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  • 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
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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 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.
• 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 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:
• 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:
• 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;
• 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.
• 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 2 is selected from hydrogen; halogen;
• R 3 is selected from:
• R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
• 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 2 is selected from hydrogen; halogen;
• 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 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 5-6 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 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 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 5-5 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.
• R 2 is phenyl, 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 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).
• 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:
• 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 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 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 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 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 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]
• 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 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 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 5-5 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 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 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.
• 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 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.
• 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 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from: hydrogen;
• 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 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 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 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 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 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
• 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 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 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 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 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 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 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 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 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
• 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:
• 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 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 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 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 5-5 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.
• 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 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 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.
• 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 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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,
• 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.
• 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.
• 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.
• 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.
• 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).
• 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 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 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 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 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 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.
• 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 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 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 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.
• 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 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.

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