WO2024059745A2 - Antagonistes du récepteur n-méthyl-d-aspartate (rnmda) et utilisations correspondantes - Google Patents

Antagonistes du récepteur n-méthyl-d-aspartate (rnmda) et utilisations correspondantes Download PDF

Info

Publication number
WO2024059745A2
WO2024059745A2 PCT/US2023/074246 US2023074246W WO2024059745A2 WO 2024059745 A2 WO2024059745 A2 WO 2024059745A2 US 2023074246 W US2023074246 W US 2023074246W WO 2024059745 A2 WO2024059745 A2 WO 2024059745A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyridine
optionally substituted
composition
alkyl
bicyclo
Prior art date
Application number
PCT/US2023/074246
Other languages
English (en)
Other versions
WO2024059745A3 (fr
Inventor
Jason WALLACH
Adeboye Adejare
James GAMRAT
Original Assignee
Bexson Biomedical, Inc.
Saint Joseph's University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bexson Biomedical, Inc., Saint Joseph's University filed Critical Bexson Biomedical, Inc.
Publication of WO2024059745A2 publication Critical patent/WO2024059745A2/fr
Publication of WO2024059745A3 publication Critical patent/WO2024059745A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D345/00—Heterocyclic compounds containing rings having selenium or tellurium atoms as the only ring hetero atoms

Definitions

  • NMD AR N-methyl-D-aspartate receptor
  • the NMD AR must be open.
  • glutamate and glycine must bind to the NMD AR and the voltage dependent Mg 2+ block must be lifted. NMDARs in this state are called “activated.”
  • NMD AR antagonists fall into several categories: Competitive antagonists bind to and block the binding site of the neurotransmitter glutamate; glycine antagonists, which bind to and block the glycine site; noncompetitive antagonists inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists, which block the active channel.
  • One example of NMD AR uncompetitive antagonists are compounds called channel blockers, like ketamine, that act by blocking the ion channel through binding to a site within NMDARs. These compounds show use dependent inhibition as they bind to “activated” NMDARs.
  • NMD AR dopamine transporter
  • SERT serotonin receptor
  • compounds that selectively bind to NMD AR receptors over other ionotropic receptors may be valuable for the treatment of the various disorders, such as pain, depression, tinnitus, post-traumatic stress disorder, psychosis, schizophrenia, agitation, obsessive compulsive disorder, sexual dysfunction, anxiety, dementias, neurodegenerative diseases, pseudobulbar affect, headache, cluster headache, migraine, acute pain, post-operative pain, pain syndromes, neuropathic pain, chronic pain, complex regional pain syndrome, fibromyalgia, substance use disorders, drug addiction, alcoholism, hallucinations, delusions, insomnia, epilepsies, bipolar disorder, anorexia, or Parkinson’s disease.
  • the compounds of the present disclosure exhibit varying degrees of selectivity for NMDARs over other CNS targets, such as DAT or SERT.
  • NMD AR dysfunction has been implicated in various somatic and central nervous system diseases and disorders.
  • Selectivity for NMDARs can reduce undesired off-target interactions which can improve drug efficacy and tolerability for certain therapeutic indications.
  • polypharmacology for NMD AR and monoamine transporters including DAT, SERT and NET may enhance the efficacy and tolerability of NMD AR antagonists.
  • NMD AR antagonists like ketamine, memantine and DXM have various pharmacological limitations there is thus a need for new NMD AR antagonists with improved clinical profiles.
  • Inhibiting NMDARs with uncompetitive antagonists which bind to the PCP site of active NMDARs (use-dependent channel blockers) is believed to underlie the therapeutic activity of ketamine as a general anesthetic and for its use in treatment resistant depression and memantine for Alzheimer’s disease as a neuroprotective agent.
  • Dextromethorphan an uncompetitive NMD AR antagonist, is also used, in combination products to inhibit its metabolism, in pseudobulbar affect and in depression.
  • NMD AR antagonism may lead to analgesic actions and can disrupt the processes of hyperalgesia and allodynia in pain disorders.
  • these existing NMD AR antagonists have limitations related to their pharmacokinetic and pharmacodynamic properties.
  • DXM has potent off-target effects at SERT, which may contribute to its side effects, and has to be administered in combination with other compounds to inhibit its metabolism.
  • Ketamine has poor oral bioavailability and a short half-life. Additionally, there are ambiguities as to the extent of dissociative effects as well as bladder issues that ketamine has been associated with. Thus, there remains a need for novel NMD AR antagonists with improved clinical profiles.
  • the present disclosure generally relates to substituted methanamine compounds, conjugates, or salts of Formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutical compositions thereof.
  • the disclosure provides a compound represented by Formula (I): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 1 is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • the disclosure provides a compound represented by Formula (II): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • the disclosure provides a compound represented by Formula (III): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • R 7 is independently selected from: hydrogen;
  • the disclosure provides a compound represented by Formula (IV): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R 2 is selected from hydrogen; halogen;
  • R 7 is independently selected from: hydrogen;
  • the disclosure provides a compound represented by Formula (V): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from: Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R 8 ; and
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • the disclosure provides a compound represented by Formula (VI): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • the disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formulas (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable excipient.
  • the present disclosure generally relates to methods for treating a physical, psychiatric, or neurological disorder comprising inhibiting an ionotropic receptor by contacting the ionotropic receptor with a compound represented by the structure of Formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutical compositions thereof.
  • the present disclosure provides a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a compound represented by the structure of Formula (I):
  • R 1 is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (II): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from: Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R 8 ; and
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (III): (ill); or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (IV): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • R 7 is independently selected from: hydrogen;
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (V): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (VI): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • a series of substituted methanamine compounds and pharmaceutical compositions for treating a physical, psychiatric, or neurological disorder examples include, but are not limited to, pain, depression, tinnitus, post-traumatic stress disorder, etc.
  • the compounds disclosed herein are V-m ethyl -D-aspartate receptor (NMD AR) antagonists.
  • methods for treating a physical, psychiatric, or neurological disorder comprising inhibiting an ionotropic receptor by contacting the ionotropic receptor with a compound disclosed herein and pharmaceutical compositions thereof.
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R 1 is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from: Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R 8 ; and C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 and R 5 are combined with the nitrogen to which it is attached to form a 6-membered heterocycle; with the proviso that the compound of Formula I is not [0028]
  • R 1 is selected from phenyl and 5- to 10-membered heteroaryl; wherein the phenyl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen, Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-5 carbocycle, each of which is optionally substituted with one or more R 7 ;
  • R 3 is C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one or more R 8 ;
  • R 4 and R 5 are each independently selected from: hydrogen, CMO alkyl, and C3-5 cycloalkyl, wherein the CMO alkyl is optionally substituted with C3-5 cycloalkyl; or R 4 and R 5 are combined with the nitrogen to which it is attached to form a 6-membered heterocycle;
  • R 6 is C O alkyl, wherein the CMO alkyl is optionally substituted with halogen;
  • R 7 is C3-5 cycloalkyl
  • R 8 is CMO alkyl.
  • R 1 is selected from phenyl, imidazolyl, thiophenyl, and selenophenyl; wherein the phenyl, imidazolyl, thiophenyl, and selenophenyl are each optionally substituted with one or more R 6 .
  • R 2 is selected from hydrogen, methyl, ethyl, propyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, and cyclopentyl, each of which is optionally substituted with one or more R 7 .
  • R 3 is cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 4 and R 5 are each independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, iso-butyl, tert-butyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, cyclopropyl, cyclobutyl, or cyclopentyl; or R 4 and R 5 are combined with the nitrogen to which it is attached to form piperidinyl.
  • R 6 is methyl or CF3.
  • R 7 is cyclopropyl or cyclobutyl.
  • R 1 is selected from phenyl and selenophenyl; wherein the phenyl and selenophenyl are each optionally substituted with one or more R 6 .
  • R 2 is selected from hydrogen, methyl, butyl, ethenyl, propenyl, butenyl, ethynyl, cyclopropyl, and cyclobutyl, each of which is optionally substituted with one or more R 7 .
  • R 3 is cyclopentyl.
  • R 4 and R 5 are each independently selected from: hydrogen, methyl, ethyl, isopropyl, sec-butyl, methyl-cyclopropyl, cyclobutyl; or R 4 and R 5 are combined with the nitrogen to which it is attached to form piperidinyl.
  • R 6 is CF3.
  • R 7 is cyclopropyl or cyclobutyl.
  • R 1 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 6 .
  • R 1 is phenyl, optionally substituted with one or more R 6 .
  • R 1 is a cycloalkyl. In some embodiments, R 1 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 6 .
  • R 1 is a cycloalkenyl.
  • R 1 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 6 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 1 is a 6-membered heteroaryl.
  • R 1 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 5-membered heteroaryl.
  • R 1 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 6-membered heterocycloalkenyl.
  • R 1 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 6 .
  • R 1 is a 5-membered heterocycloalkenyl.
  • R 1 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 6-membered heterocycloalkyl.
  • R 1 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 5-membered heterocycloalkyl.
  • R 1 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 4-membered heterocycloalkyl.
  • R 1 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 6-6 fused ring system.
  • R 1 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 6 .
  • R 1 is a 5-6 fused ring system. In some embodiments, R 1 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine,
  • R 1 is a 5-5 fused ring system. In some embodiments, R 1 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thioph
  • R 1 is a bridged ring system.
  • R 1 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 6 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl. In some embodiments, R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl. In some embodiments, R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 4-membered heterocycloalkyl.
  • R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thioph
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • the compound has the structure:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl.
  • R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 4-membered heterocycloalkyl.
  • R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine,
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be a 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be a 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • compound of Formula (II) is selected from:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system selected. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2- c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2- d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4- c]thiophene, any of which is optionally
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • the compound of Formula (III) is selected from:
  • the compound of Formula (III) is selected from:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thioph
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • the compound of Formula (IV) is selected from:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thioph
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, bicyclofl.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl. In some embodiments, R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 4-membered heterocycloalkyl.
  • R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • compound of Formula (V) is selected from: [00193]
  • R 3 is selected from:
  • Ci-io alkyl C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more R 8 ;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl.
  • R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 4-membered heterocycloalkyl. In some embodiments, R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 . In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thioph
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • compound of Formula (VI) is selected from:
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI) is selected from Table 1 or Table la.
  • Methods of administration of a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) as discussed herein may be used for the treatment of a physical, psychiatric, or neurological disorder.
  • the compounds disclosed herein are n-methyl-d-aspartate receptor (NMD AR) antagonists.
  • the compounds disclosed herein are ionotropic receptor inhibitors.
  • compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof.
  • Pharmaceutical compositions may comprise at least a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents.
  • compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation may be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound, salt or conjugate may be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
  • the pharmaceutical compositions may also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.
  • Methods for formulation of a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • the compounds, salts or conjugates may be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents).
  • active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • compositions and formulations may be sterilized. Sterilization may be accomplished by filtration through sterile filtration, heat, light, radiation, chemicals or other forms.
  • compositions described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • administration routes including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be formulated for administration as an injection.
  • formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles.
  • Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity or tonicity of the solution or suspension.
  • the solution or suspension may also contain suitable stabilizers.
  • Injections may be formulated for bolus injection or continuous infusion.
  • compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle.
  • a unit dosage injectable form e.g., solution, suspension, emulsion
  • Such vehicles may be inherently non-toxic, and non-therapeutic.
  • Vehicles may be water, saline, Ringer’s solution, dextrose solution, organic solvents (e.g., ethanol, DMF, DMSO), human serum albumin, and combinations thereof.
  • Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used. Liposomes may be used as carriers. The vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
  • the disclosure relates to methods and compositions of Formula (I), (II), (III), (IV), (V), or (VI) formulated for formulated into a pharmaceutical composition suitable for injection into the body including intramuscular, subcutaneous, intravenous, intratympanic, intraocular, epidural injection.
  • formulations suitable for injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, complexing agents (e.g., cyclodextrins) or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, cremophor and the like), vegetable oils and organic esters, such as ethyl oleate.
  • formulations suitable for subcutaneous injection contain additives such as preserving, wetting, emulsifying, and dispensing agents.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • compounds described herein are formulated in aqueous solutions, in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • Parenteral injections may involve bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative.
  • the pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • an mucoadhesive polymer selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • the disclosure relates to methods and compositions of Formula (I), (II), (III), (IV), (V), or (VI) formulated for oral delivery to a subject in need.
  • a composition is formulated so as to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the mouth or esophagus.
  • the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the stomach and/or intestines.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) are provided in modified release dosage forms.
  • suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multi-particulate devices, and combinations thereof.
  • the compositions may also comprise non-release controlling excipients.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) are provided in enteric coated dosage forms. These enteric coated dosage forms can also comprise non-release controlling excipients.
  • the compositions are in the form of enteric-coated granules, as controlled-release capsules for oral administration.
  • the compositions can further comprise cellulose, cyclodextrins, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate.
  • the compositions are in the form of enteric-coated pellets, as controlled-release capsules for oral administration.
  • compositions can further comprise cyclodextrins, glycerol monostearate 40- 50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) are enteric-coated controlled-release tablets for oral administration.
  • the compositions can further comprise carnauba wax, crospovidone, cyclodextrins, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow ferric oxide.
  • sustained-release preparations comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may also be prepared.
  • sustained-release preparations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound, salt or conjugate, and these matrices may be in the form of shaped articles (e.g., films or microcapsules).
  • sustained-release matrices may include polyesters, hydrogels (e.g., poly(2- hydroxy ethyl -methacrylate), or poly(vinyl alcohol)), polylactides, copolymers ofL-glutamic acid and y ethyl -L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 -hydroxybutyric acid.
  • polyesters e.g., poly(2- hydroxy ethyl -methacrylate), or poly(vinyl alcohol)
  • polylactides e.g., poly(2- hydroxy ethyl -methacrylate), or poly(vinyl alcohol)
  • compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer.
  • This formulation may be a lyophilized formulation or an aqueous solution.
  • Acceptable carriers, excipients, and/or stabilizers may be nontoxic to recipients at the dosages and concentrations used.
  • Acceptable carriers, excipients, and/or stabilizers may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non-ionic surfactants or polyethylene glycol.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid and methionine
  • preservatives polypeptides
  • proteins such as serum albumin or gelatin
  • hydrophilic polymers amino acids
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) can further comprise calcium stearate, crospovidone, cyclodextrins, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) are provided in effervescent dosage forms.
  • These effervescent dosage forms can also comprise nonrelease controlling excipients.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) can be provided in a dosage form that has at least one component that can facilitate the immediate release of an active agent, and at least one component that can facilitate the controlled release of an active agent.
  • the dosage form can be capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours.
  • the compositions can comprise one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi- permeable membrane and as swellable substances.
  • compositions Formula (I), (II), (III), (IV), (V), or (VI) are provided in a dosage form for oral administration to a subject, which comprise one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) provided herein can be in unit-dosage forms or multiple-dosage forms.
  • Unit-dosage forms refer to physically discrete units suitable for administration to human or non-human animal subjects and packaged individually. Each unit-dose can contain a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients.
  • unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules.
  • unit-dosage forms may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which can be administered in segregated unit-dosage form.
  • Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons.
  • the multiple dosage forms comprise different pharmaceutically active agents.
  • compositions of Formula (I), (II), (III), (IV), (V), or (VI) may also be formulated as a modified release dosage form, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to known methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126, which are herein incorporated by reference in their entirety).
  • treating physical, psychiatric, or neurological disorders comprises inhibiting an ionotropic receptor.
  • the ionotropic receptor comprises NMD AR or DAT.
  • treating physical, psychiatric, or neurological disorders comprises inhibiting NMD AR.
  • treating physical, psychiatric, or neurological disorders comprises inhibiting DAT.
  • inhibiting an ionotropic receptor comprises administering a compound or a salt thereof of Formula (I), (II), (III), (IV), (V), or (VI).
  • the physical, psychiatric, or neurological disorder comprises pain, depression, tinnitus, post-traumatic stress disorder, psychosis, schizophrenia, agitation, obsessive compulsive disorder, sexual dysfunction, anxiety, dementias, neurodegenerative diseases, pseudobulbar affect, headache, cluster headache, migraine, acute pain, post-operative pain, pain syndromes, neuropathic pain, chronic pain, complex regional pain syndrome, fibromyalgia, substance use disorders, drug addiction, alcoholism, hallucinations, delusions, insomnia, epilepsies, bipolar disorder, anorexia, or Parkinson’s disease.
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an ionotropic receptor by contacting the ionotropic receptor with a compound represented by the structure of Formula (I): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 1 is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 1 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 6 .
  • R 1 is phenyl, optionally substituted with one or more R 6 .
  • R 1 is a cycloalkyl.
  • R 1 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 6 .
  • R 1 is a cycloalkenyl.
  • R 1 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 6 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 1 is a 6-membered heteroaryl.
  • R 1 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 5-membered heteroaryl.
  • R 1 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 6-membered heterocycloalkenyl.
  • R 1 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 6 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 1 is a 5-membered heterocycloalkenyl.
  • R 1 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 6-membered heterocycloalkyl.
  • R 1 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 5-membered heterocycloalkyl.
  • R 1 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 4-membered heterocycloalkyl.
  • R 1 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 6 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 1 is a 6-6 fused ring system.
  • R 1 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 6 .
  • R 1 is a 5-6 fused ring system. In some embodiments, R 1 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 1 is a 5-5 fused ring system. In some embodiments, R 1 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c)
  • R 1 is a bridged ring system.
  • R 1 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 6 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thioph
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl. In some embodiments, R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 4-membered heterocycloalkyl. In some embodiments, R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 . In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thi
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • the compound of Formula (I) is selected from:
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (II): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 3 is selected from:
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c)
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl.
  • R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 4-membered heterocycloalkyl.
  • R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thi
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • compound of Formula (II) is selected from:
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (III): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine, o
  • R 2 is a 5-5 fused ring system selected. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2- c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2- d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4- c]thiophene, any of which is optional
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • the compound of Formula (III) is selected from:
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (IV): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 7 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 4-membered heterocycloalkyl.
  • R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).
  • R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine,
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thi
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.
  • the compound of Formula (IV) is selected from:
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by Formula (V): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 2 is selected from hydrogen; halogen;
  • R 3 is selected from:
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 2 is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R 7 .
  • R 2 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 7 .
  • R 2 is phenyl, optionally substituted with one or more R 7 .
  • R 2 is a cycloalkyl.
  • R 2 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • R 2 is a cycloalkenyl.
  • R 2 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 7 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 2 is a 6-membered heteroaryl.
  • R 2 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 5-membered heteroaryl.
  • R 2 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 6-membered heterocycloalkenyl.
  • R 2 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-membered heterocycloalkenyl.
  • R 2 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 6-membered heterocycloalkyl.
  • R 2 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 5-membered heterocycloalkyl.
  • R 2 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 7 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 2 is a 4-membered heterocycloalkyl. In some embodiments, R 2 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 7 . In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V). [00380] In some embodiments, R 2 is a 6-6 fused ring system.
  • R 2 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 7 .
  • R 2 is a 5-6 fused ring system. In some embodiments, R 2 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine,
  • R 2 is a 5-5 fused ring system. In some embodiments, R 2 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thi
  • R 2 is a bridged ring system.
  • R 2 is a bridged ring system selected from norbornane, bicyclofl.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 7 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl. In some embodiments, R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 4-membered heterocycloalkyl.
  • R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system. In some embodiments, R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[4,5-c]pyridine,
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thi
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, and 1,4-piperazine, 1,4-oxazepane, 1,4-diazepane.
  • compound of Formula (V) is selected from:
  • a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (VI): or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
  • R 3 is selected from: Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more R 8 ; and
  • C3-10 carbocycle and 3- to 10-membered heterocycle wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 8 ;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
  • R 3 is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R 8 .
  • R 3 is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R 8 .
  • R 3 is phenyl, optionally substituted with one or more R 8 .
  • R 3 is a cycloalkyl.
  • R 3 is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • R 3 is a cycloalkenyl.
  • R 3 is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R 8 .
  • the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.
  • R 3 is a 6-membered heteroaryl.
  • R 3 is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 5-membered heteroaryl.
  • R 3 is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 6-membered heterocycloalkenyl.
  • R 3 is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom selected from dihydropyridine, tetrahydropyr
  • R 3 is a 5-membered heterocycloalkenyl.
  • R 3 is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 6-membered heterocycloalkyl.
  • R 3 is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 5-membered heterocycloalkyl.
  • R 3 is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 4-membered heterocycloalkyl.
  • R 3 is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R 8 .
  • the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).
  • R 3 is a 6-6 fused ring system.
  • R 3 is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R 8 .
  • R 3 is a 5-6 fused ring system.
  • R 3 is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, ox
  • R 3 is a 5-5 fused ring system. In some embodiments, R 3 is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thi
  • R 3 is a bridged ring system.
  • R 3 is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R 8 .
  • the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.
  • each of R 4 or R 5 may independently be 3- to 10-membered heterocycle. In some embodiments, each of R 4 or R 5 may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane. [00422] In some embodiments, compound of Formula (VI) is selected from:
  • a m ethod of treating a physical, psychiatric, or neurological disorder comprises administering a composition comprising a compound of Table 1.
  • a m ethod of treating a physical, psychiatric, or neurological disorder comprises administering a composition comprising a compound of Table la.
  • the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a N-methyl-D-aspartate receptor (NMD AR).
  • NMD AR N-methyl-D-aspartate receptor
  • An inhibitor compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of NMD AR by about 5% to about 90% relative to pre-treatment value or an untreated control NMD AR.
  • an inhibitor or antagonist compound of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of NMD AR by about 5% to about 90% relative to ketamine, phencyclidine (PCP), or other inhibitor of NMD AR.
  • An inhibitor may inhibit activity of NMD AR by at least about 5% relative to pre-treatment value or an untreated control NMD AR, such as without any agonist or antagonist bound.
  • An inhibitor may inhibit activity of NMD AR by at most about 90% relative to pre-treatment value or an untreated control NMD AR, such as without any agonist or antagonist bound.
  • An inhibitor may inhibit activity of NMD AR by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about
  • the compounds of Formula (I), (II), (III), (IV), (V), or (VI) show PCP site NMD AR binding affinities (e.g., measured as a dissociation constant Kd or Ki) in the range of 0.1-100,000.
  • the inhibitors may fully inhibit NMDARs.
  • the inhibitors may inhibit 100% activity of NMDARs.
  • the compound may inhibit activity NMD AR such as by competitively binding to NMD AR, such as displacing MK-801 or TCP.
  • the compounds of Formula (I), (II), (III), (IV), (V), or (VI) may displace a ligand bound to NMD AR.
  • the compound binds to the PCP site within the NMD AR, thus acting as a channel blocker.
  • the binding activity of the compound may be determined by a radioligand binding assay.
  • the binding activity of the compound may be determined by a competitive radioligand binding assay.
  • the measured activity of the compound may be determined by a competitive radioligand binding assay relative to 3 H-MK-801 or 3 H-TCP.
  • the compound binds to NMD AR with a binding affinity (e.g., Ki). In some embodiments, the compound binds with a Ki less than 100 pM.
  • the compound binds with a Ki of about 0.1 nM to about 1 x 10 6 nM, about 0.2 nM to about 9* 10 5 nM, about 0.3 nM to about 8* 10 5 nM, about 0.4 nM to about 7* 10 5 nM, about 0.5 nM to about 6* 10 5 nM, about 0.6 nM to about 5* 10 5 nM, about 0.7 nM to about 4* 10 5 nM, about 0.8 nM to about 3 * 10 5 nM, about 0.9 nM to about 2* 10 5 nM, about 1 nM to about 1 * 10 5 nM, about 5 nM to about 5* 10 4 nM, about 10 nM to about 1 * 10 3 nM, about 50 nM to about 5* 10 3 nM, about 100 nM to about 2* 10 3 nM, or about 500 nM to about 1 * 10 3 nM.
  • the compound may bind to NMDARs with a Ki of about 5 * 10 4 nM, about 2 * 10 4 nM, about 1 * 10 4 nM, 5 * 10 3 nM, about 2* 10 3 nM, about 1 * 10 3 nM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, or about 10 nM.
  • the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a dopamine transporter (DAT).
  • DAT dopamine transporter
  • An inhibitor compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of DAT by about 5% to about 100% relative to pre-treatment value or an untreated control DAT.
  • an inhibitor or antagonist compound of Formula (I), (II), (III), (IV), (V), or (Vl) may inhibit activity of DAT by about 5% to about 90% relative to desipramine, GBR 12935, cocaine, methylphenidate, bupropion 12935 or other inhibitor of DAT.
  • An inhibitor may inhibit activity of DAT by at least about 5% relative to pre-treatment value or an untreated control DAT.
  • An inhibitor may inhibit activity of DAT by at most about 90% relative to pre-treatment value or an untreated control
  • An inhibitor may inhibit activity of DAT at a physiologically relevant concentration by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 100%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 50%, about 40%
  • an inhibitor may inhibit DAT activity at physiologically relevant concentrations by about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 60% to about 90%, about 70% to about 90%, or about 50% to about 100%.
  • An inhibitor may inhibit activity of DAT by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to pre-treatment capacity or an untreated control DAT.
  • a physiologically relevant inhibitor of DAT may have a potency estimate, such as a receptor binding affinity (e.g., I ⁇ d or Ki) of about 0.1 to about 100,000 nM.
  • the binding affinity of the compounds disclosed herein may be determined by a radioligand binding assay.
  • potency to inhibit substrate uptake at DAT can be measured from a transporter functional assay.
  • the binding affinity of the compounds disclosed herein may be determined by a competitive radioligand binding assay or a functional assay of DAT transport.
  • the method of treating a physical, psychiatric, or neurological disorder comprises binding to and reducing an activity of an ionotropic receptor, such as NMD AR, or a transporter such as DAT, or SERT.
  • An inhibitor of Formula (I), (II), (III), (IV), (V), or (VI) may show selectivity forNMDARs relative to SERT and/or DAT by about 1-fold, 2-fold, 3-fold, 5- fold, 10-fold, about 20-fold, about 30-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 500-fold, about 1,000-fold, about 2,000-fold, about 3,000-fold, 5,000-fold or about 10,000-fold.
  • the inhibitor reduces activity of the ionotropic receptor with selectivity for NMD AR relative to SERT and/or DAT by about 10-fold to about 1,000-fold, by about 20-fold to about 500-fold, by about 30-fold to about 300-fold, by about 50-fold to about 200-fold, by about 10-fold to about 500-fold, by about 20-fold to about 1,000-fold, by about 30- fold to about 2,000-fold, by about 50-fold to about 5,000-fold, by about 1,000-fold to about 5,000-fold, by about 1-fold to about 10-fold, by about 2-fold to about 20-fold, by about 3-fold to about 30-fold, or by about 5-fold to about 50-fold.
  • the binding affinity of the compounds disclosed herein may be determined by a radioligand binding assay. In some embodiments, the binding affinity of the compounds disclosed herein may be determined by a competitive radioligand binding assays. In some instances, selectivity can be determined using functional assays of channel or transporter activity. In some instances, selectivity can be determined using a combination of radioligand binding and functional assays. In some instances, the inhibitor of Formula (I), (II), (III), (IV), (V), or (VI) selectively inhibits NMDARs with selectivity over other targets, such as the monoamine transporters DAT or SERT.
  • the inhibitor of Formula (I), (II), (III), (IV), (V), or (VI) shows polypharmacology for NMD AR and one or more additional receptors or transporters such as the monoamine transporters DAT, NET and SERT.
  • the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a serotonin receptor (SERT).
  • SERT serotonin receptor
  • An inhibitor compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of SERT by about 5% to about 100% relative to pre-treatment value or an untreated control SERT.
  • an inhibitor or antagonist compound of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of SERT at a physiologically relevant concentration by about 5% to about 90% relative to untreated control.
  • An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by at least about 5% relative to pre-treatment value or an untreated control SERT, such as without any inhibitor bound.
  • An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by up to 100% relative to pre-treatment value or an untreated control SERT, such as without any inhibitor bound.
  • An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50%
  • An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% relative to pre-treatment capacity or an untreated control.
  • a physiologically relevant inhibitor of SERT may have a potency estimate, such as a receptor binding affinity (e.g., I ⁇ d or Ki) of about 0.1 to about 100,000 nM.
  • the binding activity of the compounds disclosed herein may be determined by a radioligand binding assay. In some embodiments, the binding activity of the compounds disclosed herein may be determined by a competitive radioligand binding assay.
  • the method of treating a physical, psychiatric, or neurological disorder comprises selectively binding to an NMD AR as compared to another ionotropic receptor.
  • the other ionotropic receptor comprises SERT or DAT.
  • the compound selectively binds to NMD AR by about 10% to about 100%, by about 20% to about 100%, by about 30% to about 100%, by about 40% to about 100%, by about 50% to about 100%, by about 60% to about 100%, by about 70% to about 100%, by about 80% to about 100%, by about 90% to about 100%, by about 10% to about 90%, by about 20% to about 90%, by about 30% to about 90%, by about 40% to about 90%, by about 50% to about 90%, by about 60% to about 90%, by about 70% to about 90%, by about 80% to about 90%, by about 20% to about 80%, by about 30% to about 80%, by about 40% to about 80%, by about 50% to about 80%, by about 60% to about 80%, by about 70% to about 80%, by about 80% to about 80%, by about 20% to about 70%, by about 30% to about 70%, by about 40% to about 70%, by about 50% to about 80%, by about 60% to about 80%, by about 70% to about 80%, by about 80% to about 80%, by about 20% to about 70%, by about 30% to
  • the method of the method of treating a physical, psychiatric, or neurological disorder comprises binding an compound of Formula (I), (II), (III), (IV), (V), or (VI) to NMDARs with a Ki of about 0.1 nM to about 100,000 nM.
  • the inhibitor may bind to NMDARs with a Ki of about 0.1 nM to about 1 * 10 6 nM, about 0.2 nM to about 9* 10 5 nM, about 0.3 nM to about 8* 10 5 nM, about 0.4 nM to about 7* 10 5 nM, about 0.5 nM to about 6* 10 5 nM, about 0.6 nM to about 5* 10 5 nM, about 0.7 nM to about 4* 10 5 nM, about 0.8 nM to about 3 * 10 5 nM, about 0.9 nM to about 2* 10 5 nM, about 1 nM to about 1 * 10 5 nM, about 5 nM to about 5* 10 4 nM, about 10 nM to about 1 * 10 3 nM, about 50 nM to about 5* 10 3 nM, about 100 nM to about 2* 10 3 nM, or about 500 nM to about 1 * 10 3 nM.
  • the compound may bind to NMDARs with a Ki of about 5* 10 4 nM, about 2* 10 4 nM, about 1 x 10 4 nM, 5* 10 3 nM, about 2* 10 3 nM, about 1 x 10 3 nM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, or about 10 nM.
  • the binding affinity of the compounds disclosed herein may be determined by a radioligand binding assay. In some embodiments, the binding affinity of the compounds disclosed herein may be determined by a competitive radioligand binding assay.
  • C x -y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • Ci-ealkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • -C x.y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • -Ci-ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • C x.y alkenyl and “C x.y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term -C x.y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • -C2-ealkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • the term -C x.y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain.
  • -C2-ealkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • Alkylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • an alkylene comprises one to five carbon atoms (z.e., C1-C5 alkylene).
  • an alkylene comprises one to four carbon atoms (z.e., Ci- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (z.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (z.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (z.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (z.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (z.e., C2-C5 alkylene).
  • an alkylene comprises three to five carbon atoms (z.e., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein.
  • alkenylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively.
  • an alkenylene comprises two to five carbon atoms (z.e., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (z.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (z.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (z.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (z.e., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (z.e., C3-C5 alkenylene).
  • alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein.
  • "Alkynylene” refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • an alkynylene comprises two to five carbon atoms (z.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (z.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (z.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (z.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (z.e., Cs-Cs alkynylene).
  • an alkynylene comprises three to five carbon atoms (z.e., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon.
  • Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • a bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • a bicyclic carbocycle further includes spiro bicylic rings such as spiropentane.
  • a bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbornyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclofl. l.l]pentanyl.
  • aryl refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) 7t-electron system in accordance with the Huckel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl” or the prefix "ar” (such as in "aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents such as those substituents described herein.
  • cycloalkyl refers to a saturated ring in which each atom of the ring is carbon.
  • Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings.
  • a cycloalkyl comprises three to ten carbon atoms.
  • a cycloalkyl comprises five to seven carbon atoms.
  • the cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbomyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo[l. l.l]pentanyl, and the like.
  • cycloalkyl is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents such as those substituents described herein.
  • cycloalkenyl refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • cycloalkenyl is meant to include cycloalkenyl radicals that are optionally substituted by one or more substituents such as those substituents described herein.
  • halo or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-chloromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the haloalkyl radical is optionally further substituted as described herein.
  • heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • heteroatoms include N, O, Si, P, B, S, and Se atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene.
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • a bicyclic heterocycle further includes spiro bicylic rings such as 2-oxa-6-azaspiro[3.3]heptane.
  • heterocycle is meant to encompass “heteroaryl,” “heterocycloalkyl,” and “heterocycloalkenyl.”
  • heteroaryl refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, sulfur and selenium.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) 7t-electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (
  • heterocycloalkyl refers to a saturated ring with carbon atoms and at least one heteroatom.
  • heteroatoms include N, O, Si, P, B, S, and Se atoms.
  • Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
  • heterocycloalkenyl refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. In some embodiments, heteroatoms include N, O, Si, P, B, S, and Se atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms.
  • the heterocycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydro
  • alkoxy or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes 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, z.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • substitution may cause a compound to have a formal charge.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, cyclodextrins; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium, magnesium
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, ion exchange resins, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds disclosed herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, 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 usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 C1, 123 I, 124 I, 125 I, 131 1, 32 P and 33 P.
  • isotopically-labeled compounds described herein, 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.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds disclosed herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound disclosed herein exists in the R configuration. In some embodiments, the compound disclosed herein exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • compounds disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.
  • stereoisomers are obtained by stereoselective synthesis.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • pH Measurements - pH readings were obtained using an Orion 3 star (Thermo Scientific, USA) pH meter coupled with either a Thermo pH electrode (9142BN) or an Orion 8103BNUWP Ross Ultra Semi-micro pH probe (Thermo Scientific, USA) containing 3M KC1 ROSS Orion filling solution (Thermos Scientific, USA).
  • High Performance Liquid Chromatography - HPLC spectra were obtained on an Agilent 1260 Infinity system that includes a 1260 quaternary pump VL, a 1260 ALS autosampler, a 1260 Thermostatted Column Compartment, and a 1200 DAD Multiple Wavelength Detector (Agilent Technologies, Santa Clara, CA, USA). The detection wavelength was set at 220 nm for purity. Separation for compounds was achieved using a Zorbax Eclipse Plus-C18 analytical column (5 pm, 4.6 x 150 mm) from Agilent (Agilent Technologies, Santa Clara, CA, USA).
  • Mobile phase A consisted of 10 mM aqueous ammonium formate buffer titrated to pH 4.5 (with 10 mM formic acid) and mobile phase B consisted of acetonitrile.
  • Compounds were prepared as 2 mg/mL solutions in 70:30 A:B or 50:50 A:B.
  • the injection volume of samples was 10 pL, flow rate was 1.0 mL/min, and the column temperature was set at 25 °C.
  • Run time was 10 minutes with a mobile phase ratio (isocratic) of 70% A and 30% B or 50% A and 50% B. All samples were run in duplicate with a wash of the injector (70:30 A:B or 50:50 A:B) between runs.
  • Chromatograms were analyzed using the Agilent ChemStation Software (Agilent Technologies, Santa Clara, CA, USA).
  • Biotage Automated Flash Chromatography Automated flash chromatography was performed using IsoleraTM One Flash Chromatography Systems from Biotage (Uppsala, Sweden). Separations were performed using SiO2 (Sigma-Aldrich, St. Louis, MO) as a stationary phase and the following organic solvents as mobile phases: hexanes (Sigma-Aldrich, St. Louis, MO) and ethyl acetate (EtOAc) (Sigma-Aldrich, St. Louis, MO). In some cases, triethylamine was used as an additive.
  • SiO2 was manually loaded into either SNAP KP Sil 50 g or SNAP KP Sil 100 g cartridges and equilibrated with the selected mobile phase prior to loading the sample.
  • Flow rate of solvent was 100 mL/min.
  • UV absorbance was monitored (254 and 280 nm) and the absorbance threshold for fraction collection was set to either 10 or 40 mAu.
  • Fractions 14 mL were collected in a 16 x 100 mm rack. Chromatograms were analyzed in the internal Spektra software (Biotage, Uppsala, Sweden).
  • the solution was heated with a heating mantle to maintain a temperature between 80- 90°C and then cyclopropyl phenyl ketone (1.9 mL, 2.01 g, 13.7 mmol) in dry (3 molecular sieves) toluene (10 mL) was added dropwise over ⁇ 1 hour (h) via an addition funnel.
  • the reaction was allowed to stir between 80-90°C for 1 h and then cooled to room temperature (rt) overnight.
  • the reaction was quenched by the addition of a saturated NaHCOs solution ( ⁇ 20 mL), diluted with EtOAc (-100 mL), and the resulting thick white suspension filtered through a pad of celite.
  • the solution was heated with a heating mantle to maintain a temperature between 80- 90°C and then cyclopentyl phenyl ketone (9.8 mL, 10.2 g, 58.2 mmol) was added over 5 min via syringe.
  • the reaction was allowed to stir between 80-90°C for 4 h and then cooled to rt overnight.
  • the reaction was quenched with brine ( ⁇ 20 mL), diluted with EtOAc (-100 mL), and the resulting thick white suspension filtered through a pad of celite.
  • the filter cake was washed with EtOAc (3 x 50 mL) and the combined washes and filtrate were transferred to a separatory funnel.
  • the solution was heated with a heating mantle to maintain a temperature between 80- 90°C and then cyclohexyl phenyl ketone (2.02 g, 10.7 mmol) in dry (3 A molecular sieves) toluene (20 mL) was added over 30 minutes (min) via an addition funnel.
  • the reaction was allowed to stir between 80-90°C for 2.5 h, cooled to rt, and quenched with brine (-20 mL).
  • the mixture was diluted with EtOAc (-100 mL) and the resulting thick white suspension filtered through a pad of celite.
  • the filter cake was washed with EtOAc (3 x 50 mL) and the combined washes and filtrate were transferred to a separatory funnel.
  • the oil was directly converted to the HC1 salt by dissolving in EtOH (20 mL) and titrating with concentrated HC1 until pH ⁇ 2 as determined using a pH meter.
  • the mixture was concentrated under a warm stream of air with repeat evaporation of EtOH additions (3 x -5 mL) to remove excess HC1 and water.
  • the resulting solids were washed with Et2O (3 x -5 mL) and dried to afford 1 -cyclopropyl- 1-phenylethan-l -amine (2) hydrochloride (200 mg, 30.9% yield) as a white powder.
  • the biphasic mixture was stirred vigorously for 2 h at rt and then diluted with diH2O (50 mL) and EtOAc (-150 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diftO (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum to afford a light yellow oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (40 mL) and adding concentrated HC1 (485 pL).
  • the aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with diH 2 O (20 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated under vacuum to afford a colorless transparent oil.
  • the crude product was purified by flash chromatography with a stepwise gradient (SiO2, 9: 1 hexanes:EtOAc to 8:2 hexanes:EtOAc to 7:3 hexanes :EtO Ac) to afford cyclobutyl(cyclopentyl)(phenyl)methanamine (7) (300 mg, 24%) as a colorless transparent oil.
  • the purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding concentrated HC1 (119 pL). The mixture was concentrated under a warm stream of air with evaporation of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solids were washed with Et2O (3 x -5 mL) and dried to afford a white powdery solid. The salt was crystallized by dissolving in a minimum volume of absolute EtOH and layering with Et2O followed by storing at 0°C to give a white crystalline powder.
  • the purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (128 pL). The mixture was concentrated under a warm stream of air with evaporation of repeat EtOH additions (3 x ⁇ 5 mL) to remove excess HC1 and water. The resulting solids were washed with hexanes (3 x ⁇ 10 mL) and dried to afford a white powdery solid.
  • the organic layer was extracted further with IM HC1 (3 x 100 mL) and the combined aqueous layers were basified with NH4OH.
  • the aqueous layer was extracted with EtOAc (3 x 75 mL), washed with diH 2 O (20 mL) and brine (20 mL), and dried over anhydrous Na 2 SO4.
  • the organic layer was concentrated under vacuum to afford a yellow oil.
  • the crude product was purified by flash chromatography (SiO 2 , 9: 1 hexanes :EtO Ac to 7:3 hexanes :EtO Ac) to afford 2-cy cl obutyl-1 -cyclopentyl- 1-phenylethan-l - amine (9) (200 mg, 22.8%) as a colorless transparent oil.
  • the purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (75 pL). The mixture was concentrated under a warm stream of air with evaporation of repeat EtOH additions (3 x -5 mL) to remove excess HC1 and water.
  • the biphasic mixture was stirred vigorously for 3 h at rt and then diluted with diH 2 O (30 mL) and EtOAc (-100 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diH 2 O (20 mL) and brine (20 mL), dried over anhydrous Na 2 SO4, and concentrated under vacuum to afford a yellow transparent oil.
  • the crude product was purified by flash chromatography with a stepwise gradient (SiO 2 , 8:2 hexanes:EtOAc to 7:3 hexanes:EtOAc) to afford l-cyclopentyl-l-phenylprop-2-en-l-amine (10) (200 mg, 27.3%) as a colorless transparent oil.
  • the purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (15 mL) and adding a slight excess of concentrated HC1 (91 pL). The mixture was concentrated under a warm stream of air with evaporation of repeat EtOH additions (3 x -5 mL) to remove excess HC1 and water.
  • the solution was heated with a heating mantle to maintain a temperature between 80-90°C and then a solution of cyclopentyl(3- methoxyphenyl)methanone (4.01 g, 19.6 mmol) in dry (3 molecular sieves) toluene (15 mL) was added over 45 min via syringe.
  • the reaction was allowed to stir between 80-90°C for 2.5 h and then cooled to rt overnight.
  • the reaction was quenched with 1 : 1 sat’d NaHCCh brine ( ⁇ 20 mL), diluted with EtOAc (-150 mL), and the resulting suspension filtered through a pad of celite.
  • the mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with diH2O (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to afford a yellow transparent oil.
  • the intermediate was dissolved in THF (30 mL) and 3M HC1 (30 mL) was added. The biphasic mixture was allowed to stir at rt for 4 h and then diluted with diftO (30 mL) and EtOAc (100 mL). The mixture was extracted and the organic layer was extracted further with IM HC1 (3 x 100 mL).
  • the mixture was concentrated under a warm stream of air with evaporation of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water.
  • the resulting salt was a gummy yellow solid that was vigorously scratched in the presence of hexanes.
  • the salt was cooled to -20°C and scratched with a metal spatula periodically over 3 days to afford a light yellow powdery solid.
  • the flask was fitted with an addition funnel and a solution of 1 -cyclopentyl- 1-phenylbutan-l-ol (L 18g, 5.40 mmol) in dry (3 A molecular sieves) DCM (20 mL) was added dropwise. After addition, the reaction was allowed to naturally warm to rt overnight. The mixture was quenched with saturated NaHCO 3 until pH tested ⁇ 8 via pH strips and diluted with EtOAc (-100 mL). The mixture was transferred to a separatory funnel, the organic phase collected, and the aqueous layer further extracted with EtOAc (3 x 50 mL).
  • the slurry was allowed to stir at 0°C and monitored by GC-MS for completion (1.5 h). Once complete, the mixture was quenched with ice cold TEEvdiELO (1 : 1 mixture, 50 mL) dropwise via addition funnel over 30 min. The mixture was diluted with EtOAc (100 mL), basified with KOH solution (IM, ⁇ 4 mL), and filtered. The filter cake was washed with EtOAc (100 mL) and the filtrate was transferred to a separatory funnel. The organic layer was extracted with IM HC1 (4 x 100 mL) and the combined aqueous layers were basified with NH4OH until a cloudy suspension formed.
  • the slurry was brought to reflux and monitored by GC-MS for completion ( ⁇ 2 h). Once complete, the mixture was cooled again to 0°C and quenched with ice cold THF:diH2O (1 :1 mixture, 50 mL) dropwise via addition funnel over 30 min. The mixture was diluted with EtOAc (100 mL), basified with KOH solution (IM, ⁇ 4 mL), and filtered. The filter cake was washed with EtOAc (100 mL) and the filtrate was transferred to a separatory funnel. The organic layer was extracted with IM HC1 (4 x 100 mL) and the combined aqueous layers were basified with NH4OH until a cloudy suspension formed.
  • A-(l-cyclopentyl-l-phenylethyl)acetamide In a heated, dried round-bottom flask containing a Teflon coated stir bar was added dry (3A molecular sieves) DCM (15 mL), 1- cyclopentyl-l-phenylethan-1 -amine (3) hydrochloride (800 mg, 4.23 mmol), and TEA (881 pL, 639 mg, 6.31 mmol) under argon atmosphere. The solution was stirred at 0°C and acetyl chloride (361 pL, 398 mg, 5.07 mmol) was added in one portion via micropipette.
  • the slurry was brought to reflux and monitored by GC-MS for completion ( ⁇ 10 h). Once complete, the mixture was cooled again to 0°C and quenched with ice cold THF:diH2O (1 : 1 mixture, 10 mL) dropwise via addition funnel over 30 min. The mixture was diluted with EtOAc (75 mL), basified with KOH solution (IM, ⁇ 4 mL), and filtered. The filter cake was washed with EtOAc (3 x 75 mL) and the filtrate was transferred to a separatory funnel. The organic layer was extracted with IM HC1 (3 x 100 mL) and the combined aqueous layers were basified with NH4OH until a cloudy suspension formed.
  • the mixture was diluted with EtOAc (100 mL), basified with KOH solution (IM, ⁇ 4 mL), and filtered.
  • the filter cake was washed with EtOAc (2 x 100 mL) and the filtrate was transferred to a separatory funnel.
  • the organic layers were washed with a solution of KOH (100 mL, pH > 12) and the aqueous layer was further extracted with EtOAc (2 x 100 mL).
  • the combined organics were washed with dilbO (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to a clear oil.
  • the oil was further purified via acid/base extraction by dissolving the oil in EtOAc (100 mL) and extracting the organic layer with IM HC1 (3 x 100 mL).
  • the combined aqueous layers were basified with NH4OH until a cloudy suspension formed.
  • the aqueous layers were extracted with EtOAc (3 x 75 mL) and combined organics were washed with diELO (20 mL) and brine (20 mL).
  • the organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to a colorless transparent oil.
  • the oil was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding concentrated HC1 (71 pL).
  • the oil was purified by flash chromatography (SiO2, 80:20 hexanes :EtO Ac) to afford 7V-(l-cy cl opentyl- l-phenylethyl)butan-l -amine (18) (150 mg, 46.0%) as a transparent colorless oil.
  • the oil was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding concentrated HC1 (56 pL). The mixture was concentrated under a warm stream of air with evaporation of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water.
  • N-( l-cyclopentyl-l-phenylethyl)propan-2-amine (Compound 19).
  • 1 -cyclopentyl- 1- phenylethan-1 -amine (Compound 3) hydrochloride (200 mg, 0.88 mmol), MeOH (15 mL), and glacial AcOH (111 pL, 116 mg, 1.93 mmol) at rt under argon atmosphere.
  • the oil was purified using flash chromatography (SiO2, 9: 1 hexanes :EtO Ac) to provide A-(l- cyclopentyl-l-phenylethyl)butan-2-amine (20) (290 mg, 53.5%) as a colorless transparent oil.
  • the freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (108 pL). The mixture was concentrated under a warm stream of air with evaporations of repeated EtOH additions (3 x ⁇ 5 mL) to remove excess HC1 and water.
  • the resulting salt was hygroscopic and required heating at ⁇ 60°C to solidify.
  • the reaction was fitted with a reflux condenser and brought to ⁇ 50°C on a heating mantle. The mixture was allowed to stir at ⁇ 50°C until complete by GC/MS (5 h). The mixture was quenched with KOH solution (250 mL, pH >12) and diluted with EtOAc (75 mL). The mixture was extracted and the aqueous phase was extracted further with EtOAc (2 x 75 mL). The combined organic phases were washed with diH2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to a colorless transparent oil.
  • the oil was purified by flash chromatography (SiO2, 80:20 Hexanes:EtOAc) to afford A-(l -cyclopentyl- 1- phenylethyl)cyclobutanamine (21) (210 mg, 67.5%) as a transparent colorless oil.
  • the oil was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (79 pL). The mixture was concentrated under a warm stream of air with evaporation of repeated EtOH additions (3 x ⁇ 5 mL) to remove excess HC1 and water. The resulting solids were washed with hexanes (3 x ⁇ 10 mL) and dried to afford a white powdery solid.
  • the oil was purified using flash chromatography (SiO 2 , 9:1 hexanes :EtO Ac) to provide 1 -(1 -cyclopentyl- 1- phenylethyl)piperidine (22) (1.41 g, 52.2%) as a chunky white solid.
  • the flask was fitted with a reflux condenser and heated to 90°C on a heating mantle. Once the mixture was refluxing, phenyl isopropyl ketone (5.0 g, 33.7 mmol) was dissolved in dry (3 molecular sieves) toluene (10 mL) and added dropwise over 20 minutes to the mixture via addition funnel. The mixture was allowed to stir at 90°C and monitored by TLC. After 4 h, the reaction appeared to be complete, and was cooled to rt and quenched with brine (20 mL). The resulting precipitate was filtered through a bed of celite and the filter cake was washed with EtOAc (50 mL).
  • the mixture was then diluted with EtOAc (50 mL) and stirred vigorously.
  • the mixture was basified with NH4OH, transferred to a separatory funnel, and extracted.
  • the aqueous layer was further extracted with EtOAc (3x 75 mL) and the combined organic layers were washed with diH2O (20 mL) and brine (20 mL).
  • the organic layers were dried over anhydrous Na2SO4 and solvent was removed under vacuum to give the crude product as a faint yellow oil.
  • the oil was directly converted to the HC1 salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (517 pL).
  • the biphasic mixture was vigorously stirred at rt for 3 h and then diluted with diH2O (20 mL) and EtOAc (-100 mL). The mixture was extracted and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 75 mL). The organic layer was washed with diH2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to a colorless transparent oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (40 mL) and adding a slight excess of concentrated HC1 (236 pL).
  • the intermediate was dissolved in THF (20 mL) and 3M HCI (16 mL) was added.
  • the biphasic mixture was allowed to stir overnight and then diluted with diH2O (20 mL) and EtOAc (100 mL).
  • the mixture was extracted and the organic layer was extracted further with IM HCI (3 x 100 mL).
  • the combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 75 mL).
  • the organic layer was washed with diH 2 O (20 mL) and brine (20 mL), dried over Na 2 SO 4 , and concentrated on a rotary evaporator to afford a colorless transparent oil.
  • the oil was directly converted to the HC1 salt by dissolving in EtOH (30 mL) and adding concentrated HC1 (257 pL). The mixture was concentrated under a warm stream of air with evaporations of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solid was washed with Et2O (3 x ⁇ 10 mL) and dried to afford (2-chlorophenyl)(cyclopentyl)methanamine (29) hydrochloride (480 mg, 61.0% yield) as a white powdery solid. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O followed by storing at 0°C to give a white crystalline solid.
  • the biphasic mixture was stirred vigorously for 2 h at rt and then diluted with diftO (30 mL) and EtOAc (-100 mL). The mixture was extracted and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 75 mL). The organic layer was washed with diftO (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under vacuum to afford an oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (30 mL) and adding a slight excess of concentrated HC1 (516 pL).
  • the biphasic mixture was stirred vigorously at rt for 5 min and then transferred to a separatory funnel.
  • the organic phase was collected and the aqueous phase was extracted with DCM (2 x 100 mL).
  • the combined organic phases were washed with IM HC1 (100 mL), dLLO (100 mL), and brine (100 mL).
  • the organic phase was dried over ISfeSCU and evaporated to afford A-methoxy-A-methylcyclopentanecarboxamide (13.0 g, 93.5%) a yellow oil. This intermediate was used without further purification.
  • the aqueous phase was extracted with DCM (2 x 100 mL). An emulsion formed in the aqueous phase from the solid which clarified upon basifying with sat’d NaHCOs allowing for the collection of the remaining organic phase.
  • the combined organic phases were washed with sat’d NaHCOs (50 mL) and brine (50 mL).
  • the product was further purified via flash chromatography (SiCh, 1 : 1 hexanes :EtO Ac) to afford Mmethoxy-M methylthiophene-2-carboxamide (2.36 g, 88.4%) as a clear, light yellow oil.
  • the reaction was stirred for 1 h at 0 °C, quenched with sat’d NH4CI (100 mL), and stirred for 5 min at 0C.
  • the mixture was transferred to a separatory funnel and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (50 mL), dried over Na2SO4, and concentrated to an amber oil.
  • reaction was quenched with sat’d NH4CI (50 mL) at rt and allowed to stir overnight.
  • the mixture was transferred to a separatory funnel, diluted with dH2O (100 mL), and the aqueous phase was extracted with EtOAc (3 x 100 mL).
  • EtOAc 3 x 100 mL
  • the combined organic phases were washed with sat’d NaHCCL (50 mL), dftO (50 mL), and brine (50 mL).
  • the flask was fitted with a reflux condenser and heated with a heating mantle to maintain a temperature of 80-90°C (determined by IR heat gun). This temperature was maintained for 2 h (reaction times ranged from 1-8 h) and then the reaction was cooled to rt to stir overnight. The mixture was quenched with brine (20-50 mL), diluted with EtOAc (75-150 mL), and allowed to stir at rt for 5 min. The precipitate was removed by filtration through celite and the filter cake was washed with EtOAc (2 x 100 mL). The filtrate was transferred to a separatory funnel and the aqueous layer was drained.
  • 80-90°C determined by IR heat gun
  • the product was purified via flash chromatography (SiCh, 8:2 hexanes:EtOAc to 7:3 hexanes :EtO Ac) to afford 7V-(cycl opentyl(4-fl uorophenyl )methylene)-2-m ethyl propane-2- sulfinamide (1.61 g, 31%) as a clear, amber oil.
  • the product was purified via flash chromatography (SiCh, 9: 1 hexanes:EtOAc to 8:2 hexanes :EtO Ac) to afford A-(benzo[b]thiophen-2-yl(cyclopentyl)methylene)-2-methylpropane-2- sulfinamide (2.08 g, 78.2%) as a bright yellow oil.
  • the crude product was purified via flash chromatography (SiCh, 8:2 hexanes:EtOAc to 7:3 hexanes:EtOAc) to afford 1 -cyclopentyl- l-(m- tolyl)ethan-l -amine (790 mg, 56.6% yield) as a clear, yellow oil.
  • the purified freebase was converted to the fumarate salt by dissolving in EtOH (10 mL) and adding a solution of fumaric acid (445.9 mg) in EtOH ( ⁇ 25 mL).
  • the crude freebase was purified via flash chromatography (SiCh, 8:2 hexanes:EtOAc to 7:3 hexanes :EtO Ac) to afford l-cyclopentyl-l-(thiophen-2-yl)ethan-l-amine (720 mg, 52.2% yield) as a clear, colorless oil.
  • the HC1 salt was prepared by in EtOH (30 mL) and by adding concentrated HC1 (337 pL) to afford l-cyclopentyl-l-(thiophen-2-yl)ethan-l-amine hydrochloride as an off-white crystalline solid.
  • the crude freebase was converted to the fumarate salt by dissolving in MeOH (50 mL) and adding solid fumaric acid (413 mg) with stirring. Once dissolved, the solution was evaporated to afford a solid that was crystallized 2X by dissolving in a minimum amount of hot MeOH and layering with Et2O to afford l-(benzo[d][l,3]dioxol-5-yl)-l- cyclopentylethan-1 -amine fumarate (stoichiometric salt) (1.47 g, 90.1% yield) as a white, chunky crystalline solid.
  • the HC1 salt was prepared by in MeOH (20 mL) and by adding concentrated HC1 (141 pL) to afford 1 -cyclobutyl- 1-phenylethan-l -amine hydrochloride (180 mg, 15.0% yield) as a white crystalline solid, which was only crystalized IX by dissolving in a minimum amount of MeOH and layering with EfeO.
  • the acetate salt was prepared by in MeOH (30 mL) and by adding glacial acetic acid (183 pL) to afford 1- cyclopentyl-l-(4-fluorophenyl)ethan-l -amine acetate (440 mg, 48.7% yield) as a white crystalline solid that was crystallized IX from a minimum amount of hot MeOH and Et2O.
  • the crude product was purified via flash chromatography (SiCh, 8:2 hexanes :EtO Ac to 7:3 hexanes :EtO Ac) to afford l-(benzo[b]thiophen-2-yl)-l-cyclopentylethan- 1-amine (730 mg, 65.7% yield) as a clear, yellow oil.
  • the fumarate salt was prepared from the purified freebase (560 mg) by in EtOH (20 mL) and by adding solid fumaric acid (265 mg) with stirring.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une série de nouvelles (hétéro)arylméthanamines substituées qui se lient au récepteur N-méthyl-D-aspartate. De tels composés sont utiles dans diverses indications thérapeutiques comprenant, entre autres, une douleur, une dépression, un acouphène, un trouble de stress post-traumatique, etc.
PCT/US2023/074246 2022-09-15 2023-09-14 Antagonistes du récepteur n-méthyl-d-aspartate (rnmda) et utilisations correspondantes WO2024059745A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263407052P 2022-09-15 2022-09-15
US63/407,052 2022-09-15

Publications (2)

Publication Number Publication Date
WO2024059745A2 true WO2024059745A2 (fr) 2024-03-21
WO2024059745A3 WO2024059745A3 (fr) 2024-05-23

Family

ID=90275929

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/074246 WO2024059745A2 (fr) 2022-09-15 2023-09-14 Antagonistes du récepteur n-méthyl-d-aspartate (rnmda) et utilisations correspondantes

Country Status (1)

Country Link
WO (1) WO2024059745A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2706586A1 (fr) * 2007-11-21 2009-05-28 Alan S. Florjancic Nouveaux composes en tant que ligands de recepteur de cannabinoide et leurs utilisations
EP2766352B1 (fr) * 2011-10-12 2018-06-06 University Health Network (UHN) Composés indazole utilisés comme inhibiteurs de kinase et méthode de traitement du cancer avec lesdits composés
MX370664B (es) * 2013-08-16 2019-12-19 Memorial Sloan Kettering Cancer Center Inhibidores de la proteína regulada por glucosa 94 (gpr94) selectivos y usos de los mismos.

Also Published As

Publication number Publication date
WO2024059745A3 (fr) 2024-05-23

Similar Documents

Publication Publication Date Title
CA2931583C (fr) Derives d'imidazopyridine comme modulateurs de l'activite du tnf
RU2484092C2 (ru) Спироциклические производные циклогексана
NZ548317A (en) Spirocyclic cyclohexane derivatives with affinity for the ORL1-receptor
NZ587831A (en) Substituted spirocyclic cyclohexane derivatives
JP2010523725A (ja) 皮膚疾患処置用ホスホジエステラーゼ阻害剤としてのトリアゾロピリジン
WO2007105989A2 (fr) 1-oxo-3-(1h-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines, procédés de production associés, bibliothèque combinatoire et bibliothèque ciblée
IL292585A (en) 5-ht2a agonists for use in the treatment of depression
AU2018305223A1 (en) New propanamine derivatives for treating pain and pain related conditions
HRP980554A2 (en) 3-substituted tetrahydropyridopyrimidinon derivatives, their preparation and use
FR2593818A1 (fr) Derives d'acylaminomethyl-3 imidazo(1,2-a)pyridine, leur preparation et leur application en therapeutique
WO2024059745A2 (fr) Antagonistes du récepteur n-méthyl-d-aspartate (rnmda) et utilisations correspondantes
JP2010535844A (ja) Ｇａｂａアルファリガンドとしてのピラゾロキノリンおよびピラゾロナフチリジン誘導体
AU2020214275A1 (en) Dezocine derivative and medical use thereof
KR20200097694A (ko) 통증 및 통증 관련 상태를 치료하기 위한 신규한 알콕시아미노 유도체
JP6490187B2 (ja) 置換アザスピロ（４．５）デカン誘導体
CN115515682B (zh) 用于治疗神经退行性疾病和线粒体疾病的组合物及其使用方法
KR102603671B1 (ko) 치환된 3-디알킬아미노메틸-피페리딘-4-일-벤즈아미드 및 이를 제조 및 사용하는 방법
WO2023054006A1 (fr) Antagoniste des récepteurs opioïdes et composition pharmaceutique
Deme et al. Versatile synthesis of novel tetrahydroquinolines as potentially active semicarbazide-sensitive amine oxidase (SSAO) inhibitors via tert-amino effect
WO2023212237A1 (fr) Compositions utiles pour moduler l'épissage
WO2023250060A1 (fr) Modulateurs du récepteur 88 couplé à une protéine g
WO2022241006A1 (fr) Agonistes sélectifs, partiels et polarisés de 5-ht2a avec utilité dans divers troubles
WO2024155837A1 (fr) Compositions utiles pour moduler l'épissage
WO2023250059A1 (fr) Modulateurs du récepteur couplé aux protéines g 88
JPH05213932A (ja) チエノシクロペンタノンオキシムエーテル、製造および組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23866502

Country of ref document: EP

Kind code of ref document: A2