WO2026030391A1 - Modulateurs de récepteurs n-méthyl-d-aspartate sélectifs d'une sous-unité et leurs utilisations - Google Patents

Modulateurs de récepteurs n-méthyl-d-aspartate sélectifs d'une sous-unité et leurs utilisations

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Publication number
WO2026030391A1
WO2026030391A1 PCT/US2025/039766 US2025039766W WO2026030391A1 WO 2026030391 A1 WO2026030391 A1 WO 2026030391A1 US 2025039766 W US2025039766 W US 2025039766W WO 2026030391 A1 WO2026030391 A1 WO 2026030391A1
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Prior art keywords
compound
haloalkyl
optionally substituted
alkyl
methyl
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PCT/US2025/039766
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English (en)
Inventor
Dennis C. Liotta
Stephen F. Traynelis
Lawrence J. Wilson
Yesim ALTAS TAHIROVIC
Russell G. FRITZEMEIER
Nicholas S. AKINS
Srinu PALADUGU
Jiafeng GENG
Paul J. ARCORIA
Kyler W. PUGH
Hyungyu Lee
Gregory L. Hamilton
Maia C. CIRVELLO
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Emory University
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Emory University
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Publication of WO2026030391A1 publication Critical patent/WO2026030391A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present disclosure relates to subunit-selective N-methyl-D-aspartic acid receptor (NMDAR) modulators. It also relates to pharmaceutical formulations of the subunit-selective NMDA modulators as well as methods for treating conditions, disorders, or diseases using the subunit-selective NMDAR modulators.
  • NMDAR N-methyl-D-aspartic acid receptor
  • N-methyl-D-aspartate receptors belong to the family of ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS).
  • NMDAR dysfunction has been implicated in neurological disorders such as Parkinson’s disease, bipolar disorder, schizophrenia, and depression. See Zhou, et al., Neuropharmacology, 2013, 74:69-75; Hallett, et al., Pharmacol. Then, 2004, 102(2): 155-74; Glasgow, et al., J. Physiol., 2015, 593(1):83— 95; and Mota, et al., Neuropharmacology, 2014, 76: 16-26.
  • Stimulation of one or more of the subunits of NMDARs can be beneficial for the treatment of neurological disorders and neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease (Lin, et al., Curr Pharm Des., 2014, 20(32), 5169-79), as well as neuropsychiatric conditions, such as bipolar disorder, schizophrenia, and depression (Hanson, et al., Neuropsychopharmacology, 2024, 49(1), 51-66).
  • enhancement of NMDAR function has utility in other conditions dependent on synaptic plasticity, such as motor retraining and rehabilitation after ischemic insult or traumatic brain injury, and conditions that involve impairment of movement, speech, vision, or other functions controlled by the brain.
  • NMDAR subunits which can produce NMDAR encephalitis and NMDAR hypofunction.
  • NMDAR potentiation can relieve symptoms associated with NMDAR encephalitis and NMDAR hypofunction.
  • Functional NMDARs are heterotetramers assembled from two glycine-binding GluN1 subunits with either two glutamate-binding GluN2 (A-D) subunits or a combination of one GluN2 and one GluN3.
  • Each subunit is comprised of four semiautonomous domains: the amino terminal domain (ATD), the agonist binding domain (ABD), the transmembrane domain (TMD), and the carboxyl terminal domain (CTD).
  • the GluN2 subunits are encoded by four different genes, which give rise to GluN2A, GluN2B, GluN2C, and GluN2D subunits. These four subunits show different spatiotemporal expression patterns in the brain and determine the distinct physiological processes associated with these receptors. Therefore, the development of subunit-selective modulators is of great therapeutic interest in treating diseases associated with dysfunction of NMDARs. See, for example, Hansen 2021, supra.
  • the compounds are positive allosteric modulators of the GluN2 subunit.
  • the compounds are also GluN2-subtype selective.
  • the compounds are selective for GluN2C/D over GluN2A.
  • the compounds are selective for GluN2C/D over both GluN2A and GluN2B.
  • the compounds are selective for GluN2D over GluN2A, GluN2B, and GluN2C.
  • pharmaceutical formulations of the disclosed compounds or compositions In general, the pharmaceutical formulations contain a pharmaceutically acceptable excipient.
  • the pharmaceutical formulations are in a form chosen from tablets, capsules, caplets, pills, beads, granules, particles, powders, gels, creams, solutions, suspensions, emulsions, and nanoparticulate formulations.
  • the pharmaceutical formulations are oral formulations.
  • the pharmaceutical formulations are intravenous formulations.
  • the pharmaceutical formulations are intramuscular formulations.
  • the pharmaceutical formulations are in the form of solutions, such as aqueous solutions.
  • the pharmaceutical formulations are in the form of powders, such as lyophilized powders.
  • the pharmaceutical formulations are in the form of tablets, caplets, capsules, or pills.
  • This disclosure also relates to (1) the compounds, compositions, and pharmaceutical formulations disclosed herein for treatment of a condition, disorder, or disease disclosed herein or use as a medicament, (2) the compounds, compositions, and pharmaceutical formulations disclosed herein for use in the treatment of a condition, disorder, or disease disclosed herein, or (3) the compounds, compositions, and pharmaceutical formulations disclosed herein for the manufacture of a medicament for treatment of a condition, disorder, or disease disclosed herein.
  • This disclosure also provides methods of treating a condition, disorder, or disease in a subject in need thereof. The method includes administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. In some embodiments, the compound, composition, or pharmaceutical formulation is administered orally, intravenously, intranasally, or intramuscularly.
  • condition, disorder, or disease relevant to this disclosure is related to NMDAR.
  • condition, disorder, or disease may be caused by NMDAR hypofunction or loss of function.
  • condition, disorder, or disease is a neurological disorder or condition.
  • exemplary neurological disorders or conditions include, but are not limited to, neurodegenerative disease or disorder, pain, epilepsy, essential tremor, movement disorder or impaired motor function, stroke, traumatic brain injury, transient ischemia, global ischemia, hypoxia, and spinal cord trauma.
  • condition, disorder, or disease is a neuropsychiatric disorder or condition.
  • neuropsychiatric disorders or conditions include, but are not limited to, schizophrenia, depression, post-partum depression, post- traumatic stress disorder, bipolar disorder, fragile X syndrome, sleeping disorder, anxiety disorder, autism spectrum disorder, obsessive-compulsive disorder, addiction or use dependence, uncontrolled anger, cognitive deficit disorder, headache, migraine, eating disorder, and attention- deficit disorder.
  • the top dashed line shows the maximal level LTP obtained in WT mice.
  • the four triangles on the bottom of the figure depict the applications of theta burst stimulation at the indicated times to induce LTP.
  • Figures 2A-2B show the effect of 1622-240 on the behaviors of mice monitored in an open field test (Figure 2A) and a light/dark box test (Figure 2B).
  • Figure 2A is a summary of the behaviors of mice monitored in an open field for 10 min after 1 h of a 5 or 10 mg/kg IP administration of 1622-240.
  • Figure 2B is a summary of the behaviors of mice in a light/dark chamber monitored for 10 min after 1 h of a 5 or 10 mg/kg IP administration of 1622-240.
  • *, **, and *** indicate p ⁇ 0.05, 0.01, and 0.001, respectively, by one way ANOVA (Tukey’s test).
  • Figures 3A-3B show the effect of 1622-287 on the behaviors of mice monitored in an open field test (Figure 3A) and a light/dark box test (Figure 3B).
  • Figure 3A is a summary of the behaviors of mice monitored in an open field for 10 min after 1 h of a 10 mg/kg IP administration of 1622-287.
  • Figure 3B is a summary of the behaviors of mice in a light/dark chamber monitored for 10 min after 1 h of a 10 mg/kg IP administration of 1622-287.
  • * and ** indicate p ⁇ 0.05 and 0.01, respectively, by one way ANOVA (Tukey’s test).
  • DETAILED DESCRIPTION The present disclosure describes subunit-selective NMDAR modulators.
  • the compounds are positive allosteric modulators of the GluN2 subunit.
  • the compounds are also GluN2-subtype selective.
  • the compounds are selective for GluN2C/D over GluN2A.
  • the compounds are selective for GluN2C/D over both GluN2A and GluN2B.
  • the compounds are selective for GluN2D over GluN2A, GluN2B, and GluN2C.
  • the condition, disorder, or disease relevant to this disclosure is related to NMDAR.
  • condition, disorder, or disease may be caused by NMDAR hypofunction or loss of function, especially GluN2 hypofunction or loss of function.
  • a carbon range (e.g., C 1 ⁇ C 10 ) is intended to disclose individually every possible carbon value and/or sub-range encompassed within.
  • a carbon range of C 1 ⁇ C 10 discloses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 , as well as sub-ranges encompassed therein, such as C 2 ⁇ C 9 , C 3 ⁇ C 8 , C 1 ⁇ C 5 , etc.
  • the term “subject” refers to an animal, including human and non-human animals. Human subjects may include pediatric patients and adult patients. Non-human animals may include domestic pets, livestock and farm animals, and zoo animals. In some cases, the non- human animals may be non-human primates.
  • the terms “prevent” and “preventing” include the prevention of the occurrence, onset, spread, and/or recurrence. It is not intended that the present disclosure is limited to complete prevention. For example, prevention is considered as achieved when the occurrence is delayed, the severity of the onset is reduced, or both.
  • the terms “treat” and “treating” include medical management of a condition, disorder, or disease of a subject as would be understood by a person of ordinary skill in the art (see, for example, Stedman’s Medical Dictionary). In general, treatment is not limited to cases where the subject is cured and the condition, disorder, or disease is eradicated.
  • treatment also contemplates cases where a treatment regimen containing one of the compounds, compositions, or pharmaceutical formulations of the present disclosure provides an improved clinical outcome.
  • the improved clinical outcome may include one or more of the following: abatement, lessening, and/or alleviation of one or more symptoms that result from or are associated with the condition, disorder, or disease to be treated; decreased occurrence of one or more symptoms; improved quality of life; diminishment of the extent of the condition, disorder, or disease; reaching or establishing a stabilized state (i.e., not worsening) of the condition, disorder, or disease; delay or slowing of the progression of the condition, disorder, or disease; amelioration or palliation of the state of the condition, disorder, or disease; partial or total remission; and improvement in survival (whether increase in the overall survival rate or prolonging of survival when compared to expected survival if the subject were not receiving the treatment).
  • the disclosure encompasses treatment that reduces one or more symptoms of and/or cognitive deficit associated with or caused by a brain injury.
  • halogenated and “halogenation” refer to replacement of one or more non- ionizable hydrogen atoms in a chemical compound/moiety with halogen such as fluorine.
  • a halogenated chemical compound/group/moiety may be fully halogenated (i.e., all the non- ionizable hydrogen atoms in the chemical compound/moiety are replaced with halogen such as fluorine) or partially halogenated (i.e., one or more non-ionizable hydrogen atoms, but not all the non-ionizable hydrogen atoms, in the chemical compound/group/moiety are replaced with halogen such as fluorine).
  • the terms “derivative” and “derivatives” refer to chemical compounds/groups/moieties with a structure similar to that of a parent compound/group/moiety but different from it in respect to one or more components, functional groups, atoms, etc.
  • the derivatives retain certain functional attributes of the parent compound/group/moiety.
  • the derivatives can be formed from the parent compound/group/moiety by chemical reaction(s).
  • the differences between the derivatives and the parent compound/group/moiety can include, but are not limited to, replacement of one or more functional groups with one or more different functional groups or introducing or removing one or more substituents of hydrogen atoms.
  • alkyl refers to univalent groups derived from alkanes (i.e., acyclic saturated hydrocarbons) by the removal of a hydrogen atom from any carbon atom. Alkyl groups can be linear or branched.
  • Suitable alkyl groups can have one to 30 carbon atoms, i.e., C 1 ⁇ C 30 alkyl. If the alkyl is branched, it is understood that at least three carbon atoms are present.
  • alkenyl refers to univalent groups derived from alkenes by removal of a hydrogen atom from any carbon atom. Alkenes are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Alkenyl groups can be linear or branched. Suitable alkenyl groups can have two to 30 carbon atoms, i.e., C2 ⁇ C30 alkenyl. If the alkenyl is branched, it is understood that at least three carbon atoms are present.
  • alkynyl refers to univalent groups derived from alkynes by removal of a hydrogen atom from any carbon atom. Alkynes are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond. Alkynyl groups can be linear or branched. Suitable alkynyl groups can have two to 30 carbon atoms, i.e., C2 ⁇ C30 alkynyl. If the alkynyl is branched, it is understood that at least four carbon atoms are present.
  • heteroalkyl refers to alkyl groups where one or more carbon atoms are replaced with a heteroatom such as, O, N, S, or Si.
  • the nitrogen and/or sulphur heteroatom(s) may be oxidized, and the nitrogen heteroatom(s) may be quaternized.
  • Heteroalkyl groups can be linear or branched. Suitable heteroalkyl groups can have one to 30 carbon atoms, i.e., C1 ⁇ C30 heteroalkyl. If the heteroalkyl is branched, it is understood that at least one carbon atom and at least one heteroatom are present.
  • aryl refers to univalent groups derived from arenes by removal of a hydrogen atom from a ring atom. Arenes are monocyclic or polycyclic aromatic hydrocarbons.
  • the rings can be attached together in a pendant manner, a fused manner, or a combination thereof.
  • the rings can be attached together in a pendant manner, a fused manner, or a combination thereof.
  • Suitable aryl groups can have six to 30 carbon atoms, i.e., C6 ⁇ C30 aryl.
  • the number of “members” of an aryl group refers to the total number of carbon atoms in the ring(s) of the aryl group.
  • heteroaryl refers to univalent groups derived from heteroarenes by removal of a hydrogen atom from a ring atom.
  • Heteroarenes are heterocyclic compounds derived from arenes by replacement of one or more methine ( ⁇ C ⁇ ) and/or vinylene ( ⁇ CH ⁇ CH ⁇ ) groups by trivalent or divalent heteroatoms, respectively, in such a way as to maintain the continuous ⁇ -electron system characteristic of aromatic systems and a number of out-of-plane ⁇ -electrons corresponding to the Hückel rule (4n ⁇ 2).
  • Heteroarenes can be monocyclic or polycyclic.
  • the rings can be attached together in a pendant manner, a fused manner, or a combination thereof.
  • the rings can be attached together in a pendant manner, a fused manner, or any combination thereof.
  • Suitable heteroaryl groups can have one to 30 carbon atoms, i.e., C 1 ⁇ C 30 heteroaryl.
  • the number of “members” of a heteroaryl group refers to the total number of carbon atom(s) and heteroatom(s) in the ring(s) of the heteroaryl group.
  • Carbocycle or “carbocyclyl” refers to mono- and polycyclic ring systems containing only carbon atoms as ring atoms. The mono- and polycyclic ring systems may be aromatic, non- aromatic (saturated or unsaturated), or a mixture of aromatic and non-aromatic rings.
  • Carbocyclyls are univalent, derived from carbocycles by removal of a hydrogen atom from a ring atom.
  • Carbocycles include arenes; carbocyclyls include aryls.
  • the rings can be attached together in a pendant manner (i.e., two rings are connected by a single bond), a spiro manner (i.e., two rings are connected through a defining single common atom), a fused manner (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged manner (i.e., two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom), or a combination thereof.
  • Suitable carbocycle or carbocyclyl groups can have three to 30 carbon atoms, i.e., C 3 ⁇ C 30 carbocycle or carbocyclyl.
  • the number of “members” of a carbocycle or carbocyclyl group refers to the total number of carbon atoms in the ring(s) of the carbocycle or carbocyclyl group.
  • “Heterocycle” or “heterocyclyl” refers to mono- and polycyclic ring systems containing at least one carbon atom and one or more heteroatoms independently selected from elements like nitrogen, oxygen, and sulfur, as ring atoms.
  • the nitrogen and/or sulphur heteroatom(s) may be oxidized, and the nitrogen heteroatom(s) may be quaternized.
  • the mono- and polycyclic ring systems may be aromatic, non-aromatic, or a mixture of aromatic and non-aromatic rings.
  • Heterocyclyls are univalent, derived from heterocycles by removal of a hydrogen atom from a ring atom. Heterocycles include heteroarenes; heterocyclyls include heteroaryls.
  • the rings can be attached together in a pendant manner (i.e., two rings are connected by a single bond), a spiro manner (i.e., two rings are connected through a defining single common atom), a fused manner (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged manner (i.e., two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom), or a combination thereof.
  • Suitable heterocycle or heterocyclyl groups can have one to 30 carbon atoms, i.e., C1 ⁇ C30 heterocycle or heterocyclyl.
  • the number of “members” of a heterocycle or heterocyclyl group refers to the total number of carbon atom(s) and heteroatom(s) in the ring(s) of the heterocycle or heterocyclyl group.
  • halogen and “halo” refer to fluorine, chlorine, bromine, and iodine.
  • haloalkyl refers to halogen-substituted alkyl groups.
  • the haloalkyl groups contain one halogen substituent.
  • the haloalkyl groups contain multiple halogen substituents, i.e., polyhaloalkyl.
  • the haloalkyl groups contain one or more fluorine substituents.
  • haloalkenyl refers to halogen-substituted alkenyl groups.
  • the haloalkenyl groups contain one halogen substituent.
  • the haloalkenyl groups contain multiple halogen substituents.
  • the haloalkenyl groups contain one or more fluorine substituents.
  • haloalkynyl refers to halogen-substituted alkynyl groups.
  • the haloalkynyl groups contain one halogen substituent.
  • the haloalkynyl groups contain multiple halogen substituents. In some examples, the haloalkynyl groups contain one or more fluorine substituents.
  • halocarbocyclyl refers to halogen-substituted carbocyclyl groups.
  • the halocarbocyclyl groups contain one halogen substituent.
  • the halocarbocyclyl groups contain multiple halogen substituents. In some examples, the halocarbocyclyl groups contain one or more fluorine substituents.
  • haloheterocyclyl refers to halogen-substituted heterocyclyl groups.
  • the haloheterocyclyl groups contain one halogen substituent.
  • the haloheterocyclyl groups contain multiple halogen substituents.
  • the haloheterocyclyl groups contain one or more fluorine substituents.
  • haloaryl refers to halogen-substituted aryl groups.
  • the haloaryl groups contain one halogen substituent.
  • the haloaryl groups contain multiple halogen substituents.
  • the haloaryl groups contain one or more fluorine substituents.
  • haloheteroaryl refers to halogen-substituted heteroaryl groups.
  • the haloheteroaryl groups contain one halogen substituent.
  • the haloheteroaryl groups contain multiple halogen substituents.
  • the haloheteroaryl groups contain one or more fluorine substituents.
  • substituted means that the chemical group or moiety contains one or more substituents replacing the hydrogen atom(s) in the original chemical group or moiety. It is understood that any substitution is in accordance with a permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc., under room temperature.
  • R groups are R groups.
  • the R groups in each occurrence, can be independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, halo(arylalkyl), alkylaryl, halo(alkylaryl), ⁇ OH, ⁇ SH, ⁇ NH2, ⁇ N3, ⁇ OCN, ⁇ NCO, ⁇ ONO2, ⁇ CN, ⁇ NC, ⁇ ONO, ⁇ CONH2, ⁇ NO, ⁇ NO2, ⁇ ONH2, ⁇ SCN, ⁇ SNCS, ⁇ CF3, ⁇ CH2CF3, ⁇ CH2Cl, ⁇ CHCl2, ⁇ CH2NH
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle, halocarbocycle, heterocycle, or haloheterocycle.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • amino refers to –NR d1 R d2 , wherein R d1 and R d2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be optionally and independently substituted by one or more R groups described above.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • R d1 and R d2 are each hydrogen, the amino group is a primary amino group.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • the amide group is a carbamoyl group.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle.
  • the amide group is a sulfamoyl group.
  • thiol refers to the univalent radical —SH.
  • sulfonate refers to –SO 3 -.
  • sil refers to the univalent radical derived from silane by removal of a hydrogen atom, i.e., –SiH 3 .
  • stereoisomer refers to compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable.
  • enantiomer refers to a pair of stereoisomers that are non-superimposable mirror images of one another.
  • diastereomer refers to two stereoisomers that are not mirror images but also not superimposable.
  • racemate and “racemic mixture” refer to a mixture of enantiomers.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • the term “pharmaceutically acceptable” refers to compounds, materials, compositions, or formulations which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, allergic response, or other problems or complications that commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of regulatory agencies of a certain country, such as the Food and Drug Administration (FDA) in the United States or its corresponding agencies in countries other than the United States (e.g., the European Medicines Agency (EMA) in Europe, the National Medical Products Administration (NMPA) in China).
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • NMPA National Medical Products Administration
  • salt refers to acid or base salts of the original compound.
  • the salt is formed in situ during preparation of the original compound, i.e., the designated synthetic chemistry procedures produce the salt instead of the original compound.
  • the salt is obtained via modification of the original compound.
  • the salt is obtained via ion exchange with an existing salt of the original compound.
  • salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids and phosphonic acids.
  • the salts can be prepared by treating the compounds with an appropriate amount of a non-toxic inorganic or organic acid; alternatively, the salts can be formed in situ during preparation of the original compounds.
  • Exemplary salts of the basic residue include salts with an inorganic acid selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids or with an organic acid selected from acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acids.
  • an inorganic acid selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids
  • an organic acid selected from acetic, propionic, succinic, glycolic, ste
  • the salts can be prepared by treating the compounds with an appropriate amount of a non-toxic base; alternatively, the salts can be formed in situ during preparation of the original compounds.
  • Exemplary salts of the acidic residue include salts with a base selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, and histidine.
  • the compounds are positive allosteric modulators of the GluN2 subunit. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2C/D over GluN2A. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2C/D over both GluN2A and GluN2B. In some cases, the compounds are positive allosteric modulators of the GluN2 subunit and are selective for GluN2D over GluN2A, GluN2B, and GluN2C.
  • R B in each occurrence, is independently selected from halogen, cyano, C 1 – C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C 3 –C 6 carbocyclyl, and C 3 –C 6 halocarbocyclyl.
  • R B in each occurrence, is independently selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), and isopropyloxy.
  • R B in each occurrence, is independently halogen, such as F, Cl, and Br.
  • the carbon at the para position of Ring B is not substituted by R B . In some embodiments, the carbon at the para position of Ring B is substituted by R B .
  • the carbon at the para position of Ring B is substituted by halogen, cyano, C 1 –C 3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C 1 –C 3 alkyloxy, C 1 –C 3 haloalkyloxy, primary amino, C 1 –C 3 alkylamino, C 1 –C 3 haloalkylamino, C 3 –C 6 carbocyclyl, and C 3 –C 6 halocarbocyclyl.
  • the carbon at the para position of Ring B is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • the carbon at the para position of Ring B is substituted by halogen.
  • the carbon at the para position of Ring B is substituted by Cl or Br.
  • the carbon at the para position of Ring B is substituted by Cl.
  • the carbon at the para position of Ring B is substituted by Br.
  • the carbon at the para position of Ring B is substituted by F.
  • G 1 when G 1 is CH, its carbon is not substituted by R B .
  • G 1 when G 1 is CH, its carbon is substituted by R B .
  • G 1 when G 1 is CH, its carbon is substituted by halogen, cyano, C 1 –C 3 alkyl, C 1 –C 3 haloalkyl, C 2 –C 4 alkenyl, C 2 – C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl.
  • G 1 when G 1 is CH, its carbon is substituted by halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy.
  • G 1 when G 1 is CH, its carbon is substituted by halogen.
  • G 1 when G 1 is CH, its carbon is substituted by Cl or Br.
  • G 1 when G 1 is CH, its carbon is substituted by Cl.
  • G 1 when G 1 is CH, its carbon is substituted by Br.
  • G 2 when G 2 is CH, its carbon is substituted by halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), or isopropyloxy.
  • G 2 when G 2 is CH, its carbon is substituted by halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, or ethynyl.
  • G 3 when G 3 is CH, its carbon is substituted by halogen, cyano, C 1 –C 3 alkyl, C 1 –C 3 haloalkyl, C 2 –C 4 alkenyl, C 2 – C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl.
  • G 3 when G 3 is CH, its carbon is substituted by halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy.
  • G 3 when G 3 is CH, its carbon is substituted by halogen.
  • G 3 when G 3 is CH, its carbon is substituted by Cl or Br.
  • G 3 when G 3 is CH, its carbon is substituted by Cl.
  • G 3 when G 3 is CH, its carbon is substituted by Br.
  • G 3 when G 3 is CH, its carbon is substituted by F. In some embodiments, when G 4 is CH, its carbon is not substituted by R B . In some embodiments, when G 4 is CH, its carbon is substituted by R B . In some embodiments, when G 4 is CH, its carbon is substituted by halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2– C 4 haloalkenyl, C 2 –C 4 alkynyl, C 2 –C 4 haloalkynyl, hydroxyl, C 1 –C 3 alkyloxy, C 1 –C 3 haloalkyloxy, primary amino, C 1 –C 3 alkylamino, C 1 –C 3 haloalkylamino, C 3 –C 6 carbocyclyl, or C 3 –C 6 halocarbocyclyl.
  • G 4 when G 4 is CH, its carbon is substituted by halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), or isopropyloxy.
  • G 4 when G 4 is CH, its carbon is substituted by halogen.
  • G 4 when G 4 is CH, its carbon is substituted by Cl or Br.
  • G 4 when G 4 is CH, its carbon is substituted by Cl.
  • G 4 is CH when G 4 is CH, its carbon is substituted by Br.
  • G 4 when G 4 is CH, its carbon is substituted by F.
  • G 1 , G 3 , and G 4 are CH.
  • G 1 is N, G 3 is CH, and G 4 is CH.
  • G 1 is CH, G 3 is N, and G 4 is CH.
  • G 1 is CH, G 3 is CH, and G 4 is N.
  • G 1 is N, G 3 is N, and G 4 is CH.
  • G 1 is CH, G 3 is N, and G 4 is N.
  • G 1 is N, G 3 is CH, and G 4 is N.
  • G 1 is N, G 3 is CH, and G 4 is N.
  • G 1 is N, G 3 is CH, and G 4 is N.
  • G 1 , G 3 , and G 4 are N. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, when G 1 is CH, its carbon is not substituted by R B . In some embodiments, when G 1 is CH, its carbon is substituted by R B .
  • G 1 when G 1 is CH, its carbon is substituted by F. In some embodiments, when G 3 is CH, its carbon is not substituted by R B . In some embodiments, when G 3 is CH, its carbon is substituted by R B . In some embodiments, when G 3 is CH, its carbon is substituted by halogen, cyano, C 1 –C 3 alkyl, C 1 –C 3 haloalkyl, C 2 –C 4 alkenyl, C 2 – C 4 haloalkenyl, C 2 –C 4 alkynyl, C 2 –C 4 haloalkynyl, hydroxyl, C 1 –C 3 alkyloxy, C 1 –C 3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl.
  • G 3 when G 3 is CH, its carbon is substituted by F. In some embodiments, when G 4 is CH, its carbon is not substituted by R B . In some embodiments, when G 4 is CH, its carbon is substituted by R B . In some embodiments, when G 4 is CH, its carbon is substituted by halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2– C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, or C3–C6 halocarbocyclyl.
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl.
  • the R B substituent at the G 2 position is halogen.
  • the R B substituent at the G 2 position is methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), or isopropyloxy.
  • the R B substituent at the para position of Ring B is halogen, and the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), and isopropyloxy.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), and isopropyloxy.
  • the moiety is selected from , e embodiments, the moiety some embodiments, the .
  • the R B substituent at the para position of Ring B is selected from halogen, cyano, C 1 –C 3 alkyl, C 1 –C 3 haloalkyl, C 2 –C 4 alkenyl, C 2 –C 4 haloalkenyl, C 2 –C 4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C1–C3 haloalkylamino, C3–C6 carbocyclyl, and C3–C6 halocarbocyclyl.
  • the R B substituent at the para position of Ring B is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • the R B substituent at the para position of Ring B is halogen.
  • the R B substituent at the para position of Ring B is Cl or Br.
  • the R B substituent at the para position of Ring B is Cl.
  • the R B substituent at the para position of Ring B is Br. In some embodiments, the R B substituent at the para position of Ring B is F. In some embodiments, the R B substituent at the G 2 position is selected from halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, C2–C4 alkenyl, C2–C4 haloalkenyl, C2–C4 alkynyl, C2–C4 haloalkynyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C1–C3 alkylamino, C 1 –C 3 haloalkylamino, C 3 –C 6 carbocyclyl, and C 3 –C 6 halocarbocyclyl.
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), and isopropyloxy.
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, and ethynyl.
  • the R B substituent at the G 2 position is ethynyl. In some embodiments, the R B substituent at the G 2 position is methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), or isopropyloxy.
  • the R B substituent at the para position of Ring B is halogen
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH 2 CF 3 ), and isopropyloxy.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF2, –OCH2F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • the R B substituent at the para position of Ring B is halogen
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, and ethynyl.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is Cl.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is Br.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is cyano.
  • the moiety is , s e moiety is selected from
  • Nitrogen-containing heterocyclic moiety Azetidine (n is 0) When n is 0, the nitrogen-containing heterocyclic moiety in Formula I is an azetidine moiety.
  • m is 1. In some embodiments, m is 2.
  • R C in each occurrence, is independently selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, R C , in each occurrence, is independently selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl.
  • R C in each occurrence, is independently selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , ethyl, isopropyl, and cyclopropyl.
  • one R C is halogen such as F
  • the other R C is selected from halogen, cyano, alkyl, and haloalkyl.
  • one R C is halogen such as F
  • the other R C is selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl.
  • one R C is halogen such as F, and the other R C is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, and cyclopropyl.
  • one R C is halogen such as F, and the other R C is alkyl or haloalkyl.
  • one R C is halogen, and the other R C is C1–C3 alkyl or C1–C3 haloalkyl.
  • one R C is F, and the other R C is selected from methyl, CHF2, CH 2 F, CF 3 , ethyl, isopropyl, and cyclopropyl.
  • the . Pyrrolidine (n is 1) When n is 1, the nitrogen-containing heterocyclic moiety in Formula I is an pyrrolidine moiety.
  • m is 1. In some embodiments, m is 2.
  • R C in each occurrence, is independently selected from halogen, cyano, alkyl, and haloalkyl. In some embodiments, R C , in each occurrence, is independently selected from halogen, cyano, C 1 –C 3 alkyl, and C 1 –C 3 haloalkyl.
  • R C in each occurrence, is independently selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , ethyl, isopropyl, and cyclopropyl.
  • the C some embodiments, one R is halogen such as F, and the other R C is selected from halogen, cyano, alkyl, and haloalkyl.
  • one R C is halogen such as F, and the other R C is selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl.
  • one R C is halogen such as F, and the other R C is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , ethyl, isopropyl, and cyclopropyl.
  • one R C is halogen such as F, and the other R C is alkyl or haloalkyl.
  • one R C is halogen, and the other R C is C1–C3 alkyl or C1–C3 haloalkyl.
  • one R C is F, and the other R C is selected from methyl, CHF 2 , CH2F, CF3, ethyl, isopropyl, and cyclopropyl.
  • one R C is F, and the other R C is methyl.
  • one R C is F, and the other R C is F.
  • the moiety is .
  • one R C is halogen such as F, and the other R C is selected from halogen, cyano, alkyl, and haloalkyl.
  • one R C is halogen such as F, and the other R C is selected from halogen, cyano, C1–C3 alkyl, and C1–C3 haloalkyl.
  • one R C is halogen such as F, and the other R C is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , ethyl, isopropyl, and cyclopropyl.
  • one R C is halogen such as F, and the other R C is alkyl or haloalkyl.
  • one R C is halogen, and the other R C is C1–C3 alkyl or C1–C3 haloalkyl.
  • one R C is F, and the other R C is selected from methyl, CHF 2 , CH 2 F, CF 3 , ethyl, isopropyl, and cyclopropyl.
  • one R C is F, and the other R C is methyl.
  • one R C is F, and the other R C is F. 5.
  • the R A group R A is selected from hydrogen, deuterium, methyl, CHF 2 , CH 2 F, CF 3 , CD 3 , CN, SF 5 , optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted acyl, optionally substituted amide, and Si-substituted silyl.
  • R A is selected from methyl, CHF2, CH2F, CF3, CD3, CN, SF 5 , optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted acyl, optionally substituted amide, and Si-substituted silyl.
  • the optionally substituted groups, in each occurrence, may have one or more substituents in the form of the R groups described above.
  • the R groups are selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle, halocarbocycle, heterocycle, or haloheterocycle.
  • R A is selected from hydrogen, deuterium, methyl, CD 3 , CHF 2 , CH 2 F, CF 3 , CN, and SF 5 .
  • R A is selected from methyl, CD 3 , CHF 2 , CH 2 F, CF 3 , CN, and SF5. In some embodiments, R A is selected from methyl, CD3, CHF2, CH2F, and CF3. In some embodiments, R A is H. In some embodiments, R A is deuterium. In some embodiments, R A is methyl. In some embodiments, R A is CD 3 . In some embodiments, R A is CHF 2 . In some embodiments, R A is CH2F. In some embodiments, R A is CF3. In some embodiments, R A is CN. In some embodiments, R A is SF 5 .
  • R A is selected from optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, R A is selected from optionally substituted alkyl, optionally substituted carbocyclyl, and optionally substituted aryl. In some embodiments, R A is selected from:
  • R A is selected from: In some embodiments, . In some embodiments, R A is selected from:
  • R A is optionally substituted heterocyclyl. In some embodiments, R A is selected from: In some embodiments, R A is optionally substituted heteroaryl. In some embodiments, R A is selected from:
  • R A is selected from:
  • R A is optionally substituted (heterocyclyl)propyl. In some embodiments, R A is optionally substituted (heterocyclyl)ethyl. In some embodiments, R A is optionally substituted (heterocyclyl)methyl. In some embodiments, R A is selected from:
  • R A is optionally substituted (heteroaryl)propyl. In some embodiments, R A is optionally substituted (heteroaryl)ethyl. In some embodiments, R A is optionally substituted (heteroaryl)methyl. In some embodiments, R A is selected from:
  • R A is selected from:
  • R A is In some embodiments, R A is . In some embodiments, some embodiments A , R is . In some embodiments, . In some embodiments, . In some embodiments, R A is selected from:
  • R A is . In some embodiments, s In some embodiments, R A is optionally substituted acyl. In some embodiments, R A is selected from:
  • R A is selected from: In some embodiments, R A is optionally substituted amide. In some embodiments, R A is selected from:
  • R A is optionally Si-substituted silyl. In some embodiments, R A is selected from: In some embodiments, R A is , wherein: R A1 is selected from optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and R A2 and R A3 are (i) independently selected from hydrogen, halogen, cyano, alkyl, haloalkyl, hydroxyl, alkyloxy, haloalkyloxy, primary amino, alkylamino, and haloalkylamino, or (ii) join with the carbon atom to which they are attached to form a 3–6 membered carbocycle, 3–6 membered halocarbocycle, 3–6 membered heterocycle, or 3–6 membered haloheterocycle.
  • R A2 and R A3 are independently selected from hydrogen, halogen, cyano, C1–C3 alkyl, C1–C3 haloalkyl, hydroxyl, C1–C3 alkyloxy, C1–C3 haloalkyloxy, primary amino, C 1 –C 3 alkylamino, and C 1 –C 3 haloalkylamino.
  • R A2 and R A3 are independently selected from hydrogen, halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, hydroxyl, methoxy, trifluoromethoxy, –NH2, – NH(CH 3 ), and –N(CH 3 ) 2 .
  • R A2 and R A3 are hydrogen. In some embodiments, R A2 is F and R A3 is hydrogen. In some embodiments, R A2 is methyl and R A3 is hydrogen. In some embodiments, R A2 and R A3 are methyl. In some embodiments, R A2 and R A3 join with the carbon atom to which they are attached to form a 3–6 membered carbocycle or 3–6 membered halocarbocycle. In some embodiments, R A i In some embodiments, R A1 is optionally substituted carbocyclyl or optionally substituted aryl. In some embodiments, R A1 is selected from: In some embodiments, R A1 is selected from: .
  • R A1 is selected from: . In some embodiments, R A1 is optionally substituted heterocyclyl. In some embodiments, R A1 is selected from: In some embodiments, R A1 is selected from: In some embodiments, R A1 is optionally substituted heteroaryl. In some embodiments, R A1 is selected from:
  • R A1 is selected from:
  • R A1 is . In some embodiments, R A1 is . In some embodiments, some embodiments, R A1 is A1 . In some embodiments, R . In some embodiments, R A1 A1 is . In some embodiments, R is . In some embodiments, R A1 is optionally substituted nitrogen-containing 5-membered heteroaryl.
  • n W, W, W, W, and W are independently and individually C, CH, N, or NH, wherein at least one of W 1 , W 2 , W 3 , W 4 , and W 5 is C or CH, wherein at least one of W 1 , W 2 , W 3 , W 4 , and W 5 is N or NH, wherein s is 0, 1, 2, 3, or 4, wherein R y , in each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl such as methyl, haloalkyl such as CF 3 , alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl,
  • W 1 is N. In some embodiments, W 1 is C. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, R y , in each occurrence, is independently and individually halogen, cyano, alkyl such as methyl, or haloalkyl such as CF 3 . In some embodiments, R y , in each occurrence, is independently and individually halogen, cyano, methyl, or CF3. In some embodiments, W 1 is N, and s is 1.
  • W 1 is N, s is 1, and R y is selected from halogen, methyl, CF3, and cyano. In some embodiments, W 1 is N, and s is 0. In some embodiments, at least two of W 1 , W 2 , W 3 , W 4 , and W 5 are independently N or NH.
  • R A1 is a diazole optionally substituted by R y . In one implementation, R A1 is an unsubstituted diazole. In one implementation, R A1 is a diazole mono-substituted by halogen, methyl, CF 3 , or cyano.
  • W 1 , W 2 , W 3 , W 4 , and W 5 are independently N or NH.
  • R A1 is a triazole optionally substituted by R y .
  • R A1 is an unsubstituted triazole.
  • R A1 is a triazole mono- substituted by halogen, methyl, CF 3 , or cyano.
  • at least four of W 1 , W 2 , W 3 , W 4 , and W 5 are independently N or NH.
  • R A1 is a tetrazole optionally substituted by R y .
  • R A1 is an unsubstituted tetrazole. In one implementation, R A1 is a tetrazole mono-substituted by halogen, methyl, CF 3 , or cyano. In some embodiments, R A1 is selected from , , . In some embodiments, R A1 is . In some embodiments, R A1 some embodiments, A1 some embodiments, R is embodiments, R A1 is . In some embodiments, R A1 is . In some embodiments, R A1 is . In some embodiments, R y , in each occurrence, is independently and individually halogen, cyano, alkyl such as methyl, or haloalkyl such as CF 3 . In some embodiments, R y , in each occurrence, is independently and individually halogen, cyano, methyl, and CF3. , ,
  • R A is selected from: . In some embodiments, R A is . In some embodiments, R A is . In some embodiments, some embodiments, R A is . In some embodiments, R A is . In some embodiments, R A is . In some embodiments, R A is . In some embodiments, R A is , wherein R A1 is as described above for r 6.
  • the compounds have a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof: Formula I wherein W is O; wherein Y is O; wherein Z is –CH2–; wherein the moiety is selected from: e as those described above. In some embodiments, R 6 is hydrogen.
  • R 7 is hydrogen.
  • R 8 is selected from hydrogen, methyl, CHF2, CH2F, CF3, ethyl, isopropyl, cyclopropyl, cyclobutyl, .
  • R 8 is hydrogen.
  • R 8 is methyl.
  • R 8 is CHF 2 , CH 2 F, or CF 3 .
  • R 8 is ethyl.
  • R 8 is isopropyl.
  • R 8 is cyclopropyl.
  • R 8 is cyclobutyl.
  • R 8 is .
  • R 8 is .
  • R 8 is .
  • R is selected from hydrogen, halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , ethyl, isopropyl, cyclopropyl, cyclobutyl, .
  • R is hydrogen.
  • R 9 is halogen such as F or Cl.
  • R 9 is cyano.
  • R 9 is methyl.
  • R 9 is CHF 2 , CH 2 F, or CF 3 .
  • R 9 is ethyl.
  • R 9 is isopropyl.
  • R 9 is cyclopropyl. In some embodiments, R 9 is cyclobutyl. In some embodiments, R 9 is . In s 9 i In some embodiments, the moiety is selected from: . I embodi , In some embodiments, the R B substituent at the para position of Ring B is halogen, and the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF2, CH2F, CF3, isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, ethynyl, methoxy, –OCHF 2 , –OCH 2 F, trifluoromethoxy, ethoxy, –O(CH2CF3), and isopropyloxy.
  • the R B substituent at the para position of Ring B is halogen
  • the R B substituent at the G 2 position is selected from halogen, cyano, methyl, CHF 2 , CH 2 F, CF 3 , isopropyl, cyclopropyl, and ethynyl.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is Cl.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is Br.
  • the R B substituent at the para position of Ring B is F
  • the R B substituent at the G 2 position is cyano.
  • moiety some embodiments, the s moiety i embodiments, the moiety .
  • one R C is halogen, and the other R C is alkyl or haloalkyl.
  • one R C is F, and the other R C is selecte l, isopropyl, and cyclopropyl.
  • R A is selected from methyl, CD3, CHF2, CH2F, and CF3In some embodiments, R A is methyl.
  • R A is CD3.
  • R A is CHF2.
  • R A is CH 2 F.
  • R A is CF 3 .
  • R A is . In some embodiments, R A A . In some embodiments, R In some embo R A is In some embodiments, R A is selected from: In some embodiments, some embodiments, some embodiments, some embodime A nts, R is . In some embodiments, In some embodiments, R A is selected from: . In some embodiments, some embodiments, some embodiments, some embodiments, R A is . In some embodiments, s In some embodiments, R A is selected from:
  • R A is . In some embodiments, R A is embodiments, A some embodiments, R is . In some embodiments, . In some embodiments A , R is .
  • Exemplary compounds include, but are not limited to, the following structures and their salts, hydrates, or hydrated salts thereof:
  • the moiety i some embodiments, the moiety . In some embodiments, the moiety . In some embodiments, the moiety . In some embodiments, the moiety i . In some embodiments, the moiety i some embodiments, the moiety i some embodiments, the moiety i some embodiments, the moiety .
  • Exemplary compounds include, but are not limited to, the following structures and their salts, hydrates, or hydrated salts thereof:
  • the compound in the composition is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess.
  • the compound in the composition is in greater than 95% enantiomeric or diastereomeric excess.
  • the disclosed compounds may be present in a mixture of a salt form and a non-salt form. In some embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the compound in the mixture may be in the non-salt form, calculated as the ratio of the weight of the non-salt form to the total weight of the mixture.
  • more than 90% of the compound in the mixture may be in the non-salt form. In some embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the compound in the mixture may be in the salt form, calculated as the ratio of the weight of the salt form to the total weight of the mixture. In some embodiments, more than 90% of the compound in the mixture may be in the salt form.
  • IV. FORMULATIONS Disclosed are pharmaceutical formulations containing a compound or composition described herein. Generally, the pharmaceutical formulations also contain one or more pharmaceutically acceptable excipients.
  • the pharmaceutical formulations can be in a form chosen from tablets, capsules, caplets, pills, powders, beads, granules, particles, creams, gels, solutions (such as aqueous solutions, e.g., buffer, saline, and buffered saline), emulsions, suspensions (including nano- and micro- suspensions), nanoparticulate formulations, etc.
  • the pharmaceutical formulations are formulated for oral administration.
  • the pharmaceutical formulations are formulated for intravenous administration.
  • the pharmaceutical formulations are formulated for intramuscular administration.
  • the pharmaceutical formulations are in the form of tablets, caplets, capsules, or pills.
  • the tablets, caplets, capsules, and pills have an enteric coating to prevent the gastric acids in the stomach from dissolving or degrading the active ingredients.
  • enteric coatings are known in the art and described in the sections below.
  • emulsion refers to a mixture of non-miscible components homogenously blended together.
  • the non-miscible components include a lipophilic component and an aqueous component.
  • an emulsion may be a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase.
  • oil or an oleaginous substance is the dispersed liquid and water or an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or an aqueous solution is the dispersed phase and oil or an oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion.
  • biocompatible refers to materials that are neither themselves toxic to the host (e.g., a non-human animal or human), nor degrade (if the material degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host.
  • biodegradable refers to degradation or breakdown of a polymeric material into smaller (e.g., non-polymeric) subunits or digestion of the material into smaller subunits.
  • enteric polymers refers to polymers that become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as they pass through the gastrointestinal tract.
  • nanoparticulate formulations generally refers to formulations containing nanoparticles, which are particles having a diameter from about 1 nm to about 1000 nm, from about 10 nm to about 1000 nm, from about 100 nm to about 1000 nm, or from about 250 nm to about 1000 nm.
  • nanoparticulate formulations can also refer to formulations containing microparticles, which are particles having a diameter from about 1 micron to about 100 microns, from about 1 to about 50 microns, from about 1 to about 30 microns, from about 1 micron to about 10 microns.
  • the nanoparticulate formulation may contain a mixture of nanoparticles, as defined above, and microparticles, as defined above.
  • surfactant refers to any agent which preferentially absorbs to an interface between two immiscible phases, such as the interface between water (or aqueous solution) and an organic solvent (or organic solution), between water (or aqueous solution) and air, or between organic solvent (or organic solution) and air.
  • Surfactants generally possess a hydrophilic moiety and a lipophilic moiety.
  • gel is a semisolid system containing a dispersion of the active ingredient, i.e., a compound or composition according to the present disclosure, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle.
  • the liquid vehicle may include a lipophilic component, an aqueous component or both.
  • hydrogel refers to a swollen, water-containing network of finely dispersed polymer chains that are water-insoluble, where the polymer molecules are in the external or dispersion phase and water (or an aqueous solution) forms the internal or dispersed phase.
  • the polymer chains can be chemically cross-linked (chemical gels) or physically cross-linked (physical gels). Chemical gels possess polymer chains connected through covalent bonds, whereas physical gels have polymer chains linked by non-covalent interactions, such as van der Waals interactions, ionic interactions, hydrogen bonding interactions, and hydrophobic interactions.
  • beads refers to beads made with the active ingredient (i.e., a compound or composition according to the present disclosure) and one or more pharmaceutically acceptable excipients.
  • the beads can be produced by applying the active ingredient to an inert support, e.g., inert sugar core coated with the active ingredient.
  • the beads can be produced by creating a “core” comprising both the active ingredient and at least one of the one or more pharmaceutically acceptable excipients.
  • granules refers to a product made by processing particles of the active ingredient (i.e., a compound or composition according to the present disclosure) that may or may not include one or more pharmaceutical acceptable excipients.
  • granules do not contain an inert support and are bigger in size compared to the particles used to produce them.
  • beads, granules and particles may be formulated to provide immediate release, beads and granules are usually employed to provide delayed release.
  • enzymeally degradable polymers refers to polymers that are degraded by bacterial enzymes present in the intestines and/or lower gastrointestinal tract.
  • the pharmaceutical formulations can be prepared in various forms, such as tablets, capsules, caplets, pills, granules, powders, nanoparticle formulations, solutions (such as aqueous solutions, e.g., buffer, saline, and buffered saline), suspensions (including nano- and micro-suspensions), emulsions, creams, gels, and the like.
  • the pharmaceutical formulations are in a solid dosage form suitable for simple administration of precise dosages.
  • the solid dosage form may be selected from tablets, soft or hard gelatin or non-gelatin capsules, and caplets for oral administration.
  • the solid dosage form is hard gelatin capsules.
  • the solid dosage form is a lyophilized powder that can be readily dissolved and converted to a liquid dosage form for intravenous or intramuscular administration.
  • the lyophilized powder is manufactured by dissolving the active ingredient (i.e., a compound or composition disclosed herein) in an aqueous medium followed by lyophilization.
  • the aqueous medium is water, normal saline, PBS, or an acidic aqueous medium such as an acetate buffer.
  • the pharmaceutical formulations are in a liquid dosage form suitable for intravenous or intramuscular administration.
  • Exemplary liquid dosage forms include, but are not limited to, solutions, suspensions, and emulsions.
  • the pharmaceutical formulations are in the form of a sterile aqueous solution.
  • the sterile aqueous solution is a sterile normal saline solution.
  • the sterile aqueous solution is a sterile PBS solution.
  • the sterile aqueous solution is an acidic, sterile aqueous solution such as a sterile acetate buffer.
  • the sterile aqueous solution is manufactured by dissolving a lyophilized powder containing the active ingredient (i.e., a compound or composition disclosed herein) in an aqueous medium.
  • the sterile aqueous solution can be prepared by dissolving the lyophilized powder containing the active ingredient in a dose-appropriate volume of sterile water, sterile normal saline, sterile PBS, or acidic, sterile aqueous medium such as a sterile acetate buffer.
  • the lyophilized powder containing the active ingredient is the same as those described in the paragraph above.
  • the pharmaceutical formulations are in a unit dosage form, and may be suitably packaged, for example, in a box, blister, vial, bottle, syringe, sachet, ampoule, or in any other suitable single-dose or multi-dose holder or container, optionally with one or more leaflets containing product information and/or instructions for use.
  • compositions include, but are not limited to, diluents, binders, lubricants, disintegrants, pH-modifying or buffering agents, salts (such as NaCl), preservatives, antioxidants, solubility enhancers, wetting or emulsifying agents, plasticizers, colorants (such as pigments and dyes), flavoring or sweetening agents, thickening agents, emollients, humectants, stabilizers, glidants, solvents or dispersion mediums, surfactants, pore formers, and coating or matrix materials.
  • diluents binders, lubricants, disintegrants, pH-modifying or buffering agents, salts (such as NaCl), preservatives, antioxidants, solubility enhancers, wetting or emulsifying agents, plasticizers, colorants (such as pigments and dyes), flavoring or sweetening agents, thickening agents, emollients, humectants, stabilizer
  • the powders described herein, including the lyophilized powders contain one or more of the following pharmaceutically acceptable excipients: pH-modifying or buffering agents, salts (such as NaCl), and preservatives.
  • the tablets, beads, granules, and particles described herein contain one or more of the following pharmaceutically acceptable excipients: coating or matrix materials, diluents, binders, lubricants, disintegrants, pigments, stabilizers, and surfactants. If desired, the tablets, beads, granules, and particles may also contain a minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH-buffering agents, and preservatives.
  • the coating or matrix materials include, but are not limited to, cellulose polymers (such as methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, and carboxymethylcellulose sodium), vinyl polymers and copolymers (such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer), acrylic acid polymers and copolymers (such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, or ethyl methacrylate, as well as meth
  • the coating or matrix materials may contain one or more excipients such as plasticizers, colorants, glidants, stabilizers, pore formers, and surfactants.
  • the coating or matrix materials are pH-sensitive or pH-responsive polymers, such as the enteric polymers commercially available under the tradename EUDRAGIT®.
  • EUDRAGIT® L30D-55 and L100-55 are soluble at pH 5.5 and above; EUDRAGIT® L100 is soluble at pH 6.0 and above; EUDRAGIT® S is soluble at pH 7.0 and above.
  • the coating or matrix materials are water-insoluble polymers having different degrees of permeability and expandability, such as EUDRAGIT® NE, RL, and RS.
  • the decomposition/degradation or structural change of the pharmaceutical formulations may occur at different locations of the gastrointestinal tract.
  • the coating or matrix materials are selected such that the pharmaceutical formulations can survive exposure to gastric acid and release the active ingredient in the intestines after oral administration. Diluents can increase the bulk of a solid dosage formulation so that a practical size is provided for compression of tablets or formation of beads, granules, or particles.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate, powdered sugar, and combinations thereof. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet, bead, granule, or particle remains intact after the formation of the solid dosage formulation.
  • Suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as acacia, tragacanth, and sodium alginate), cellulose (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and ethylcellulose), veegum, and synthetic polymers (such as acrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, and polyvinylpyrrolidone), and combinations thereof.
  • sugars such as sucrose, glucose, dextrose, lactose, and sorbitol
  • polyethylene glycol such as acacia, tragacanth, and sodium alginate
  • cellulose such as
  • Lubricants are used to facilitate tablet manufacture. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. Disintegrants are used to facilitate disintegration or “breakup” of a solid dosage formulation after administration. Suitable disintegrants include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, gums, and cross-linked polymers, such as cross-linked polyvinylpyrrolidone (e.g., POLYPLASDONE® XL).
  • Suitable disintegrants include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, gums, and cross-linked polymers, such
  • Plasticizers are normally present to produce or promote plasticity and flexibility and to reduce brittleness.
  • plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil, and acetylated monoglycerides.
  • Stabilizers are used to inhibit or retard decomposition reactions of the active ingredient in the pharmaceutical formulations or stabilize particles in a dispersion.
  • the stabilizer can be an antioxidant or a reducing agent.
  • Stabilizers also include nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are used to reduce sticking effects during film formation and drying. Exemplary glidants include, but are not limited to, talc, magnesium stearate, and glycerol monostearates. Preservatives can inhibit the deterioration and/or decomposition of a pharmaceutical formulation. Deterioration or decomposition can be brought about by one or more of microbial growth, fungal growth, and undesirable chemical or physical changes.
  • Suitable preservatives include benzoate salts (e.g., sodium benzoate), ascorbic acid, methyl hydroxybenzoate, ethyl p- hydroxybenzoate, n-propyl p-hydroxybenzoate, n-butyl p-hydroxybenzoate, potassium sorbate, sorbic acid, propionate salts (e.g., sodium propionate), chlorobutanol, benzyl alcohol, and combinations thereof.
  • Surfactants may be anionic, cationic, amphoteric, or nonionic surface-active agents. Exemplary anionic surfactants include, but are not limited to, those containing a carboxylate, sulfonate, or sulfate ion.
  • anionic surfactants include sodium, potassium, and ammonium salts of long-chain (e.g., 13-21) alkyl sulfonates (such as sodium lauryl sulfate), alkylaryl sulfonates (such as sodium dodecylbenzene sulfonate), and dialkyl sulfosuccinates (such as sodium bis-(2-ethylthioxyl)-sulfosuccinate).
  • alkyl sulfonates such as sodium lauryl sulfate
  • alkylaryl sulfonates such as sodium dodecylbenzene sulfonate
  • dialkyl sulfosuccinates such as sodium bis-(2-ethylthioxyl)-sulfosuccinate.
  • cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, poloxamers (such as poloxamer 401), stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate,
  • amphoteric surfactants include, but are not limited to, sodium N-dodecyl- ⁇ -alanine, sodium N-lauryl- ⁇ -iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.
  • Pharmaceutical formulations in the liquid dosage forms typically contain a solvent or dispersion medium such as water, aqueous solution (e.g., buffer, saline, buffered saline), ethanol, polyol (such as glycerol, propylene glycol, and polyethylene glycol), oil (such as vegetable oil, e.g., peanut oil, corn oil, sesame oil), and combinations thereof.
  • the pharmaceutical formulations in the liquid dosage forms are aqueous formulations.
  • Suitable solvents or dispersion mediums for aqueous formulations include, but are not limited to, water, buffers (such as acidic buffers), salines (such as normal saline), buffered salines (such as PBS), and Ringer’s solution.
  • the pharmaceutical formulations contain ⁇ -cyclodextrin or derivatives thereof.
  • the pharmaceutical formulations contain sulfobutyl ether ⁇ - cyclodextrin.
  • the pharmaceutical formulations contain hydroxypropyl- ⁇ - cyclodextrin.
  • Such pharmaceutical formulations can be in a solid or liquid dosage form.
  • the pharmaceutical formulations are prepared using a pharmaceutically acceptable carrier, which encapsulates, embeds, entraps, dissolves, disperses, absorbs, and/or binds to a compound or composition disclosed herein.
  • the pharmaceutical acceptable carrier is composed of materials that are considered safe and can be administered to a subject without causing undesirable biological side effects or unwanted interactions.
  • the pharmaceutically acceptable carrier does not interfere with the effectiveness of the compound or composition in performing its function.
  • the pharmaceutically acceptable carrier can be formed of biodegradable materials, non-biodegradable materials, or combinations thereof.
  • One or more of the pharmaceutical acceptable excipients described above may be present in the pharmaceutical acceptable carrier.
  • the pharmaceutical acceptable carrier is a controlled-release carrier, such as delayed-release carriers, sustained-release (extended-release) carriers, and pulsatile- release carriers.
  • the pharmaceutical acceptable carrier is pH-sensitive or pH- responsive.
  • the pharmaceutical acceptable carrier can decompose or degrade in a certain pH range.
  • the pharmaceutical acceptable carrier can experience a structural change when experiencing a change in the pH.
  • Exemplary pharmaceutical acceptable carriers include, but are not limited to: nanoparticles, microparticles, and combinations thereof; liposomes; hydrogels; polymer matrices; and solvent systems.
  • the pharmaceutical acceptable carrier is nanoparticles, microparticles, or a combination thereof.
  • the compound or composition is embedded in the matrix formed by the materials of the nanoparticles, microparticles, or combination thereof.
  • the nanoparticles, microparticles, or combination thereof can be biodegradable, and optionally are capable of biodegrading at a controlled rate for delivery of the compound or composition.
  • the nanoparticles, microparticles, or combination thereof can be made of a variety of materials. Both inorganic and organic materials can be used. Both polymeric and non-polymeric materials can be used.
  • the nanoparticles, microparticles, or combination thereof are formed of one or more biocompatible polymers. In some forms, the biocompatible polymers are biodegradable. In some forms, the biocompatible polymers are non-biodegradable.
  • the nanoparticles, microparticles, or combination thereof are formed of a mixture of biodegradable and non-biodegradable polymers.
  • the polymers used to form the nanoparticles, microparticles, or combination thereof may be tailored to optimize different characteristics of the nanoparticles, microparticles, or combination thereof, including: (i) interactions between the active ingredient and the polymer to provide stabilization of the active ingredient and retention of activity upon delivery; (ii) rate of polymer degradation and, thereby, rate of release; (iii) surface characteristics and targeting capabilities; and (iv) particle porosity.
  • Exemplary polymers include, but are not limited to, polymers prepared from lactones (such as poly(caprolactone) (PCL)), polyhydroxy acids and copolymers thereof (such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lactic acid-co-glycolic acid) (PLGA)), polyalkyl cyanoacrylate, polyurethanes, polyamino acids (such as poly-L-lysine (PLL), poly(valeric acid), and poly-L-glutamic acid), hydroxypropyl methacrylate (HPMA), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, ethylene vinyl acetate polymer (EVA), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters (such as poly(vinyl acetate)), polyvinyl halides (such as poly(vinyl chloride) (
  • the one or more biocompatible polymers forming the nanoparticles, microparticles, or combination thereof include an FDA-approved biodegradable polymer such as polyhydroxy acids (e.g., PLA, PGA, and PLGA), polyanhydrides, and polyhydroxyalkanoate (e.g., poly(3-butyrate) and poly(4-butyrate)).
  • Materials other than polymers may be used to form the nanoparticles, microparticles, or combination thereof. Suitable materials include surfactants.
  • surfactants in the nanoparticles, microparticles, or combination thereof may improve surface properties by, for example, reducing particle-particle interactions, and render the surface of the particles less adhesive.
  • surfactants include, but are not limited to, phosphoglycerides such as phosphatidylcholines (e.g., L- ⁇ -phosphatidylcholine dipalmitoyl), diphosphatidyl glycerol, hexadecanol, fatty alcohols, polyoxyethylene-9-lauryl ether, fatty acids such as palmitic acid and oleic acid, sorbitan trioleate, glycocholate, surfactin, poloxomers, sorbitan fatty acid esters such as sorbitan trioleate, tyloxapol, and phospholipids.
  • phosphoglycerides such as phosphatidylcholines (e.g., L- ⁇ -phosphatidylcholine dipalmitoyl), diphosphatidyl glycerol, hexadecanol, fatty alcohols, polyoxyethylene-9-lauryl ether, fatty acids such as palmitic acid and oleic acid, sorb
  • the nanoparticles, microparticles, or combination thereof may contain a plurality of layers.
  • the layers can have similar or different release kinetic profiles for the active ingredient.
  • the nanoparticles, microparticles, or combination thereof can have a controlled-release core surrounded by one or more additional layers.
  • the one or more additional layers can include an instant-release layer, preferably on the surface of the nanoparticles, microparticles, or combination thereof.
  • the instant-release layer can provide a bolus of the active ingredient shortly after administration.
  • the composition and structure of the nanoparticles, microparticles, or combination thereof can be selected such that the nanoparticles, microparticles, or combination thereof are pH-sensitive or pH-responsive.
  • the nanoparticles, microparticles, or combination thereof are formed of one or more pH-sensitive or pH-responsive polymers such as the enteric polymers commercially available under the tradename EUDRAGIT®, as described above.
  • the decomposition/degradation or structural change of the nanoparticles, microparticles, or combination thereof may occur at different locations of the gastrointestinal tract.
  • the particle materials are selected such that the nanoparticles, microparticles, or combination thereof can survive exposure to gastric acid and release the active ingredient in the intestines after oral administration.
  • the pharmaceutical formulations can be controlled-release formulations.
  • controlled-release formulations examples include extended-release formulations, delayed-release formulations, and pulsatile-release formulations.
  • extended-release formulations are prepared as diffusion or osmotic systems, for example, as described in “Remington – The science and practice of pharmacy” (20th Ed., Lippincott Williams & Wilkins, 2000).
  • a diffusion system is typically in the form of a matrix, generally prepared by combining the active ingredient with a slowly dissolving, pharmaceutically acceptable carrier, optionally in a tablet form. Suitable materials used in the preparation of the matrix include plastics, hydrophilic polymers, and fatty compounds.
  • Suitable plastics include, but are not limited to, acrylic polymer, methyl acrylate-methyl methacrylate copolymer, polyvinyl chloride, and polyethylene.
  • Suitable hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl ethyl cellulose, hydroxyalkylcelluloses (such as hydroxypropylcellulose and hydroxypropylmethylcellulose), sodium carboxymethylcellulose, CARBOPOL® 934, polyethylene oxides, and combinations thereof.
  • Suitable fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate, wax-type substances such as hydrogenated castor oil and hydrogenated vegetable oil, and combinations thereof.
  • the plastic is a pharmaceutically acceptable acrylic polymer.
  • the pharmaceutically acceptable acrylic polymer is chosen from acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylate copolymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • the pharmaceutically acceptable acrylic polymer can be an ammonio methacrylate copolymer.
  • Ammonio methacrylate copolymers are well known in the art and are described as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the pharmaceutically acceptable acrylic polymer is an acrylic resin lacquer such as those commercially available under the tradename EUDRAGIT®.
  • the pharmaceutically acceptable acrylic polymer contains a mixture of two acrylic resin lacquers, EUDRAGIT® RL (such as EUDRAGIT® RL30D) and EUDRAGIT® RS (such as EUDRAGIT® RS30D).
  • EUDRAGIT® RL30D and EUDRAGIT® RS30D are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral methacrylic esters being 1:20 in EUDRAGIT® RL30D and 1:40 in EUDRAGIT® RS30D.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these polymers.
  • EUDRAGIT® RL/RS mixtures are insoluble in water and in digestive fluids. However, multi-particulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the EUDRAGIT® RL/RS mixtures may be prepared in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable release profile. Suitable sustained-release, multi-particulate systems may be obtained, for instance, from 90% EUDRAGIT® RL + 10% EUDRAGIT® RS, to 50% EUDRAGIT® RL + 50% EUDRAGIT® RS, and to 10% EUDRAGIT® RL + 90% EUDRAGIT® RS.
  • the pharmaceutically acceptable acrylic polymer can also be or include other acrylic resin lacquers, such as EUDRAGIT® S-100, EUDRAGIT® L-100, and mixtures thereof. Matrices with different release mechanisms or profiles can be combined in a final dosage form containing single or multiple units.
  • Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing beads, granules, and/or particles of the active ingredient.
  • An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended-release core using a coating or compression process or in a multiple unit system such as a capsule containing both extended- and immediate-release beads.
  • Extended-release tablets containing one or more of the hydrophilic polymers can be prepared by techniques commonly known in the art such as direct compression, wet granulation, and dry granulation.
  • Extended-release tablets containing one or more of the fatty compounds can be prepared using methods known in the art such as direct blend methods, congealing methods, and aqueous dispersion methods.
  • the active ingredient is mixed with the fatty compound(s) and congealed.
  • the extended-release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to a solid dosage form. In the latter case, the desired release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportions.
  • Delayed release Delayed-release formulations can be prepared by coating a solid dosage form with a coating. In some embodiments, the coating is insoluble and impermeable in the acidic environment of the stomach and becomes soluble or permeable in the less acidic environment of the intestines and/or the lower GI tract.
  • the solid dosage form is a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated-core” dosage form, or a plurality of beads, granules, and/or particles containing the active ingredient, for incorporation into either a tablet or capsule.
  • Suitable coating materials may be bioerodible polymers, gradually hydrolysable polymers, gradually water-dissolvable polymers, and enzymatically degradable polymers.
  • the coating material is or contains enteric polymers. Combinations of different coating materials may also be used. Multilayer coatings using different coating materials may also be applied.
  • the coating may also contain one or more additives, such as plasticizers described above (optionally representing about 10 wt % to 50 wt % relative to the dry weight of the coating), colorants as described above, stabilizers as described above, glidants as described above, etc. 3.
  • Pulsatile release Pulsatile-release formulations release a plurality of doses of the active ingredient at spaced- apart time intervals. Generally, upon administration, such as oral administration, of the pulsatile- release formulations, release of the initial dose is substantially immediate, e.g., the first release “pulse” occurs within about three hours, two hours, or one hour of administration.
  • This initial pulse may be followed by a first time-interval (lag time) during which very little or no active ingredient is released from the formulations, after which a second dose may be released.
  • a second lag time (nearly release-free interval) between the second and third release pulses may be designed.
  • the duration of the lag times will vary depending on the formulation design, especially on the length of the dosing interval, e.g., a twice daily dosing profile, a three-time daily dosing profile, etc.
  • pulsatile-release formulations providing a twice daily dosage profile, they deliver two release pulses of the active ingredient.
  • the one nearly release-free interval between the first and second release pulses may have a duration of between 3 hours and 14 hours.
  • pulsatile-release formulations providing a three daily dosage profile, they deliver three release pulses of the active ingredient.
  • the two nearly release-free interval between two adjacent pulses may have a duration of between 2 hours and 8 hours.
  • the pulsatile-release formulations contain a plurality of pharmaceutically acceptable carriers with different release kinetics.
  • the pulsatile-release formulations contain a pharmaceutically acceptable carrier with a plurality of layers loaded with the active ingredient.
  • the layers may have different release kinetics.
  • the layers may be separated by a delayed-release coating.
  • the pulsatile-release formulations may have a first layer loaded with the active ingredient on the surface for the first release pulse and a second layer, e.g., a core loaded with the active ingredient, for the second release pulse; the second layer may be surrounded by a delayed-release coating, which creates a lag time between the two release pulses.
  • the pulsatile-release profile is achieved with formulations that are closed and optionally sealed capsules housing at least two “dosage units” wherein each dosage unit within the capsules provides a different release profile.
  • at least one of the dosage units is a delayed-release dosage unit.
  • Control of the delayed-release dosage unit(s) may be accomplished by a controlled-release polymer coating on the dosage unit(s) or by incorporation of the active ingredient in a controlled-release polymer matrix.
  • each dosage unit may comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different release profile.
  • Exemplary formulations for different routes of administration A subject suffering from a condition, disorder, or disease as described herein, can be treated by either targeted or systemic administration, via oral, inhalation, topical, trans- or sub-mucosal, subcutaneous, intramuscular, intravenous, or transdermal administration of a pharmaceutical formulation containing a compound or composition described herein. In some embodiments, the pharmaceutical formulation is suitable for oral administration.
  • the pharmaceutical formulation is suitable for subcutaneous, intravenous, or intramuscular administration. In some embodiments, the pharmaceutical formulation is suitable for inhalation or intranasal administration. In some embodiments, the pharmaceutical formulation is suitable for transdermal or topical administration. In some embodiments, the pharmaceutical formulation is an oral pharmaceutical formulation.
  • the active ingredient may be incorporated with one or more pharmaceutically acceptable excipients as described above and used in the form of tablets, pills, caplets, or capsules.
  • the corresponding oral pharmaceutical formulation may contain one or more of the following pharmaceutically acceptable excipients or those of a similar nature: a binder as described above, a disintegrant as described above, a lubricant as described above, a glidant as described above, a sweetening agent (such as sucrose and saccharin), and a flavoring agent (such as methyl salicylate and fruit flavorings).
  • a binder as described above
  • a disintegrant as described above
  • a lubricant as described above
  • a glidant as described above
  • a sweetening agent such as sucrose and saccharin
  • a flavoring agent such as methyl salicylate and fruit flavorings
  • a flavoring agent such as methyl salicylate and fruit flavorings.
  • a liquid carrier such as a fatty oil
  • each capsule when the oral pharmaceutical formulation is in the form of capsules, each capsule may contain a plurality of beads, granules, and/or particles of the active ingredient.
  • the oral pharmaceutical formulation may contain one or more other materials which modify the physical form or one or more pharmaceutical properties of the dosage unit, for example, coatings of polysaccharides, shellac, or enteric polymers as described in previous sections.
  • the oral pharmaceutical formulation can be in the form of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active ingredient, one or more sweetening agents (such as sucrose and saccharine), one or more flavoring agents, one or more preservatives, and/or one or more dyes or colorings.
  • the pharmaceutical formulation is a subcutaneous, intramuscular, or intravenous pharmaceutical formulation.
  • the subcutaneous, intramuscular, or intravenous pharmaceutical formulation can be enclosed in an ampoule, syringe, or a single or multiple dose vial made of glass or plastic.
  • the subcutaneous, intramuscular, or intravenous pharmaceutical formulation contains a liquid pharmaceutically acceptable carrier for the active ingredient.
  • Suitable liquid pharmaceutically acceptable carriers include, but are not limited to, water, buffer, saline, buffered saline (such as PBS), and combinations thereof.
  • the pharmaceutical formulation is a topical pharmaceutical formulation.
  • Suitable forms of the topical pharmaceutical formulation include lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, and suppositories for application to rectal, vaginal, nasal, or oral mucosa.
  • thickening agents such as mineral oil, lanolin and its derivatives, and squalene
  • humectants such as sorbitol
  • stabilizers can be used to prepare the topical pharmaceutical formulations.
  • thickening agents include petrolatum, beeswax, xanthan gum, and polyethylene.
  • the pharmaceutical formulation is an intranasal pharmaceutical formulation.
  • the intranasal pharmaceutical formulation is in the form of an aqueous suspension, which can be optionally placed in a pump spray bottle.
  • the aqueous suspension may contain one or more pharmaceutically acceptable excipients, such as suspending agents (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl-methyl cellulose), humectants (e.g., glycerol, propylene glycol), acids, bases, and/or pH-buffering agents for adjusting the pH (e.g., citric acid, sodium citrate, phosphoric acid, sodium phosphate, and combinations thereof), surfactants (e.g., polysorbate 80), and preservatives (e.g., benzalkonium chloride, phenylethyl alcohol, potassium sorbate).
  • the pharmaceutical formulation is an inhalation pharmaceutical formulation.
  • the inhalation pharmaceutical formulation may be in the form of an aerosol suspension, a dry powder, or a liquid suspension.
  • the inhalation pharmaceutical formulation may be prepared for delivery as a nasal spray or an inhaler, such as a metered dose inhaler (MDI).
  • MDIs can deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11 and CFC-12, or non-chlorofluorocarbons or alternate propellants such as fluorocarbons (e.g., HFC-134A, HFC-227), with or without surfactants or suitable bridging agents.
  • Dry-powder inhalers can also be used, either breath activated or delivered by pressure.
  • the active ingredient is prepared with a pharmaceutically acceptable carrier that will protect it against rapid degradation or elimination from the body of the subject after administration, such as the controlled-release formulations described in previous sections.
  • a pharmaceutically acceptable carrier that will protect it against rapid degradation or elimination from the body of the subject after administration, such as the controlled-release formulations described in previous sections.
  • the methods include administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject.
  • the compound, composition, or pharmaceutical formulation can be administered in a variety of manners, depending on whether local or systemic administration is desired.
  • the compound, composition, or pharmaceutical formulation is administered in a systemic manner, such as enteral administration (e.g., oral administration) and parenteral administration (e.g., injection, infusion, and implantation).
  • the compound, composition, or pharmaceutical formulation is directly administered to a specific bodily location of the subject, e.g., topical administration and intranasal administration.
  • exemplary administration routes include oral administration, intravenous administration such as intravenous injection or infusion, intramuscular administration such as intramuscular injection, intranasal administration, and topical administration.
  • the compound, composition, or pharmaceutical formulation is administered orally.
  • the compound, composition, or pharmaceutical formulation is administered intravenously.
  • the compound, composition, or pharmaceutical formulation is administered intranasally.
  • the compound, composition, or pharmaceutical formulation is administered intramuscularly.
  • the compound, composition, or pharmaceutical formulation is administered for a sufficient time period to alleviate one or more undesired symptoms and/or one or more clinical signs associated with the condition, disorder, or disease being treated.
  • the compound, composition, or pharmaceutical formulation is administered less than three times daily.
  • the compound, composition, or pharmaceutical formulation is administered once or twice daily.
  • the compound, composition, or pharmaceutical formulation is administered once daily.
  • the compound, composition, or pharmaceutical formulation is administered in a single oral dosage once a day.
  • the compound, composition, or pharmaceutical formulation is administered in a single intravenous dosage once a day.
  • the subject is a human. In some embodiments, the subject is an adult patient.
  • the subject is a pediatric patient.
  • the subject is a non-human animal, such as domestic pets, livestock and farm animals, and zoo animals.
  • the non-human animal may be a non-human primate.
  • A. Indications As discussed above, NMDARs are heterotetramers containing GluN2. Stimulation of one or more of the subunits can be beneficial for the treatment of a wide range of neurological and neuropsychiatric disorders or conditions, conditions dependent on synaptic plasticity such learning, memory, cognition, motor function, and motor retraining and rehabilitation, as well as conditions that involve impairment of movement, speech, vision, or other normal functions controlled by the brain.
  • the compounds disclosed herein can enhance maximal current, prolong deactivation, increase agonist potency, reduce single channel conductance, and/or decrease relative calcium permeability.
  • the compounds can increase charge transfer for NMDAR-mediated EPSCs in both pyramidal cells and interneurons with more robust actions on interneurons. This can reflect enhanced potentiation of GluN2D, since GluN2D is expressed in interneurons.
  • the preferential enhancement of NMDAR function on interneurons can increase inhibitory tone, which has been shown to have numerous effects including anticonvulsant actions, antidepressant actions, and anxiolytic actions.
  • the compounds can decrease input resistance of interneurons but not pyramidal cells, reflective of interneuron expression of GluN2D. In certain instances, the compounds can depolarize and increase spike firing in interneurons. In certain instances, the compounds can produce anxiolytic effect. In certain instances, the compounds can reverse long-term potentiation caused by GluN2 hypofunction. In certain instances, the compounds can rectify deficits in NMDAR-dependent synaptic plasticity and mitigate behavioral deficits produced by non-selective NMDAR blockade. In view of the foregoing, the compounds and pharmaceutical formulations thereof can be used to treat or prevent neurological and neuropsychiatric disorders or conditions, which includes abnormalities of the nervous system as well as genetic alterations that impact brain function.
  • Neurode disorders can be characterized by primary location, dysfunction/abnormality, or cause.
  • Central nervous system disorders impact the brain or spinal cord, while peripheral nervous system disorders affect the nerves.
  • Causes may include, for example, genetic abnormalities, developmental abnormalities, injury, ischemia or trauma, infection, cancer, and diseases and disorders of the vasculature that supplies the nervous system, e.g., stroke.
  • the neurological and neuropsychiatric disorder or condition may be associated with NMDAR, including NMDAR hypofunction or loss of function.
  • the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2, including NMDAR GluN2 hypofunction or loss of function.
  • the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2B, including NMDAR GluN2B hypofunction or loss of function. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2C, including NMDAR GluN2C hypofunction or loss of function. In some embodiments, the neurological and neuropsychiatric disorder or condition may be associated with NMDAR GluN2D, including NMDAR GluN2D hypofunction or loss of function. Neurological disorders or conditions In some embodiments, the compounds and pharmaceutical formulations can be used to treat neurological disorders or conditions.
  • the pain may include, without limitation, neurodegenerative disease or disorder, pain, epilepsy, essential tremor, movement disorder or impaired motor function, stroke, traumatic brain injury, transient ischemia, global ischemia, hypoxia, spinal cord trauma, and other neurologic events.
  • Multiple forms of pain can be treated by the compounds and pharmaceutical formulations.
  • the pain is neuropathic pain, inflammatory pain, perioperative pain, or nociceptive pain.
  • the pain is acute pain.
  • the pain is chronic pain.
  • the pain is selected from peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndromes, peripheral neuropathies, chemotherapy- induced neuropathic pain, cancer neuropathic pain, neuropathic low back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain.
  • the pain is neuropathic pain.
  • Neuropathic pain may result from peripheral or central nervous system pathologic events, including, but not limited to, trauma, ischemia, infections or endocrinologic disorders (e.g., diabetes mellitus, diabetic neuropathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathies with monoclonal proteins, vasculitis neuropathy, HIV infection, herpes zoster shingles, and postherpetic neuralgia), neuropathy associated with Guillain-Barre syndrome, neuropathy associated with Fabry’s disease, entrapment due to anatomic abnormalities, trigeminal and other CNS neuralgias, malignancies, inflammatory conditions or autoimmune disorders (e.g., demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome), cryptogenic causes (e.g., idiopathic distal small-fiber neuropathy).
  • endocrinologic disorders e.
  • neuropathic pain can be treated by the compounds and pharmaceutical formulations described herein include, but are not limited to, exposure to toxins or drugs (such as arsenic, thallium, alcohol, vincristine, cisplatin, and dideoxynucleosides), dietary or absorption abnormalities, immuno-globulinemias, hereditary abnormalities, and amputations (including mastectomy).
  • Neuropathic pain can also result from compression of nerve fibers, such as radiculopathies and carpal tunnel syndrome.
  • the pain is perioperative pain, such as those associated with incision.
  • the pain is nociceptive pain, such as those caused by burn or tissue damage.
  • neurodegenerative diseases or disorders can be treated by the compounds and pharmaceutical formulations.
  • the neurodegenerative diseases or disorders may include, without limitation, Alzheimer’s disease, dementia such as frontotemporal dementia and AIDS- induced dementia, chronic traumatic encephalopathy (CTE), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, spinal muscular atrophy, bulbar muscular atrophy, spinocerebellar ataxia, familial spastic paraparesis, Machado Joseph disease, Friedreich’s ataxia, and Lewy body disease such as Lewy body dementia.
  • Treatment by the compound or pharmaceutical formulation may reduce or reverse cognitive or memory impairment associated with these diseases or disorders.
  • the neurodegenerative disease or disorder is Alzheimer’s disease. In some embodiments, the neurodegenerative disease or disorder is Parkinson’s disease. In some embodiments, the neurodegenerative disease or disorder is Huntington’s disease. In some embodiments, the neurodegenerative disease or disorder is ALS. In some embodiments, the neurodegenerative disease or disorder is frontotemporal dementia. In some embodiments, the neurodegenerative disease or disorder is chronic traumatic encephalopathy (CTE). In some embodiments, the neurodegenerative disease or disorder is Lewy body dementia. In some embodiments, the neurodegenerative disease or disorder is spinal muscular atrophy or spinocerebellar ataxia. In some embodiments, the neurodegenerative disease or disorder is the result of a prion disease.
  • CTE chronic traumatic encephalopathy
  • the neurodegenerative disease reflects or is caused by neuronal loss due to epileptic encephalopathy.
  • epilepsy or seizure disorder can be treated by the compounds and pharmaceutical formulations.
  • the epilepsy or seizure disorder may be selected from epilepsies that are inadequately controlled by existing medications (i.e., treatment- resistant epilepsy), infantile spasms, and epilepsies or seizure disorders caused by a rare disease or genetic condition (e.g., genetic mutation) that produces epilepsies, seizures, spasms, abnormally hypersynchronous brain activity, and/or other conditions associated with enhanced neuronal synchrony.
  • a rare disease or genetic condition e.g., genetic mutation
  • the subject may be a pediatric patient suffering from the epilepsy or seizure disorder. In some embodiments, the subject may be an adult patient suffering from the epilepsy or seizure disorder. In some embodiments, the compound or pharmaceutical formulation is used to reduce the severity and/or intensity of the epilepsy or seizure disorder. In some embodiments, the compound or pharmaceutical formulation is used to reduce the frequency of the epilepsy or seizure disorder.
  • the epilepsy is refractory epilepsy, such as Refractory Status Epilepticus. In some embodiments, the epilepsy is CDKL5 Deficiency Disorder. In some embodiments, the epilepsy is Established Status Epilepticus. In some embodiments, the epilepsy is Tuberous Sclerosis Complex.
  • the epilepsy is Lennox-Gastaut Syndrome. In some embodiments, the epilepsy is Dravet Syndrome. In some embodiments, the epilepsy is Developmental and Epileptic Encephalopathy. Many forms of movement disorder or impaired motor function can be treated by the compounds and pharmaceutical formulations. They may include ataxia, dyskinesia, and dystonia. Neuropsychiatric disorders or conditions In some embodiments, the compounds and pharmaceutical formulations can be used to treat neuropsychiatric disorders or conditions.
  • the neuropsychiatric disorder or condition is schizophrenia, depression, addiction or use dependence, anxiety disorder, autism spectrum disorder, or bipolar disorder.
  • the neuropsychiatric disorder or condition is schizophrenia.
  • the neuropsychiatric disorder or condition is depression or post- partum depression.
  • the depression is major depressive disorder.
  • the depression is treatment-resistant depression.
  • the depression is bipolar depression.
  • the neuropsychiatric disorder or condition is addiction or use dependence.
  • the addiction or use dependence is alcohol addiction or use dependence, such as alcohol abuse.
  • the addiction or use dependence is substance addiction or use dependence, such as substance abuse.
  • Treatment by the compound or pharmaceutical formulation may reduce or reverse cognitive or memory impairment associated with these disorders or conditions.
  • the neuropsychiatric disorder or condition is autism spectrum disorder.
  • the neuropsychiatric disorder or condition is anxiety disorder, such as generalized anxiety disorder, agoraphobia, and panic disorder.
  • the neuropsychiatric disorder or condition is bipolar disorder.
  • the bipolar disorder is cyclothymic disorder.
  • the bipolar disorder is treatment-resistant bipolar disorder.
  • the neuropsychiatric disorder or condition is sleeping disorder, such as those comorbid with other neuropsychiatric disorders or conditions.
  • the neuropsychiatric disorder or condition is attention deficit disorder.
  • the neuropsychiatric disorder or condition is cognitive deficit disorder.
  • the neuropsychiatric disorder or condition is uncontrolled anger.
  • the neuropsychiatric disorder or condition is headache or migraine.
  • the neuropsychiatric disorder or condition is eating disorder.
  • the compounds and pharmaceutical formulations disclosed herein can be used to treat genetic mutations of NMDARs, especially those causing a loss of function in GluN2B, GluN2C, and/or GluN2D. Additionally, the compounds and pharmaceutical formulations disclosed herein can be used to promote or improve neuroplasticity. In some embodiments, the compounds and pharmaceutical formulations disclosed herein can be used to promote or improve synaptic plasticity. NMDARs play an important role in synaptic plasticity, learning, and memory. Deficits in synaptic plasticity are thought to contribute to cognitive dysfunction in a wide range of indications, including Alzheimer’s disease, autism, developmental delay, cognitive disability, schizophrenia, depression, and Parkinson’s disease.
  • the present disclosure further relates to methods of improving synaptic plasticity, learning, and memory by administering a compound or pharmaceutical formulation disclosed herein to a subject in need thereof.
  • the compounds and pharmaceutical formulations disclosed herein can be used to treat NMDAR encephalitis, an autoimmune condition in which the patient has antibodies against NMDARs.
  • NMDAR encephalitis can produce a spectrum of complex neuropsychiatric features, including hallucinations and schizophrenia-like symptoms.
  • EXAMPLES The examples below describe studies to synthesize and evaluate subunit-selective NMDAR modulators.
  • the synthetic methods disclosed herein are compatible with a wide variety of functional groups and starting materials. Thus, a wide variety of compounds can be obtained from the disclosed methods.
  • the hydroxyl group may be oxidized (e.g., by Dess-Martin oxidation) after the coupling reaction to generate the ketone analog. See, for example, 1622-358, 1622-373, 1622-374, 1622-375, 1622-376, 1622-377, 1622- AAA, 1622-AAB).
  • alkyne-containing precursors that were not commercially available, they were synthesized using the procedure below, with slight modifications as needed.
  • Propargyl bromide 80% wt in PhCH3, 1.1 eq
  • ACN a solution of the heterocycle (1.0 eq) and K2CO3 (2.0 eq) in ACN (0.35 M) at 0 °C and stirred at room temperature for 16 h.
  • the reaction was quenched with water and stirred for 30 min and then extracted with DCM (3 ⁇ ).
  • the combined organic layers were washed with brine (1 ⁇ ), dried over Na2SO4, and concentrated.
  • the resulting oil was used without further purification.
  • Example 1 a solution of the heterocycle (1.0 eq) and K2CO3 (2.0 eq) in ACN (0.35 M) at 0 °C and stirred at room temperature for 16 h.
  • the reaction was quenched with water and stirred for 30 min and then extracted with DCM (3 ⁇ ).
  • the combined organic layers
  • Oocyte preparation, cRNA synthesis, cRNA microinjections were all performed as previously described (Hansen et al., Molecular Pharmacology, 2013, 84(1), 114-127; Myers et al., Human Molecular Genetics, 2023, 32(19), 2857-2871).
  • Tested compounds were prepared as 20 mM stock solutions in DMSO and diluted to the final experimental concentrations in the recording solution (specified below). DMSO content was 0.05 ⁇ 0.5% (v/v).
  • Two-electrode voltage-clamp recordings were performed on oocytes expressing recombinant rat GluN1/GluN2A, GluN1/GluN2B, GluN1/GluN2C, or GluN1/GluN2D receptors.
  • Wild-type cDNAs for rat GluN1-1a (referred to as GluN1; NCBI Reference Sequence NM_017010.2), GluN2A (NM_012573.4), GluN2B (NM_012574.1), GluN2C (NM_012575.3), and GluN2D (NM_022797.2) were provided by Dr. S. Heinemann, Dr. S. Nakanishi, and Dr. P. Seeburg. Oocytes were injected with 5-10 ng of cRNA in RNAse-free water with a GluN1:GluN2 ratio ranging from 1:1 to 1:5.
  • Oocytes were incubated at 15-19 °C in Barth’s solution containing (in mM) 88 NaCl, 1 KCl, 2.4 NaHCO3, 10 HEPES, 0.82 MgSO4, 0.33 Ca(NO3)2, and 0.41 CaCl2.
  • the Barth’s solution was supplemented with 100 ⁇ g/mL gentamycin, 40 ⁇ g/mL streptomycin, and 50 ⁇ g/mL penicillin.
  • recordings were performed using a recording solution containing (in mM) 90 NaCl, 1 KCl, 10 HEPES, 0.5 BaCl2, and 0.01 EDTA and adjusted to pH 7.4 with NaOH.
  • Example 3 In vitro pharmacology of 1622-240 Electrophysiological recordings from Xenopus oocytes, HEK cells, and cultured cerebellar and cortical neurons were used to determine the mechanisms of action of a representative member (1622-240) of this class of NMDAR modulators. A.
  • Oocytes were stored at 16 °C in media containing (in millimolar) 88 NaCl, 2.4 NaHCO3, 1 KCl, 0.33 Ca(NO3)2, 0.41 CaCl2, 0.82 MgSO4, 5 HEPES, 1 U/ml penicillin, 0.1 mg/ml gentamicin sulfate, and 1 ⁇ g/mL streptomycin (pH 7.4, adjusted with NaOH), stored for 1-4 days after injection.
  • Two-electrode voltage clamp recordings were performed on oocytes subjected to superfusion at room temperature (23°C) with a solution containing (in millimolar) 90 NaCl, 1 KCl, 10 HEPES, 0.5 BaCl 2 , and 0.01 EDTA (pH 7.4 by NaOH).
  • Oocytes were voltage clamped at -40 mV unless specified otherwise; only oocytes with a current response greater than 50 nA were included in the study.
  • Concentration-response curves were generated in saturating glutamate and glycine, with variable concentrations of test compound prepared as 20 mM stock and diluted to final concentration (0.01-0.25% v/v DMSO).
  • D,L- APV or 7-CKA Concentrations of D,L- APV or 7-CKA were determined by the Cheng-Prusoff Equation, where K i is the inhibitory constant of either D,L-APV or 7-CKA, IC 50 is the concentration of inhibitor required to reduce current by 50%, and A is the concentration of either glutamate or glycine. See equation 5.
  • HEK cell culture HEK293T (CRL 3216, ATCC) were cultured in DMEM (Thermo Fisher Scientific, 10566016) supplemented with 10% Fetal Bovine Serum, 10 U ml ⁇ 1 penicillin and 10 ⁇ g ml ⁇ 1 streptomycin and maintained at 5% CO2 in a 37 °C incubator.
  • the cerebellum was dissected from animals, placed in ice-cold DMEM supplemented with 10% FBS, 10 U ml ⁇ 1 penicillin, 10 ⁇ g ml ⁇ 1 streptomycin, minced finely, and strained through a 200- micrometer nylon mesh filter (PluriSelect) into media, and then plated onto coverslips coated with 0.1 mg/mL -1 poly-D-lysine. The following day, 50% of the medium was changed and subsequently every three days, and cultures kept for up to ten days in an incubator with 5% CO 2 and 95% humidified air at 37 °C. Granule cells were the most numerous cell type in these cultures and readily identified by their small round shape and low cellular capacitance.
  • the neurons were cultured in glial-conditioned neurobasal media (Fisher) supplemented with 0.5 mM Glutamax (Gibco), 10 U ml ⁇ 1 penicillin, 10 ⁇ g ml ⁇ 1 streptomycin, and 2% B27 (Invitrogen), where 50% of the media was exchanged every four days.
  • the cultures were maintained in an incubator with 5% CO 2 and 95% humidified air mixture at 37 °C. All experiments were performed on neurons maintained 7-10 days in vitro (DIV).
  • Rapid solution exchange was performed by lifting HEK cells from the coverslip into the solution flowing from a two-barrel theta tube, the position of which was rapidly translated using a piezoelectric manipulator (Siskiyou). Solution exchange around an open tip (10–90% rise time) was ⁇ 1 ms. Vehicle and 1622-240 recordings were not performed in the same cell to prevent contaminant 1622-240 that may reside in the recording chamber from prolonging the deactivation time course in control. When current responses were recorded in response to single agonist, the antagonist concentration was calculated as described in equations 6 and 7 (see below).
  • Patch pipettes were prepared from thick-walled boroscillicate (OD 1.5 mm ⁇ 0.86 mm; Sutter Instrument Co.), quartz (OD 1.5 mm ⁇ ID 0.75 mm; Sutter Instrument Co.) or aluminosilicate (OD 1.5 mm ⁇ ID 1 mm; Sutter Instruments Co.) micropipettes that were coated with Sylgard 184 (Sigma-Aldrich) and the tips fire polished to final resistance of 4-10 M ⁇ .
  • the external bath solution contained (in millimolar) 150 NaCl, 3 KCl, 10 HEPES, 5 mannitol, 0.01 EDTA, 0.5 CaCl2.
  • the internal solution for HEK cells contained (in mM) 110 D-gluconate, 110 CsOH, 30 CsCl, 5 BAPTA, 5 HEPES, 4 NaCl, 2 MgCl2, 2 Na-ATP, 0.5 CaCl2, 0.3 Na-GTP (pH 7.35).
  • the internal solution contained (in mM) 110 CsF, 30 CsCl, 4 NaCl, 0.5 CaCl 2 , 5 K-BAPTA, 5 K-HEPES (pH 7.35).
  • solutions had either 100 ⁇ M glutamate and glycine (plus 0.012% DMSO) or glutamate and glycine supplemented with 2.4 ⁇ M 1622-240 (0.012% DMSO).
  • solutions contained 200 ⁇ M D,L-APV and 10 ⁇ M 1622-240 with or without 10 ⁇ M glycine.
  • solutions contained 200 ⁇ M 7-CKA and 2.4 ⁇ M 1622-240 with and without 2 ⁇ M glutamate. All recordings were made at room temperature (23 °C). Data analysis Concentration-response data were analyzed using GraphPad Prism 10.0.
  • the Z value was calculated from the response to saturating glycine alone, and when glycine concentration-response curves were measured, the Z value was calculated from the response to saturating glutamate alone.
  • the applicant set the value [A] in the Cheng-Prusoff equation as the concentration determined as contaminant agonist from the water source, defined by the Zr parameter in equation 2.
  • A is the contaminant glutamate (i.e. Z for glutamate from equation 2).
  • EC50 is the concentration of glutamate required to elicit half maximal efficacy for 1622-240-bound receptor, and the applicant used the values determined from the agonist concentration-response curves for this value.
  • Ki for D-APV is 0.46-1.6 ⁇ M, which the applicant increased 2-fold since the applicant used racemic D,L-APV.
  • the equation then takes the form of ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ 3.2 which yields an IC 50 value of 3.65 ⁇ M.
  • 200 ⁇ M D,L-APV is 55-fold the IC 50 needed to block contaminant glutamate, resulting in near-complete inhibition of glutamate binding.
  • the applicant inserted 0.0086 ⁇ M as the contaminant glycine concentration (i.e., Z for glycine from equation 2), and 0.085 ⁇ M as glycine EC50 in the presence of 1622-240.
  • Ki for 7-CKA is 0.2 ⁇ M.
  • Equation to calculate the necessary concentration to block GluN1 by 7-CKA by equation 5 takes the form of ⁇ ⁇ ⁇ ⁇ . ⁇ ⁇ ⁇ 0.2 ⁇ ⁇ . ⁇ ⁇ ⁇ 1 ⁇ (7) which yields an IC50 value of 0.22 ⁇ M. Therefore, 200 ⁇ M 7-CKA is 909-fold the IC50 needed to block contaminant glycine.
  • NMDAR deactivation time courses following rapid glutamate removal were fitted by a two-component exponential function and the time constants and relative amplitude were determined for the fast and slow components, according to ⁇ )
  • ⁇ FAST is the fast deactivation time constant
  • ⁇ SLOW is the slow deactivation time constant
  • amplitudeFAST is the current amplitude of the fast deactivation component
  • amplitudeSLOW is the current amplitude of the slow deactivation component.
  • the weighted deactivation time constant ( ⁇ W ) was calculated using the following equation ⁇
  • the current-voltage (I-V) relationship for Mg 2+ blockade was established by holding oocytes at a membrane potential of 0 mV and then stepping the membrane potential between -80 and +30 mV in 15 mV increments; the applicant did not correct for the junction potential.
  • the current-voltage relationship was fitted by the Woodhull equation: ⁇ ⁇ ⁇ where V rev was the reversal potential, z ⁇ was the product of the Mg 2+ charge and the distance of the Mg 2+ binding site in the pore, Vm was the holding potential, and KD,0mV was the Mg 2+ affinity at 0 mV membrane potential.
  • Single channel analysis Unitary current recordings from excised outside out patches were filtered off-line between 1-4 kHz (-3dB, Bessel), and single channel openings were idealized using a custom threshold crossing algorithm that detected openings that reached 30% of maximum levels and closings that dropped to 70% of a given open level (ChanneLab).
  • Individual durations were taken at 50% of the current amplitude determined for each open or closed period, using interpolation to obtain the duration at exactly 50% of the amplitude.
  • the duration of brief open and closed periods was corrected empirically by determining the change in 50% duration after filtering for simulated waveforms that were 1, 2, 3, 4, etc., times the duration of a single digitized datapoint.
  • nPo was calculated for multi-channel patches according to ⁇ ⁇ where the integral Q was the product of mean current and time, time is the total time of the analyzed sections, and i is the single channel current determined as the mean of multiple sublevels. Po was then determined for these multi-channel patches by dividing nPo by the total number of channels in the patch (n), which could be determined from the maximum number of simultaneously opening channels in the presence of 1622-240. The applicant assumes that the increased open probability in potentiator is high enough so that the applicant can always detect the maximum number of channels.
  • Statistical analysis Data presented in tables and text are the mean ⁇ SEM. Data shown in figures are mean ⁇ s.d. Comparisons were made using paired or unpaired t-test, as appropriate.
  • 1622-240 transforms NMDARs so that they can be opened when only glutamate or glycine is bound (Table 7).1622-240-bound NMDARs channels activated by a single agonist (glutamate or glycine) open to a unique conductance level with different pore properties and Mg 2+ sensitivity, in contrast to channels arising from activation of NMDARs with both co- agonists bound (Tables 8 and 9). These results demonstrate that distinct gating steps can be controlled by glutamate and glycine binding, and shows that 1622-240 enables glutamate- or glycine-bound NMDARs to generate open conformations with different pore properties. Table 2. Effect of 1622-240 on agonist potency
  • mice were kept in a closely monitored vivarium, where they received constant care from trained technical and veterinary personnel to ensure their well-being and proper husbandry. In each cage, a maximum of five mice had free access to food and water. For experimentation, animals were randomly selected from various breeder pairs or trios.
  • the brain was rapidly placed into ice-cold artificial cerebral spinal fluid (aCSF), hemisected, and glued to the stage of a vibrating microtome (Leica VT1200S, Wetzlar, Germany), and 280-300 ⁇ m slices that contained the hippocampal region were cut.
  • aCSF artificial cerebral spinal fluid
  • hemisected hemisected
  • glued to the stage of a vibrating microtome Leica VT1200S, Wetzlar, Germany
  • the slices were bathed in an ice-cold (0-2 °C) sucrose-based aCSF containing (in mM) 230 sucrose, 24 NaHCO 3 , 10 glucose, 2.5 KCl, 1.25 NaH 2 PO 4 , 3 Na-pyruvate, 5 Na-L-ascorbate, 12 Na-acetyl cysteine, 10 MgCl2, and 0.25 CaCl2 saturated with 95% O2/5% CO 2 .
  • slices were transferred to a holding chamber with the same solution, except that Mg 2+ was lowered to 1.5 mM. Slices were incubated at 32 °C for 30 minutes in this solution before returning them to room temperature, for at least 1 hour recovery prior to use.
  • the external aCSF solution for the slice recordings contained (in mM) 126 NaCl, 26 NaHCO3, 10 glucose, 2.5 KCl, 1.25 NaH2PO4, 1.5 MgSO4, and 1.5 CaCl2 bubbled with 95% O2/5% CO2. Recordings were made using a Multiclamp 700B amplifier (Molecular Devices), filtered at 2 kHz using an 8-pole Bessel filter (-3dB), and digitized at 20 kHz using Axon pClamp10 software. The temperature of the external solution was heated to 30-32 o C by a TC-344C inline heater system (Warner Instruments).
  • a weighted time constant was calculated by fitting a dual exponential to each response.
  • Evoked-action potential firing frequency was calculated in response to a 500 ms current injection every 2 seconds starting at -40 pA and increasing by 20 pA until the cell displayed depolarization-induced block of firing.
  • the unpolished pipettes were filled with internal solution containing (in mM) 105 Cs ⁇ gluconate, 5 CsCl, 8 NaCl, 5 Na-phosphocreatine, 5 MgCl2, 2 Na ⁇ ATP, 0.3 Na ⁇ GTP, 0.6 EGTA, 5 BAPTA, 40 HEPES and 5 QX314 (pH 7.3, adjusted with CsOH, ⁇ 290 mOsm).
  • Pipette resistances were 4-7 M ⁇ .
  • 10 ⁇ M gabazine, and 10 ⁇ M NBQX were added to the external solution to block GABA A receptors and AMPA receptors, respectively.
  • NMDAR-mediated EPSCs in cells held at +40 mV were evoked by injecting 50-120 ⁇ A of current for 0.1 ms using a monopolar platinum-iridium stimulating electrode (FHC) placed within the Schaffer collaterals in the stratum radiatum.
  • FHC platinum-iridium stimulating electrode
  • the NMDAR pore blocker MK-801 was applied at the end of each recording to block NMDARs that were potentiated by 1622-240, which confirmed that the current was NMDAR-mediated.
  • the internal pipette solution contained (in mM) 110 Cs-gluconate, 4 NaCl, 30 CsCl, 5 BAPTA, 5 HEPES, 0.5 CaCl2, 2 MgCl2, 2 Na-ATP, 0.3 Na-GTP.
  • the aCSF for sIPSC recording contained (in mM) 130 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 25 NaHCO 3 , 1 MgCl 2 , 2 CaCl 2 , 20 glucose.
  • sIPSCs were isolated by holding the CA1 pyramidal cell at the EPSC reversal potential , which was +10mV for our solutions.
  • Outward current mediated by Cl- was measured and analyzed to determine the sIPSC frequency and amplitude.
  • the experimental recording protocol was 5 minutes baseline recording, followed by wash-in of 3 ⁇ M 1622-240 for 10 minutes. Recordings were finished by switching to aCSF that contained 1622-240 plus 10 ⁇ M gabazine to confirm that the currents the applicant recorded were mediated by GABAA receptors.
  • Parallel control experiments were completed with the same recording protocol perfusing 400 ⁇ M DL-APV in the aCSF to competitively antagonize NMDARs throughout the entire recording period. Series resistance was monitored throughout experiments and was typically 8-12 M ⁇ .
  • Evoked-EPSCs were analyzed by t-test, current clamp data were analyzed by ordinary one-way ANOVA with Dunnett's multiple comparisons test, bicuculline-treated intrinsic membrane properties were analyzed by repeated measures ANOVA with Tukey's multiple comparisons test (details can be found in each Table). When multiple tests were performed on the same recording, the applicant corrected for family-wise error.
  • 1622-240 did not produce any detectable effects on the instantaneous firing frequency, resting membrane potential, and input resistance in CA1 pyramidal cells (Table 11). These results demonstrate that the larger effects of 1622-240 on GluN2D-containing receptors may underlie increased actions of 1622-240 on interneurons than CA1 pyramidal cells, given most hippocampal interneurons express GluN2D. Table 11. CA1 interneuron and CA1 pyramidal cell intrinsic properties To confirm that the expression of GluN2D-containing NMDARs is involved in the differential effects of 1622-240 on neuronal activity of CA1 interneurons and pyramidal cells, current clamp recordings with the same protocol were performed on brain slices from GluN2D- knockout (GluN2D-KO) mice.
  • Spontaneous inhibitory post-synaptic current (sIPSC) recordings were performed on CA1 pyramidal cells at a holding at +10 mV under voltage clamp.1622-240 (3 ⁇ M) shifted the sIPSC inter-event interval (IEI) significantly left of the baseline level (p ⁇ 0.0001, two-sample Kolmogorov-Smirnov test), indicating a change of sIPSC event frequency.
  • fEPSP evoked field EPSP
  • 1622-240 potentiates evoked-NMDAR EPSCs on both CA1 pyramidal cells and interneurons, it preferentially enhances interneuron excitability over principal cell excitability. This results from depolarization, increased spike firing, and enhanced NMDAR- mediated current charge transfer in interneurons. By contrast, 1622-240 did not detectably depolarize CA1 pyramidal cells, but did have modest effects when bicuculline was used to block GABA receptor signaling. These data demonstrate that 1622-240 can enhance interneuron function with modest effects on the CA1 pyramidal cells, which can provide therapeutically beneficial effects secondary to enhanced interneuron excitability.
  • 1622-240 shows a preferential potentiation effect on GluN2D-containing CA1 interneurons over GluN2A/GluN2B-expressing CA1 pyramidal cells, making it effective in modulating circuit function in a variety of pathological conditions, including anxiety, treatment-resistant depression, and cognitive dysfunction.
  • Example 5 Effects of 1622-240 on LTP in GluN2B-E413G mice A. Materials and methods Knockin C57BL/6J mice harboring the Grin2b-Glu413Gly variant were used for field potential recordings from hippocampal slices; both genders were included (P20-P25). This variant reduces glutamate potency >50-fold and impairs LTP of synaptic transmission, a cellular model of synaptic plasticity.
  • Brain slices were coronally cut at 400 ⁇ m and transferred into recovery solution for 1 hour recovery.
  • the protocol for recording and analyzing field potentials corresponding to evoked EPSPs in the stratum radiatum was previously described (PMID: 30132892).
  • a platinum stimulating electrode was used to stimulate Shaffer Collateral fiber while recording electrode was placed at CA1 stratum radiatum. Recording electrodes had resistances of 6-8 M ⁇ . Internal solution within recording electrode was 0.9% saline. Stimulation level was 0.1 ms duration with 40-100 ⁇ A amplitude.
  • Example 6 In vivo pharmacokinetic and behavioral studies A.
  • IP dose solutions for rats were prepared by adding PEG400 (19.91 mL) to the test compound and vortexed for 2 min followed by sonication for 10 min. Then, a solution of 10% dextrose in water (19.91 mL) was added, and the tube was vortexed for 1 min followed by sonication for 1 min. PO dose solutions for rats were prepared by adding DMSO (3.746 mL) to the test compound and vortexed for 1 min followed by sonication for 1 min. Then EtOH (3.746 mL) was added, and the tube was vortexed for 1 min followed by sonication for 1 min.
  • mice were treated with the test compound 60 mins prior to behavioral testing.
  • the light/dark box was conducted over a 10 min period in a two-chamber apparatus with a 22 ⁇ 43 cm photobeam frame with equally spaced photocells across an enclosed dark chamber and an exposed light chamber. There was an average ⁇ lux of 300 lx for the light/dark box test. The number of entries, distance traveled, and the amount of time spent in the light chamber were measured using automated Motor Monitor software (Hamilton-Kinder).
  • IP administration of 10 mg/kg 1622- 240 generated a reduction in avoidance behaviors in the light/dark box test (an increase in the percent distance traveled and percent time spent in the light chamber), compared to either vehicle or 5 mg/kg 1622-240 (Figure 2B).
  • the increased time and distance exploring the light chamber is consistent with reduced anxiety, which reflects enhanced interneuron function.
  • 1622-287 generated a reduction in avoidance behaviors in both the open field test ( Figure 3A) and the light/dark box test (Figure 3B). Moreover, 1622-287 generated an increase in acute exploratory behaviors, as evidenced by an increase in the number of light entries in the light/dark box test ( Figure 3B) and an increase in the total distance traveled in both the open field test and the light/dark box test ( Figure 3).

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Abstract

Sont divulgués des modulateurs du récepteur N-méthyl-D-aspartique (NMDAR) sélectifs d'une sous-unité. Dans certains cas, les composés sont des modulateurs allostériques positifs de la sous-unité GluN2. Dans certains cas, les composés sont des modulateurs allostériques positifs de la sous-unité GluN2 et sont sélectifs pour GluN2C/D sur GluN2A. Dans certains cas, les composés sont des modulateurs allostériques positifs de la sous-unité GluN2 et sont sélectifs pour GluN2C/D sur les deux GluN2A et GluN2B. La présente divulgation concerne également des formulations pharmaceutiques des modulateurs de NMDAR sélectifs de sous-unité ainsi que des méthodes de traitement d'états, de troubles ou de maladies à l'aide des composés et des formulations pharmaceutiques divulgués.
PCT/US2025/039766 2024-07-29 2025-07-29 Modulateurs de récepteurs n-méthyl-d-aspartate sélectifs d'une sous-unité et leurs utilisations Pending WO2026030391A1 (fr)

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