to the value itself. For example, if the value "10” is disclosed, then “about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 1 1, 12, 13, and 14 are also disclosed.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • allosteric site refers to a ligand binding site that is topographically distinct from the orthosteric binding site.
  • modulator refers to a molecular entity (e.g., but not limited to, a ligand and a disclosed compound) that modulates the activity of the target receptor protein.
  • ligand refers to a natural or synthetic molecular entity that is capable of associating or binding to a receptor to form a complex and mediate, prevent or modify a biological effect.
  • ligand encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates and analogs of natural substrates.
  • natural ligand and “endogenous ligand” are used interchangeably, and refer to a naturally occurring ligand, found in nature, which binds to a receptor.
  • GluN2B As used herein, the terms “GluN2B”, “NR2B”, “NR2B-containing NMDA receptor”, “2B” and “NMDA receptor subunit GluN2B”, are used interchangeably, and refer to the presence of a specific NMDA receptor subunit subtype within a tetrameric NMDA complex (e.g. GluNl/GluN2B/GluN2/GluN2B).
  • a specific NMDA receptor subunit subtype e.g. GluNl/GluN2B/GluN2/GluN2B.
  • GluN2A can be used interchangeably with NR2A, GluN2D with NR2D, GluN2C with NR2C, GluN3A with NR3A, GluN3B with NR3B, and GluNl with NR1.
  • the term "orthosteric site” refers to the primary binding site on a receptor that is recognized by the endogenous ligand or agonist for that receptor.
  • the orthosteric site in the NMDA GluN2 receptor is the site that glutamate binds.
  • NMDA receptor antagonist refers to any exogenously administered compound or agent that is capable of partially or completely inhibiting, or reversing, the effect of an agonist (e.g. glutamate and/or glycine) on the NMDA receptor.
  • the term is inclusive of compounds or agents characterized or described as antagonists, noncompetitive antagonists, uncompetitive antagonists, partial antagonists, and negative allosteric modulators.
  • NMDA receptor antagonists can mediate their effects by binding to the orthosteric site or to allosteric sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity.
  • a NMDA receptor antagonist directly or indirectly inhibits the activity of the NMDA receptor in the presence or in the absence of glutamate, glycine or another agonist, in an animal, in particular a mammal, for example a human.
  • a NMDA receptor antagonist is a type of compound or agent that does not provoke a biological response itself upon binding to the NMDA receptor, but blocks or dampens agonist-mediated responses.
  • NMDA receptor antagonists have affinity but no efficacy for their cognate receptors, and binding of a NMDA receptor antagonist will disrupt the interaction of the endogenous ligand, an agonist or inverse agonist with NMDA receptors, and thus, inhibit their response to such activators.
  • a NMDA receptor antagonist decreases the activity of the NMDA receptor in a cell in the presence of extracellular glutamate.
  • the cell can be a Xenopus oocyte injected with cRNA for human NMDA receptor, e.g., GluNl and/or GluN2.
  • the cell can be a Xenopus oocyte injected with cRNA for rat NMDA receptor, e.g., GluNl and/or GluN2.
  • the cell can be a Xenopus oocyte injected with cRNA for mammalian NMDA receptor, e.g., GluNl and/or GluN2.
  • the compound that is a "NMDA receptor antagonist” includes a compound that is a "NMDA receptor competitive antagonist,” a “NMDA receptor noncompetitive antagonist,” a “NMDA receptor partial antagonist,” a “NMDA receptor uncompetitive antagonist,” and a “NMDA receptor negative allosteric modulator.”
  • NMDA receptor competitive antagonist refers to any exogenously administered compound or agent that is capable of binding to the orthosteric site of NMDA receptors without activating the receptor.
  • a competitive antagonist can interact with a NMDA receptor and compete with an endogenous ligand, glutamate and/or glycine, for binding to the receptor and decrease the ability of the receptor to conduct ions and/or transduce an intracellular signal in response to endogenous ligand binding.
  • NMDA receptor non-competitive antagonist refers to any exogenously administered compound or agent that binds to site that is not the orthosteric binding site of NMDA receptors, and is capable of partially or completely inhibiting, or reversing, the effect of an agonist (e.g. glutamate and/or glycine) on the NMDA receptor.
  • a non-competitive antagonist can interact with a NMDA receptor and decrease the binding of an endogenous ligand, e.g. glutamate and/or glycine, to the receptor and/or decrease the ability of the receptor to conduct ions and/or transduce an intracellular signal in response to endogenous ligand binding.
  • NMDA partial antagonist refers to any exogenously administered compound or agent that can bind to an orthosteric or an allosteric site, but the effect of binding is to only partially block effect of NMDA receptor response to an agonist, e.g. glutamate and/ or glycine.
  • a non-competitive antagonist can interact with a NMDA receptor, but is not capable of fully inhibiting the response of the NMDA receptor to an agonist, e.g. glutamate and/ or glycine.
  • NMDA negative allosteric modulator refers to any exogenously administered compound or agent that directly or indirectly inhibits the activity of the NMDA receptor in the presence of glutamate and/or glycine, or another agonist, in an animal, in particular a mammal, for example a human.
  • a selective NMDA negative allosteric modulator can preferentially bind to the NMDA receptor GluNl subunit, the GluN2 subunit, or both, and decrease NMDA receptor activity in the presence of glutamate by acting as a non-competitive antagonist.
  • the cell can be a Xenopus oocyte injected with cRNA for human NMDA receptor, e.g., GluNl and/or GluN2.
  • the cell can be a Xenopus oocyte injected with cRNA for rat NMDA receptor, e.g., GluNl and/or GluN2.
  • the cell can be a Xenopus oocyte injected with cRNA for mammalian NMDA receptor, e.g., GluNl and/or GluN2.
  • the term "subject" can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for inhibition of NMDA receptor activity prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for partial inhibition of NMDA receptor activity prior to the administering step.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • domesticated animals e.g., cats, dogs, etc.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • diagnosisd means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • diagnosis with a disorder treatable by modulation of NMDA means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can modulate NMDA.
  • diagnosis with a need for modulation of NMDA refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition characterized by NMDA activity. Such a diagnosis can be in reference to a disorder, such as a neurodegenerative disease, and the like, as discussed herein.
  • diagnosis with a need for inhibition of NMDA receptor activity refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by inhibition of NMDA receptor activity.
  • diagnosisd with a need for partial or uncompetative antagonism of NMDA receptor activity means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by partial or uncompetative antagonism of NMDA receptor activity.
  • diagnosisd with a need for treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have one or more neurological and/or psychiatric disorder associated with glutamate dysfunction.
  • the phrase "identified to be in need of treatment for a disorder," or the like, refers to selection of a subject based upon need for treatment of the disorder.
  • a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to NMDA receptor activity) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder.
  • the identification can, in one aspect, be performed by a person different from the person making the diagnosis.
  • the administration can be performed by one who subsequently performed the administration.
  • administering refers to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • contacting refers to bringing a disclosed compound and a cell, target NMDA glutamate receptor, or other biological entity together in such a manner that the compound can affect the activity of the target (e.g., spliceosome, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.
  • the target e.g., spliceosome, cell, etc.
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as a recorded presentation.
  • instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as a recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates. [0053] as used herein, the terms "therapeutic agent” includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic,
  • immunogenic, and/or physiologic effect by local and/or systemic action encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term "therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • EC5 0 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process, or component of a process.
  • EC5 0 can refer to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay.
  • an EC5 0 for NMDA receptor can be determined in an in vitro or cell-based assay system.
  • Such in vitro assay systems frequently utilize a cell line that either expresses endogenously a target of interest, or has been transfected with a suitable expression vector that directs expression of a recombinant form of the target such as NMDA receptor, e.g., GluNl or GluN2.
  • a suitable expression vector that directs expression of a recombinant form of the target such as NMDA receptor, e.g., GluNl or GluN2.
  • the EC5 0 for GluNl or GluN2 can be determined using Xenopus oocytes injected with a cRNA for human NMDA receptor, e.g., GluNl and/or GluN2.
  • the EC 50 for GluNl or GluN2 can be determined using Xenopus oocytes injected with cRNA for rat NMDA receptor, e.g., GluNl and/or GluN2.
  • the EC5 0 for GluNl or GluN2 can be determined using Xenopus oocytes injected with cRNA for mammalian NMDA receptor, e.g., GluNl and/or GluN2.
  • IC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process.
  • IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • an IC 50 for NMDA receptor can be determined in an in vitro or cell-based assay system.
  • receptor assays including suitable assays for NMDA, make use of a suitable cell-line, e.g.
  • a cell line that either expresses endogenously a target of interest, or has been transfected with a suitable expression vector that directs expression of a recombinant form of the target such as NMDA receptor, e.g., GluNl or GluN2.
  • NMDA receptor e.g., GluNl or GluN2.
  • the IC 50 for GluNl or GluN2 can be determined using Xenopus oocytes injected with a cRNA for human NMDA receptor, e.g., GluNl and/or GluN2.
  • the IC 50 for GluNl or GluN2 can be determined using Xenopus oocytes injected with a cRNA for rat NMDA receptor, e.g., GluNl and/or GluN2.
  • the IC 50 for GluNl or GluN2 can be determined using Xenopus oocytes injected with a cRNA for mammalian NMDA receptor, e.g., GluNl and/or GluN2.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • the term "derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the term "pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 0- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more -CO(CH 2 ) 8 CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 " are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or "aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms.
  • Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, n- butyl, isobutyl, s-butyl, t-butyl, w-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group is acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a "lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a CI alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both
  • halogenated alkyl or haloalkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • monohaloalkyl specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • alkyl is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0065] This practice is also used for other groups described herein.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an "alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a "halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an "alkenylalcohol,” and the like.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • the cycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • polyalkylene group as used herein is a group having two or more CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula— (CH 2 ) a — , where "a" is an integer of from 2 to 500.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as— OA 1 — OA 2 or— OA 1 — (OA 2 ) a — OA 3 , where "a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,
  • the cycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • the cycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry , (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde,— H 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasing is a specific type of aryl group and is included in the definition of "aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond.
  • biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • amine or “amino” as used herein are represented by the formula— NA X A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is— NI3 ⁇ 4.
  • alkylamino as used herein is represented by the formulas
  • the alkyl group can be a CI alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, CI -CIO alkyl, and the like, up to and including a C1-C24 alkyl.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, N-ethyl-N-methylamino group, N-methyl- -propylamino group, and N-ethyl-N-propylamino group.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N- methyl-N -propylamino group, N-ethyl-N-propylamino group, and the like.
  • the term "monoalkylamino" as used herein is represented by the formula — NH(— alkyl), where alkyl is as described herein.
  • the alkyl group can be a CI alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, Cl- C9 alkyl, CI -CIO alkyl, and the like, up to and including a C1-C24 alkyl.
  • dialkylamino as used herein is represented by the formula — N(— alkyl) 2 , where alkyl is as described herein.
  • the alkyl group can be a CI alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, Cl- C9 alkyl, CI -CIO alkyl, and the like, up to and including a C1-C24 alkyl. It is understood that each alkyl group can be independently varied, e.g. as in the representative compounds such as N-ethyl-N-methylamino group, N-methyl-N-propylamino group, and N-ethyl-N- propylamino group.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N- propylamino group, and the like.
  • esters as used herein is represented by the formula— ⁇ (0) ⁇ ⁇ or— C(0)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula— (A 1 0(0)C-A 2 -C(0)0) a — or— (A 1 0(0)C-A 2 -OC(0)) a — , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a” is an integer from 1 to 500.
  • Polyyester is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A x OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula— (A 1 0-A 2 0) a — , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a" is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • pseudohalide pseudohalogen or "pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides.
  • Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted, and the heteroaryl group can be monocyclic, bicyclic or multicyclic aromatic ring.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. . It is understood that a heteroaryl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heteroaryl ring.
  • heteroaryl groups include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations thereof.
  • Non-limiting examples of heteroaryl rings include furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl, triazinyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionapthene, indolyl, benzazolyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl,
  • monocyclic heteroaryl refers to a monocyclic ring system which is aromatic and in which at least one of the ring atoms is a heteroatom.
  • Monocyclic heteroaryl groups include, but are not limited, to the following exemplary groups: pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxadiazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4- thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, and
  • bicyclic heteroaryl refers to a ring system comprising a bicyclic ring system in which at least one of the two rings is aromatic and at least one of the two rings contains a heteroatom.
  • Bicyclic heteroaryl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heteroaryl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • bicyclic heteroaryl groups include without limitation indolyl, isoindolyl, indolyl, indolinyl, indolizinyl, quinolinyl, isoquinolinyl, benzofuryl, bexothiophenyl, indazolyl, benzimidazolyl, benzothiazinyl, benzothiazolyl, purinyl, quinolizyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolizinyl, quinoxalyl, naphthyridinyl, and pteridyl.
  • Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • a heterocycloalkyl can include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited, to the following exemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • heterocycloalkyl group can also be a C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5 heterocycloalkyl, C2-C6 heterocycloalkyl, C2-C7 heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C9 heterocycloalkyl, C2-C10 heterocycloalkyl, C2-C11 heterocycloalkyl, and the like up to and including a C2-C14 heterocycloalkyl.
  • a C2 heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like.
  • a C5 for example, a C5
  • heterocycloalkyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, and the like. It is understood that a heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The heterocycloalkyl group can be substituted or unsubstituted.
  • the heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • hydroxyl or "hydroxy” as used herein is represented by the formula -OH.
  • ketone as used herein is represented by the formula A 1 C(0)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitro as used herein is represented by the formula— N0 2 .
  • nitrile or "cyano” as used herein is represented by the formula— CN.
  • sil as used herein is represented by the formula— SiA A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas— S(0)A 1 ,— S(0) 2 A 1 ,— OS(0) 2 A 1 , or— OS(0) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula— S(0) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfone as used herein is represented by the formula A 1 S(0) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(0)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 y 2 R e , -(haloR*), -(CH 2 y 2 OH, -(CH 2 y 2 OR e , -(CH 2 y
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR * 2 ) 2 _ 3 0- wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00105] Suitable substituents on the aliphatic group of R include halogen, -
  • R -(haloR*), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR", -NR' 2 , or -NO2, wherein each R' is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , - S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R", -(haloR*), -OH, -OR", -O(haloR'), -CN, -C(0)OH, -C(0)OR e , -NH 2 , -NHR*, -NR' 2 , or -N0 2 , wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH 2 Ph, -0(CH 2 )o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • leaving group refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, "Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
  • organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
  • a very close synonym of the term "residue” is the term "radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • radical refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4- thiazolidinedione radical in a particular compound has the structure
  • radical for example an alkyl
  • substituted alkyl can be further modified (i.e., substituted alkyl) by having bonded thereto one or more "substituent radicals.”
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Inorganic radicals contain no carbon atoms and therefore comprise only atoms other than carbon.
  • Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations.
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together.
  • inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and
  • a compound prefixed with (-) or 1 meaning that the compound is levorotatory or a compound prefixed with (+) or d is dextrorotatory.
  • these compounds called stereoisomers, are identical except that they are non-superimposable mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*).
  • bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F and 36 CI, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et. al, The Royal Society of Chemistry, 1889-1896, 2004.
  • Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.
  • ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
  • pyridinones can exist in two tautomeric forms, as shown below. [00122] Unless stated to the contrary, the invention includes all such possible tautomers.
  • polymorphic forms or modifications It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula:
  • n is typically an integer. That is, R" is understood to represent five independent substituents, R" (a) , R" (b) , R" (c) , R" (d) , and R" (e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(h) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • ACN means acetonitrile
  • EtOAc means ethyl acetate
  • DCE 1,2-dichloroethane
  • DCM means dichloromethane
  • DIPE means diisopropylether
  • DMF means N,N-dimethylformamide
  • EtOH means ethanol
  • HATU means 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
  • HPLC means high-performance liquid chromatography
  • LCMS means liquid chromatography/mass spectrometry
  • MeOH means methanol
  • Ms means methylsulfonyl
  • Ms means methylsulfonyl
  • TFAA means trifluoroacetic anhydride
  • DMSO means dimethyl s
  • compositions of the invention Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
  • the invention relates to compounds useful as modulators of the NMDA receptor, such as an inhibitor of NMD A receptor activity. More specifically, in one aspect, the present invention relates to compounds that are antagonists of the NMDA receptor. The compounds can, in one aspect, exhibit subtype selectivity.
  • the compounds of the invention are useful in the treatment of neurological and/or psychiatric disorders associated with glutamate dysfunction and other diseases in which NMDA receptors are involved, as further described herein.
  • each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.
  • the invention relates to a compound having a structure represented by a formula:
  • Ar 1 is selected from phenyl and heterocyclyl; and wherein Ar 1 is substituted with 0-2 groups independently selected from halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, Cl- C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein L is selected from:
  • each occurrence of R ia , R 1D , R 1C , and R 1Q when present, is independently selected from hydrogen, halogen,— H 2 ,—OH,— CN, and C1-C3 alkyl; wherein m is an integer from 1-3; wherein n is an integer from 1-4; wherein q is an integer from 0-1 ; wherein r is an integer from 0-1; wherein Y 1 , when present, is selected from— O— and— CR 2a R 2b — ; wherein each of R 2a and R 2b is independently selected from hydrogen, halogen,— H 2 ,—OH,— CN, and C1-C3 alkyl; wherein Z 1 , when present, is a 4- to 7-membered hetercycloalkyl selected from: > RH 4 R 4 I-Q R 4 H H R 4 V Q R 4 and V C5 R 4 ⁇ wherein A 1 is N or CR 3 ; wherein R 3
  • each of R 9 when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected from
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • Ar 1 is selected from phenyl and heterocyclyl; and wherein Ar 1 is substituted with 0-2 groups independently selected from halogen, -NH 2 , -OH,— CN, C1 -C3 alkyl, C1 -C3 haloalkyl, C l- C3 polyhaloalkyl, C1 -C3 alkoxy, C 1-C3 alkylamino, and C1 -C3 dialkylamino; wherein each occurrence of R la and R lb is independently selected from hydrogen, halogen,— N3 ⁇ 4,—OH, — CN, and C1 -C3 alkyl; wherein n is an integer from 1 -4; wherein Z 1 is a 4- or 5-membered hetercycloalkyl selected from:
  • a 1 is selected from N and CR 3 ; wherein R 3 is selected from hydrogen and C 1 -C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen, — NH 2 , -OH, -CN, C1-C3 alkyl, C 1-C3 monohaloalkyl, C 1-C3 polyhaloalkyl, C 1-C3 alkoxy, C1 -C3 alkylamino, and C1-C3 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR*; and wherein A 4 is selected from N and CR 6c ; wherein each of R a , R , and R c , when present, is independently selected from hydrogen, halogen, -NH 2 , -OH, -CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, Cl- C3
  • the invention relates to a compound having a structure represented by the formul
  • the invention relates to a compound having a structure represented by the formula
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R a -R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by the formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by the formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl,
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a -R is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure selected fro
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • each of R 21a , R , R , and R is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl,
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R c , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure selected from:
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl,
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure selected from:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • Ar 1 is selected from phenyl and heterocyclyl; and wherein Ar 1 is substituted with 0-2 groups independently selected from halogen, -NH 2 , -OH,— CN, C1-C3 alkyl, C1-C3 haloalkyl, Cl- C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 alkylamino, and C1-C3 dialkylamino; wherein each occurrence of R la and R lb is independently selected from hydrogen, halogen,— H 2 ,—OH, — CN, and C1-C3 alkyl; wherein n is an integer from 1-4; wherein Y 1 is selected from— O— and— CR 2 R 2b — ; wherein each of R 2a and R 2b is independently selected from hydrogen, halogen,— N3 ⁇ 4,—OH,— CN, and C1-C3 alkyl;
  • hetercycloalkyl selected from:
  • a 1 is selected from and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen, -NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR*; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— H 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhalo
  • the invention relates to a compound having a structure represented by a formula:
  • hetercycloalkyl selected from:
  • a 1 is selected from and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen, -NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR*; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— NH 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhal
  • the invention relates to a compound having a structure represented by a formula:
  • a 1 is selected from N and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen, -NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR*; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— H 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhal
  • the invention relates to a compound having a structure represented by a formula:
  • a 1 is selected from N and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen,— NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR 613 ; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— NH 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C
  • the invention relates to a compound having a structure represented by a formula:
  • a 1 is selected from N and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen,— NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR 613 ; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— NH 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C
  • the invention relates to a compound having a structure represented by a formula:
  • Ar is selected from phenyl and heterocyclyl; and wherein Ar 1 is substituted with 0-2 groups independently selected from halogen, -NH 2 , -OH, -CN, C1-C3 alkyl, C1-C3 haloalkyl, Cl- C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 alkylamino, and C1-C3 dialkylamino; wherein each occurrence of R la and R lb is independently selected from hydrogen, halogen,— H 2 ,—OH, — CN, and C1-C3 alkyl; wherein n is an integer from 1-4; wherein Z 1 is a 4- to 7-membered hetercycloalkyl selected from:
  • a 1 is selected from and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen,— NH 2 , -OH,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR 613 ; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— NH 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3
  • the invention relates to a compound having a structure represented by a formula:
  • Ar is selected from phenyl and heterocyclyl; and wherein Ar 1 is substituted with 0-2 groups independently selected from halogen, -NH 2 , -OH, -CN, C1-C3 alkyl, C1-C3 haloalkyl, Cl- C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 alkylamino, and C1-C3 dialkylamino; wherein each occurrence of R la and R lb is independently selected from hydrogen, halogen,— H 2 ,—OH, — CN, and C1-C3 alkyl; wherein n is an integer from 1-4; wherein Z 1 is a 4- to 7-membered hetercycloalkyl selected from:
  • a 1 is selected from and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen,— NH 2 , -OH,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR 613 ; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— NH 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3
  • the invention relates to a compound having a structure represented by a formula:
  • a 1 is selected from and CR 3 ; wherein R 3 is selected from hydrogen, halogen, —OH, and C1-C3 alkyl; wherein each occurrence of R 4 is independently selected from hydrogen, halogen,— NH 2 , -OH,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino; wherein A 2 is selected from N and CR 6a ; wherein A 3 is selected from N and CR 613 ; and wherein A 4 is selected from N and CR 6c ; wherein each of R 6a , R 6b , and R 6c , when present, is independently selected from hydrogen, halogen,— NH 2 ,—OH,— CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R c , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • R 21a wherein is an optional covalent bond, wherein valence is satisfied; wherein each of R R , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a -R is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a -R is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R a , R , R , and R is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R c , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a -R is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21c , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R a , R , R , and R e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a , R 21b , R 21d , and R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula: wherein is an optional covalent bond, wherein valence is satisfied; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formula:
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a fo
  • R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least three of R 21a -R 21e is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formu
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • R 21b , R 21c , and R 21d is independently selected from hydrogen, halogen,— CN, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 21a -R 21d is hydrogen; and wherein all other variables are as defined herein; or a pharmaceutically acceptable salt thereof.

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Abstract

Dans un aspect, l'invention concerne des modulateurs d'un récepteur NMDA, des dérivés de ceux-ci, et des composés associés, qui sont utiles en tant qu'inhibiteurs du récepteur NMDA ; des procédés synthétiques pour fabriquer les composés ; des compositions pharmaceutiques comprenant les composés ; et des méthodes de traitement ou de prévention de troubles neurologiques et psychiatriques associés à un dysfonctionnement du récepteur NMDA à l'aide des composés et des compositions. Cet abrégé est destiné être un outil de balayage dans des fins de recherche dans la technique particulière et n'est pas destiné à être limitant de la présente invention.
PCT/US2013/040408 2012-05-09 2013-05-09 Composés pour le traitement de troubles neurologiques WO2013170072A2 (fr)

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US9040581B1 (en) 2013-02-21 2015-05-26 The Florida State University Research Foundation, Inc. Methods of treatment using D-serine
WO2016030310A1 (fr) * 2014-08-27 2016-03-03 F. Hoffmann-La Roche Ag Dérivés d'azétidine substitués en tant que ligands de taar
CN107793362A (zh) * 2016-08-30 2018-03-13 江苏恩华药业股份有限公司 一种苯基哒嗪酮类衍生物的合成及其应用
WO2019012001A1 (fr) 2017-07-12 2019-01-17 Syngenta Participations Ag Dérivés d'oxadiazole microbiocides
WO2020007658A1 (fr) 2018-07-02 2020-01-09 Syngenta Crop Protection Ag Dérivés de 3-(2-thiényl)-5-(trifluorométhyl) -1,2,4-oxadiazole en tant que fongicides agrochimiques
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11484519B2 (en) 2019-03-07 2022-11-01 Florida State University Research Foundation, Inc. D-serine inhibit neuroinflammation due to a brain injury
US11547704B2 (en) 2016-06-08 2023-01-10 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof

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US5264125A (en) * 1989-09-08 1993-11-23 Ionics' Incorporated Process for manufacturing continuous supported ion selective membranes using non-polymerizable high boiling point solvents
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US5264125A (en) * 1989-09-08 1993-11-23 Ionics' Incorporated Process for manufacturing continuous supported ion selective membranes using non-polymerizable high boiling point solvents
US20100004261A1 (en) * 2004-12-30 2010-01-07 Richard Apodaca Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
US20110160223A1 (en) * 2008-05-09 2011-06-30 Dingledine Raymond J NMDA Receptor Antagonists for the Treatment of Neuropsychiatric Disorders

Cited By (21)

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Publication number Priority date Publication date Assignee Title
US9040581B1 (en) 2013-02-21 2015-05-26 The Florida State University Research Foundation, Inc. Methods of treatment using D-serine
US10307387B1 (en) 2013-02-21 2019-06-04 Florida State University Research Foundation, Inc. D-serine treatment for neurological disorders that cause seizures
US9925159B1 (en) 2013-02-21 2018-03-27 The Florida State University Research Foundation, Inc. D-serine treatment for neurological disorders that cause seizures
CN107001259A (zh) * 2014-08-27 2017-08-01 豪夫迈·罗氏有限公司 作为taar配体的取代的氮杂环丁烷衍生物
JP2017526661A (ja) * 2014-08-27 2017-09-14 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｔａａｒリガンドとしての置換アゼチジン誘導体
KR20170031763A (ko) * 2014-08-27 2017-03-21 에프. 호프만-라 로슈 아게 Taar 리간드로서의 치환된 아제티딘 유도체
US10023559B2 (en) 2014-08-27 2018-07-17 Hoffman-La Roche Inc. Substituted azetidine derivatives
KR101894681B1 (ko) 2014-08-27 2018-09-04 에프. 호프만-라 로슈 아게 Taar 리간드로서의 치환된 아제티딘 유도체
WO2016030310A1 (fr) * 2014-08-27 2016-03-03 F. Hoffmann-La Roche Ag Dérivés d'azétidine substitués en tant que ligands de taar
CN107001259B (zh) * 2014-08-27 2019-12-06 豪夫迈·罗氏有限公司 作为taar配体的取代的氮杂环丁烷衍生物
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11498896B2 (en) 2014-12-19 2022-11-15 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11547704B2 (en) 2016-06-08 2023-01-10 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
CN107793362A (zh) * 2016-08-30 2018-03-13 江苏恩华药业股份有限公司 一种苯基哒嗪酮类衍生物的合成及其应用
CN107793362B (zh) * 2016-08-30 2022-04-22 江苏恩华药业股份有限公司 一种苯基哒嗪酮类衍生物的合成及其应用
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
WO2019012001A1 (fr) 2017-07-12 2019-01-17 Syngenta Participations Ag Dérivés d'oxadiazole microbiocides
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
WO2020007658A1 (fr) 2018-07-02 2020-01-09 Syngenta Crop Protection Ag Dérivés de 3-(2-thiényl)-5-(trifluorométhyl) -1,2,4-oxadiazole en tant que fongicides agrochimiques
US11484519B2 (en) 2019-03-07 2022-11-01 Florida State University Research Foundation, Inc. D-serine inhibit neuroinflammation due to a brain injury

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