Zervimesine for treating neurodegenerative disease

Abstract

The present disclosure provides a method of treating or inducing cognitive preservation in a patient with Alzheimer's disease, comprising administering an effective amount of CT1812. The effective amount of CT1812 is 100 mg or 300 mg administered orally once daily. The method demonstrates improvements in cognitive outcomes compared to placebo across multiple measures including ADAS-Cog11, MMSE, ADCS-ADL, and ADCS-CGIC. The method demonstrates improvements in cognitive outcomes in patients with low plasma levels of phosphorylated tau 217 prior to administration.

Description

ZERVIMESINE FOR TREATING NEURODEGENERATIVE DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims priority to U.S. Provisional Application No. 63 / 676,763 filed on July 29, 2024 and U.S. Provisional Application No. 63 / 712,801 filed on October 28, 2024, which are incorporated herein by reference in their entirety.FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] The invention described herein was made with government support under Grant No. R01AG054176 awarded by the National Institute on Aging of the National Institutes of Health. The government has certain rights in the invention.SUMMARY

[0003] According to an aspect of the present disclosure, a method of inducing cognitive preservation in a subject is provided. The method includes administering to the subject a therapeutically effective amount of a compound of formula:

[0004] pharmaceutically acceptable salt.

[0005] According to another aspect of the present disclosure, a method of improving cognition in a subject is provided. The method includes administering to the subject a therapeutically effective amount of a compound of formula:

[0006]

[0007] According to another aspect of the present disclosure, a method of treating Alzheimer's disease in a subject is provided. The method includes administering to the subject a therapeutically effective amount of a compound of formula:

[0008] pharmaceutically acceptable salt.

[0009] According to any aspect of the present disclosure, the methods may include administration of any compound to a subject, wherein the subject has reduced levels of Tau protein phosphorylated at amino acid 217 (pTau-217). In some embodiments, the reduced plasma levels of pTau-217 are detected prior to administrationof the compound or pharmaceutically acceptable salt thereof.

[0010] According to other aspects of the present disclosure, the methods may include one or more of the following features. The pharmaceutically acceptable salt may be a fumarate salt. The subject may be diagnosed with Alzheimer's disease. The subject may be diagnosed with mild cognitive impairment. The subject may be diagnosed with mild to moderate cognitive impairment. The subject may have a positive amyloid PET scan or cerebrospinal fluid biomarker consistent with Alzheimer's disease. The subject may have a Mini-Mental State Examination (MMSE) score between 18 and 26. The subject may have a mini-mental state examination (MMSE) score between about 22-26. The subject may have an MMSE score greater than, or equal to 24. The subject may be aged less than 50 years. The subject may be aged between 50 and 80 years. The subject may have undergone magnetic resonance imaging (MRI) that shows no significant abnormality. The subject may not have major depressive disorder, schizophrenia, or bipolar disorder. The subject may be on a stable regimen of acetylcholinesterase inhibitors or memantine.

[0011] The compound may be administered orally. The compound may be administered for about 6 months. The compound may be administered for at least about 6 months. The therapeutically effective amount may be a total daily dose of about 100 mg to about 300 mg. The therapeutically effective amount may be about 100 mg. The therapeutically effective amount may be about 200 mg. The therapeutically effective amount may be about 300 mg. The therapeutically effective amount may be a total daily dose of about 100 mg to about 300 mg. The therapeutically effective amount may be a total daily dose of about 100 mg. The therapeutically effective amount may be a total daily dose of about 200 mg. The therapeutically effective amount may be a total daily dose about 300 mg. The total daily dose may be administered for about 6 months. The total daily dose may be administered for at least about 6 months.

[0012] Administering the compound may result in a reduction in the rate of cognitive decline compared to placebo. Administering the compound may result in a reduction in theAlzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to placebo. Administering the compound may result in an improvement in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score compared to placebo. Administering the compound may result in an improvement in the Clinical Global Impression of Change (CGIC) score compared to placebo. Administering the compound may result in an improvement in the Neuropsychological Test Battery (NTB) score compared to placebo. Administering the compound may result in an improvement in the Mini-Mental State Examination (MMSE) score compared to placebo. Administering the compound may result in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease. The one or more CSF biomarkers may be neurofilament light chain (NfL), amyloid beta (Abeta), tau, and phosphorylated tau. Administration may result in a reduction in the concentration of NfL compared to a placebo. The Abeta may be Abeta 40 or Abeta 42. Administration may result in a reduction in the concentration of Abeta 42 compared to a placebo.

[0013] Administering the compound may result in a reduction in the rate of cognitive decline compared to the start of treatment. Administering the compound may result in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment. Administering the compound may result in an improvement in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score compared to the start of treatment. Administering the compound may result in an improvement in the Clinical Global Impression of Change (CGIC) score compared to the start of treatment. Administering the compound may result in an improvement in the Neuropsychological Test Battery (NTB) score compared to the start of treatment. Administering the compound may result in an improvement in the Mini-Mental State Examination (MMSE) score compared to the start of treatment. Administering the compound may result in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease. The one or more CSF biomarkers may be neurofllament light chain (NfL), amyloid beta (Abeta), tau, and phosphorylated tau. Administration may result in a reduction in the concentration of NfL compared to the start of treatment. The Abeta may be Abeta 40 or Abeta 42. Administration may result in a reduction in the concentration of Abeta 42 compared to the start of treatment.

[0014] Administering a therapeutically effective amount of the compound may result in a reduction in the Alzheimer's Disease Assessment Score (ADAS-COG) score of a subject as compared to the ADAS-COG score of the subject before treatment. Administering a therapeutically effective amount of the compound may result in at a least 3 -point reduction in the Alzheimer's Disease Assessment Score (ADAS-COG) score of a subject. An incidence oftreatment-emergent adverse events (TEAEs) may be comparable to placebo. The method may further comprise monitoring liver function tests (LFTs) during treatment. Less than about 20% of patients treated with 300 mg CT1812 may experience LFT elevations >3x upper limit of normal (ULN) for AST or ALT. The liver function tests may return to normal after cessation of treatment with the compound.BRIEF DESCRIPTION OF DRAWINGS

[0015] FIG. 1 depicts a graph showing changes in ADAS-Cog 11 scores over time for different treatment groups, according to an embodiment.

[0016] FIG. 2 illustrates a graph showing change in ADAS-Cog 11 scores over time for different treatment groups, according to aspects of the present disclosure.

[0017] FIG. 3 depicts a graph showing changes in ADAS-Cog 11 scores over time for different treatment groups, according to an embodiment.

[0018] FIG. 4 illustrates a graph showing change in ADAS-Cog 11 scores over time for different treatment groups, according to aspects of the present disclosure.

[0019] FIG. 5 depicts two graphs showing results of a clinical trial measuring ADAS-Cog 11 scores over time, according to an embodiment.

[0020] FIG. 6 illustrates a line graph showing changes in ADAS-Cog 11 over time for mild and moderate cases, according to aspects of the present disclosure.

[0021] FIG. 7 depicts a line graph showing changes in MMSE scores over time for moderate Alzheimer's disease patients, according to an embodiment.

[0022] FIG. 8 illustrates a line graph showing changes in MMSE scores over time for mild Alzheimer's disease patients, according to aspects of the present disclosure.

[0023] FIG. 9 depicts a graph showing changes in MMSE scores over time for different treatment groups, according to an embodiment.

[0024] FIG. 10 illustrates a graph showing change in MMSE scores over time for different treatment groups, according to aspects of the present disclosure.

[0025] FIG. 11 depicts a graph showing changes in MMSE scores over time for different treatment groups, according to an embodiment.

[0026] FIG. 12 illustrates a graph showing change in MMSE scores over time for different treatment groups, according to aspects of the present disclosure.

[0027] FIG. 13 depicts a graph showing changes in ADAS-Cog 13 scores over time for different treatment groups, according to an embodiment.

[0028] FIG. 14 illustrates a graph showing change in ADAS-Cog 13 scores over time for different treatment groups, according to aspects of the present disclosure.

[0029] FIG. 15 depicts a graph showing changes in cognitive composite scores over time for different treatment groups, according to an embodiment.

[0030] FIG. 16 illustrates a graph showing changes in cognitive composite scores over time for different treatment groups, according to aspects of the present disclosure.

[0031] FIG. 17 depicts a graph showing change in cognitive composite scores over time for different treatment groups, according to an embodiment.

[0032] FIG. 18 illustrates a graph showing changes in ADCS-ADL scores over time for different treatment groups, according to aspects of the present disclosure.

[0033] FIG. 19 depicts a graph showing changes in ADCS-ADL scores over time for different treatment groups, according to an embodiment.

[0034] FIG. 20 illustrates a graph showing changes in ADCS-ADL scores over time for different treatment groups, according to aspects of the present disclosure.

[0035] FIG. 21 depicts a graph showing changes in ADCS-ADL scores over time for different treatment groups, according to an embodiment.

[0036] FIG. 22 illustrates a graph showing changes in ADCS-CGIC scores over time for different treatment groups, according to aspects of the present disclosure.

[0037] FIG. 23 depicts a graph showing change in ADCS-CGIC scores over time for different treatment groups, according to an embodiment.

[0038] FIG. 24 illustrates a graph showing ADCS-CGIC scores over time for different treatment groups, according to aspects of the present disclosure.

[0039] FIG. 25 depicts a graph showing change in ADCS-CGIC scores over time for different treatment groups, according to an embodiment.

[0040] FIG. 26 illustrates a graph comparing effects of different treatments on CSF biomarkers in Alzheimer's disease patients, according to aspects of the present disclosure.

[0041] FIG. 27 depicts two bar graphs showing changes in biomarkers related to Alzheimer's disease treatment, according to an embodiment.

[0042] FIG. 28 depicts a graph showing changes in ADAS-Cog 11 scores over time for different treatment groups, according to an embodiment.

[0043] FIG. 29 depicts a graph showing changes in MMSE scores over time for different treatment groups, according to an embodiment.

[0044] FIG. 30 depicts a graph showing change in ADCS-ADL scores over time for different treatment groups, according to aspects of the present disclosure.

[0045] FIG. 31 depicts a graph showing changes in ADCS-CGIC scores over time for different treatment groups, according to an embodiment.

[0046] FIG. 32 depicts a graph showing the changes in ADAS-Cog 11 scores over time within the mITT population.

[0047] FIG. 33 plots plasma p-tau217 by baseline MMSE scores of the mITT population.

[0048] FIG. 34 depicts a graph showing the changes in ADAS-Cog 11 scores over time in participants with low p-tau217 levels.

[0049] FIG. 35 depicts a graph showing the changes in ADAS-Cog 11 scores after treatment compared to placebo in patients with low p-tau217 levels.

[0050] FIG. 36 depicts a graph showing the changes in ADAS-Cog 11 scores after treatment compared to placebo in patients with above median p-tau217 levels.

[0051] FIG. 37 depicts a graph showing the changes in ADAS-Cog 11 scores after treatment in patients with low p-tau217 and mild cognitive impairment.

[0052] FIG. 38 depicts a graph showing the changes in ADAS-Cog 11 scores after treatment in patients with low p-tau217 and moderate cognitive impairment.DETAILED DESCRIPTION

[0053] Before compounds, compositions and methods are described in detail, it is to be understood that this disclosure is not limited to the particular processes, compositions, ormethodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, the preferred methods, devices, and materials are now described.

[0054] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.Definitions

[0055] The singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a “cell” is a reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.

[0056] As used herein, the term “about” means plus or minus 10 % of a given value. For example, “about 50 %” means in the range of 45 % - 55 %.

[0057] “Sigma-2 ligand” refers to a compound that binds to a sigma-2 receptor and includes agonists, antagonists, partial agonists, inverse agonists and simply competitors for other ligands of this receptor or protein.

[0058] The term "agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.

[0059] The term "partial agonist" refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.

[0060] The term "antagonist" refers to an entity, e.g., a compound, antibody or fragment, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor. As used herein, the term “sigma-2 receptor antagonist” is used to describea compound that acts as a “functional antagonist” at the sigma-2 receptor in that it blocks Abeta effects, for example, Abeta oligomer-induced synaptic dysfunction, for example, as seen in an in vitro assay, such as a membrane trafficking assay, or a synapse loss assay, or Abeta oligomer mediated sigma-2 receptor activation of caspase-3, or in a behavioral assay, or in a patient in need thereof. The functional antagonist may act directly by inhibiting binding of, for example, an Abeta oligomer to a sigma-2 receptor, or indirectly, by interfering with downstream signaling resultant from Abeta oligomer binding the sigma-2 receptor.

[0061] The term “sigma-2 receptor antagonist compound” refers to a molecule that binds to a sigma-2 receptor in a measurable amount and acts as a functional antagonist with respect to Abeta effects oligomer induced synaptic dysfunction resultant from sigma-2 receptor binding.

[0062] The term “selectivity” or “selective” refers to a difference in the binding affinity of a compound (Ki) for a sigma receptor, for example, a sigma-2 receptor, compared to a nonsigma receptor. The sigma-2 antagonists possess high selectivity for a sigma receptor in synaptic neurons. The Ki for a sigma-2 receptor or both a sigma-2 and a sigma- 1 receptor is compared to the Ki for a non-sigma receptor. In some embodiments, the selective sigma-2 receptor antagonist, or sigma-1 receptor ligand, has at least 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 100-fold, or 500-fold higher affinity, or more, for binding to a sigma receptor compared to a non-sigma receptor as assessed by a comparison of binding dissociation constant Ki values, or IC50 values, or binding constant, at different receptors. Any known assay protocol can be used to assess the Ki or IC50 values at different receptors, for example, by monitoring the competitive displacement from receptors of a radiolabeled compound with a known dissociation constant, for example, by the method of Cheng and Prusoff (1973) (Biochem. Pharmacol. 22, 3099-3108), or specifically as provided herein. In some embodiments, the sigma-2 antagonist compound is an antibody, or active binding fragment thereof, specific for binding to a sigma-2 receptor compared to a non- sigma receptor. In the case of an antibody, or fragment, binding constants at a sigma-2 receptor, or fragment, can be calculated and compared to binding constants at a non-sigma receptor by any means known in the art, for example, by the method of Beatty et al., 1987, J Immunol Meth, 100(1-2): 173-179, or the method of Chaiquest, 1988, J. Clin. Microbiol. 26(12): 2561-2563. The non-sigma receptor is, for example, selected from a muscarinic M1-M4 receptor, serotonin (5- HT) receptor, alpha adrenergic receptor, beta adrenergic receptor, opioid receptor, serotonin transporter, dopamine transporter, adrenergic transporter, dopamine receptor, or NMDA receptor.

[0063] In the present application, the term "high affinity" is intended to mean a compound which exhibits a Ki value of less than 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, less than 150nM, less than 100 nM, less than 80 nM, less than 60 nM, or preferably less than 50 nM in a sigma receptor binding assay, for example against [3H]-DTG, as disclosed by Weber et al., Proc. Natl. Acad. Sci (USA) 83: 8784-8788 (1986), incorporated herein by reference, which measures the binding affinity of compounds toward both the sigma- 1 and sigma-2 receptor sites. Especially preferred sigma ligands exhibit Ki values of less than about 150 nM, preferably less than 100 nM, less than about 60 nM, less than about 10 nM, or less than about 1 nM against [3H]-DTG.

[0064] The term “therapeutic phenotype” is used to describe a pattern of activity for compounds in the in vitro assays that is predictive of behavioral efficacy. A compound that (1) selectively binds with high affinity to a sigma-2 receptor, and (2) acts as a functional antagonist with respect to Abeta oligomer-induced effects in a neuron, is said to have the “therapeutic phenotype” if (i) it blocks or reduces AP-induced membrane trafficking deficits; (ii) it blocks or reduces AP-induced synapse loss and (iii) it does not affect trafficking or synapse number in the absence of Abeta oligomer. This pattern of activity in the in vitro assays is termed the “therapeutic phenotype” and is predictive of behavioral efficacy.

[0065] The term “therapeutic profile” is used to describe a compound that meets the therapeutic phenotype, and also has good brain penetrability (the ability to cross the blood brain barrier), good plasma stability and good metabolic stability.

[0066] The term “drug-like properties” is used herein to describe the pharmacokinetic and stability characteristics of the sigma-2 receptor ligands upon administration, including brain penetrability, metabolic stability and / or plasma stability.

[0067] “Abeta species” or “AP” or “Abeta” or “Amyloid beta” shall include compositions comprising soluble amyloid peptide-containing components such as Abeta monomers, Abeta oligomers, or complexes of Abeta peptide (in monomeric, dimeric or polymeric form) with other soluble peptides or proteins as well as other soluble Abeta assemblies, including any processed product of amyloid precursor protein. Soluble Ap oligomers are known to be neurotoxic. Even API-42 dimers are known to impair synaptic plasticity in mouse hippocampal slices. In one theory known in the art, native APi-42 monomers are considered neuroprotective, and self-association of Ap monomers into soluble Abeta oligomers is required for neurotoxicity. However, certain Ap mutant monomers (arctic mutation (E22G) are reported to be associated with familial AD. See, for example, Giuffrida et al., - Amyloid monomers are neuroprotective. J. Neurosci. 2009 29(34): 10582-10587. Nonlimiting examples of preparations comprising Abeta species are disclosed in U.S. patent application serial number 13 / 021,872; U.S. Patent Publication2010 / 0240868; International Patent Application WO / 2004 / 067561; International Patent Application WO / 2010 / 011947; U.S. Patent Publication 20070098721; U.S. Patent Publication 20100209346; International Patent Application WO / 2007 / 005359; U.S. Patent Publication 20080044356; U.S. Patent Publication 20070218491; WO / 2007 / 126473; U.S. Patent Publication 20050074763; International Patent Application WO / 2007 / 126473, International Patent Application WO / 2009 / 048631, and U.S. Patent Publication 20080044406, each of which is incorporated herein by reference.

[0068] “Administering,” when used in conjunction with the compounds of the disclosure, means to administer a compound directly into or onto a target tissue or to administer a compound systemically or locally to a patient or other subject.

[0069] The term “animal” as used herein includes, but is not limited to, humans and nonhuman vertebrates such as wild, experimental, domestic and farm animals and pets.

[0070] As used herein, the terms “subject,” “individual,” and “patient,” are used interchangeably and refer to any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, non-human primates, humans, and the like.

[0071] As used herein, the term “contacting” refers to the bringing together or combining of molecules (or of a molecule with a higher order structure such as a cell or cell membrane) such that they are within a distance that allows for intermolecular interactions such as the non-covalent interaction between two peptides or one protein and another protein or other molecule, such as a small molecule. In some embodiments, contacting occurs in a solution in which the combined or contacted molecules are mixed in a common solvent and are allowed to freely associate. In some embodiments, the contacting can occur at or otherwise within a cell or in a cell-free environment. In some embodiments, the cell-free environment is the lysate produced from a cell. In some embodiments, a cell lysate may be a whole-cell lysate, nuclear lysate, cytoplasm lysate, and combinations thereof. In some embodiments, the cell-free lysate is lysate obtained from a nuclear extraction and isolation wherein the nuclei of a cell population are removed from the cells and then lysed. In some embodiments, the nuclei are not lysed, but are still considered to be a cell-free environment. The molecules can be brought together by mixing such as vortexing, shaking, and the like.

[0072] The term “improves” is used to convey that the disclosure changes either the characteristics and / or the physical attributes of the tissue to which it is being provided, applied or administered. The term “improves” may also be used in conjunction with a disease state such thatwhen a disease state is “improved” the symptoms or physical characteristics associated with the disease state are diminished, reduced, eliminated, delayed or averted.

[0073] The term “inhibiting” includes the blockade, aversion of a certain result or process, or the restoration of the converse result or process. In terms of prophylaxis or treatment by administration of a compound of the disclosure, “inhibiting” includes protecting against (partially or wholly) or delaying the onset of symptoms, alleviating symptoms, or protecting against, diminishing or eliminating a disease, condition or disorder.

[0074] The term “inhibiting trafficking deficits” refers to the ability to block soluble Ab oligomer-induced membrane trafficking deficits in a cell, preferably a neuronal cell. A compound capable of inhibiting trafficking deficits has an EC50 < 20 pM, less than 15 pM, less than 10 pM, less than 5 pM, and preferably less than 1 pMin the membrane trafficking assay, and further is capable of at least 50%, preferably at least 60%, and more preferably at least 70% maximum inhibition of the Abeta oligomer effects of soluble Abeta oligomer-induced membrane trafficking deficits, for example, as described in Example 6.

[0075] The term “log P” refers to the partition coefficient of a compound. The partition coefficient is the ratio of concentrations of un-ionized compound in each of two solution phases, for example, octanol and water. To measure the partition coefficient of ionizable solute compounds, the pH of the aqueous phase is adjusted such that the predominant form of the compound is un-ionized. The logarithm of the ratio of concentrations of the un-ionized solute compound in the solvents is called log P. The log P is a measure of lipophilicity . For example, log Poct / wat = log ([solute] octanol / [S01ute]im-ionized, water).

[0076] At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that embodiments of the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose e.g. methyl (Ci alkyl), ethyl (C2 alkyl), C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl as well as, e.g. C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C2-C3 alkyl, C2-C4 alkyl, C3-C6alkyl, C4-C5 alkyl, and C5-C6alkyl.

[0077] For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, then the two R groups can represent different moieties selected from the Markush group defined for R.

[0078] The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5- membered heteroaryl group.

[0079] As used herein, the term “alkyl” is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t- butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. The term “alkylene” refers to a divalent alkyl linking group. An example of alkylene is methylene (CH2).

[0080] As used herein, “alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include, but are not limited to, ethenyl, propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to a divalent linking alkenyl group.

[0081] As used herein, “alkynyl” refers to an alkyl group having one or more triple carboncarbon bonds. Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like. The term “alkynylenyl” refers to a divalent linking alkynyl group.

[0082] As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents selected from F, Cl, Br, and / or I. Example haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, CH2CF3, and the like.

[0083] As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.

[0084] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. A cycloalkyl group can contain from 3 to about 15, from 3 to about 10, from 3 to about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5, or from 5 to about 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Example of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-lH-indene-l-yl, or 1H- inden-2(3H)-one-l-yl). Preferably, “cycloalkyl” refers to cyclized alkyl groups that contain up to 20 ring-forming carbon atoms. Examples of cycloalkyl preferably include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like

[0085] As used herein, “heteroaryl” groups refer to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms each independently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, carbon atoms as ring-forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ringforming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0086] As used herein, “heterocycloalkyl” refers to non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can be mono or polycyclic (e.g., both fused and spiro systems). Example “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfIdo. For example, a ringforming S atom can be substituted by 1 or 2 oxo [i.e., form a S(O) or S(O)2]. For another example, a ring-forming C atom can be substituted by oxo (i.e., form carbonyl). Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., havinga bond in common with) to the nonaromatic heterocyclic ring, for example pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indoline, isoindoline, isoindolin-l-one-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3- c]pyridin-7(4H)-one-5-yl, and 3,4-dihydroisoquinolin-l(2H)-one-3yl groups. Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0087] As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

[0088] As used herein, “alkoxy” refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0089] As used herein, “haloalkoxy” refers to an -O-haloalkyl group. An example haloalkoxy group is OCF3. As used herein, “trihalomethoxy” refers to a methoxy group having three halogen substituents. Examples of trihalomethoxy groups include, but are not limited to, - OCF3, -OCCIF2, -OCCI3, and the like.

[0090] As used herein, “arylalkyl” refers to a C1-6 alkyl substituted by aryl and “cycloalkylalkyl” refers to C1-6 alkyl substituted by cycloalkyl.

[0091] As used herein, “hetero arylalkyl” refers to a C1-6 alkyl group substituted by a heteroaryl group, and “heterocycloalkylalkyl” refers to a C1-6 alkyl substituted by heterocycloalkyl.

[0092] As used herein, “amino” refers to NH2.

[0093] As used herein, “alkylamino” refers to an amino group substituted by an alkyl group.

[0094] As used herein, “dialkylamino” refers to an amino group substituted by two alkyl groups.

[0095] As used here, C(O) refers to C(=O).

[0096] As used herein, the term “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valence of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH3) is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups, in indicated.

[0097] As used herein, an “amyloid beta effect”, for example, a “nonlethal amyloid beta effect”, or “Abeta oligomer effect”, refers to an effect, particularly a nonlethal effect, on a cell that is contacted with an Abeta species. For example, it has been found that when a neuronal cell is contacted with a soluble Amyloid-beta (“Abeta”) oligomer, the oligomers bind to a subset of synapses on a subset of neuronal cells in vitro. This binding can be quantified in an assay measuring Abeta oligomer binding in vitro for example. Another documented effect of Abeta species is a reduction in synapse number, which has been reported to be about 18% in the human hippocampus (Scheff et al, 2007) and can be quantified (for example, in an assay measuring synapse number). As another example, it has been found that, when a neuronal cell is contacted with an Amyloid-beta (“Abeta”) oligomer, membrane trafficking is modulated and alteration of membrane trafficking ensues. This abnormality can be visualized with many assays, including but not limited to, an MTT assay. For example, yellow tetrazolium salts are endocytosed by cells and the salts are reduced to insoluble purple formazan by enzymes located within vesicles in the endosomal pathway. The level of purple formazan is a reflection of the number of actively metabolizing cells in culture, and reduction in the amount of formazan is taken as a measure of cell death or metabolic toxicity in culture. When cells that are contacted with a yellow tetrazolium salt are observed through a microscope, the purple formazan is first visible in intracellular vesicles that fill the cell. Over time, the vesicles are exocytosed and the formazan precipitates as needle- shaped crystals on the outer surface of the plasma membrane as the insoluble formazan is exposed to the aqueous media environment. Still other effects of Abeta species include cognitive decline, such as a decline in the ability to form new memories and memory loss which can be measured in assays using animal models in vivo. In some embodiments, an Abeta effect is selected from Abeta oligomer-induced synaptic dysfunction, for example, as seen in an in vitro assay, such as a membrane trafficking assay, or a synapse loss assay, or Abeta oligomer mediated sigma-2 receptor activation of caspase-3, or Abeta induced neuronal dysfunction, Abeta mediated decrease in long term potentiation (LTP), or in cognitive decline in a behavioral assay, or in a patient in need thereof.

[0098] In some embodiments, a test compound is said to be effective to treat cognitive decline or a disease associated therewith when it can inhibit an effect associated with soluble Abeta oligomer species on a neuronal cell more than about 10%, preferably more than 15%, and preferably more than 20% as compared to a negative control. In some embodiments, a test agent is said to be effective when it can inhibit a processed product of amyloid precursor protein- mediated effect more than about 10%, preferably more than 15%, and preferably more than 20% as compared to a positive control. For example, as shown in the Examples below, inhibition of Abeta oligomer binding by only 18% inhibits synapse reduction completely. Although the present specification focuses on inhibition of nonlethal effects of Abeta species, such as abnormalities in neuronal metabolism and synapse number reduction, these are shown to correlate with cognitive function and are furthermore expected, over time, to result in reduction (compared to untreated subjects) of downstream measurable symptoms of amyloid pathology, notably clinical symptoms such as 1) fibril or plaque accumulation measured by amyloid imaging agents such as fluorbetapir, PittB or any other imaging agent, 2) synapse loss or cell death as measured by glucose hypometabolism detected with FDG-PET, or 3) changes in protein expression or metabolite amount in the brain or body detectable by imaging or protein / metabolite detection in cerebrospinal fluid, brain biopsies or plasma obtained from patients by ELISA, (such as changes in levels and or ratios of Abeta 42, phosphorylated tau, total tau measured by ELISA, or patterns of protein expression changes detectable in an ELISA panel (see reference: Wyss-Coray T. et al. Modeling of pathological traits in Alzheimer's disease based on systemic extracellular signaling proteome. Mol Cell Proteomics 2011 Jul 8, which is hereby incorporated by reference in its entirety), 4) cerebral vascular abnormalities as measured by the presence of vascular edema or microhemorrhage detectable by MRI and any other symptoms detectable by imaging techniques, and 5) cognitive loss as measured by any administered cognitive test such as ADAS-Cog, MMSE, CBIC or any other cognitive testing instrument.

[0099] As used herein, the term “a neuronal cell” refers to cell originating from the nervous system that transmits information through electrical or chemical signals. The term can refer to a single cell or to a population of cells. In some embodiments, the neuronal cell is a primary neuronal cell. In some embodiments, the neuronal cell is an immortalized or transformed neuronal cell or a stem cell. A primary neuronal cell is a neuronal cell that cannot differentiate into other types of neuronal cells, such as glia cells. A stem cell is one that can differentiate into neurons and other types of neuronal cells such as glia. In some embodiments, assays utilize a composition comprising at least one neuronal cell is free of glia cells. In some embodiments, the composition comprises less than about 30%, 25%, 20%, 15%, 10%, 5%, or 1% of glia cells, whichare known to internalize and accumulate Abeta. The primary neuronal cell can be derived from any area of the brain of an animal. In some embodiments, the neuronal cell is a hippocampal or cortical cell. The presence of glia cells can be determined by any method. In some embodiments, glia cells are detected by the presence of GFAP and neurons can be detected by staining positively with antibodies directed against MAP2.

[0100] The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are generally regarded as safe and nontoxic. In particular, pharmaceutically acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other ingredients, and do not typically produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a patient. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The phrase "pharmaceutically acceptable salt(s)", as used herein, includes those salts of compounds of the disclosure that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the disclosure or in compounds identified pursuant to the methods of the disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the disclosure can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0101] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, protect against or improve an unwanted condition or disease of a subject.

[0102] As used herein, the term “effective amount” refers to an amount that results in measurable inhibition of at least one symptom or parameter of a specific disorder or pathologicalprocess. For example, an amount of a sigma-2 ligand of the disclosure that provides a measurably lower synapse reduction in the presence of Abeta oligomer qualifies as an effective amount because it reduces a pathological process even if no clinical symptoms of amyloid pathology are altered, at least immediately.

[0103] A “therapeutically effective amount” or “effective amount” of a compound or composition of the disclosure is a predetermined amount which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker ) or subjective (i.e., subject gives an indication of or feels an effect or physician observes a change). An effective amount of a compound of the disclosure may broadly range from about 0.01 mg / Kg to about 500 mg / Kg, about 0.1 mg / Kg to about 400 mg / Kg, about 1 mg / Kg to about 300 mg / Kg, about 0.05 to about 20 mg / Kg, about 0.1 mg / Kg to about 10 mg / Kg, or about 10 mg / Kg to about 100 mg / Kg. The effect contemplated herein includes both medical therapeutic and / or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this disclosure to obtain therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed and the duration of the treatment;. The effective amount administered will be determined by the physician in the light of the foregoing relevant circumstances and the exercise of sound medical judgment. A therapeutically effective amount of a compound of this disclosure is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue. The total daily dose of the compounds of this disclosure administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 mg / Kg to about 500 mg / Kg, about 0.1 mg / Kg to about 400 mg / Kg, about 1 mg / Kg to about 300 mg / Kg, about 10 mg / Kg to about 100 mg / Kg, or more usually from 0.1 to 25 mg / kg body weight per day. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the disclosure comprise administration to a patient in need of such treatment will usually include from about 1 mg to about 5000 mg, 10 mg to about 2000 mg of the compound(s), 20 to 1000 mg, preferably 20 to 500 mg and most preferably about 50 mg, of acompound according to Formula I, and / or Formula II, or a pharmaceutically acceptable salt thereof, per day in single or multiple doses.

[0104] The terms “treat”, “treated”, or “treating” as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to protect against (partially or wholly) or slow down (e.g., lessen or postpone the onset of) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results such as partial or total restoration or inhibition in decline of a parameter, value, function or result that had or would become abnormal. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent or vigor or rate of development of the condition, disorder or disease; stabilization (z.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether or not it translates to immediate lessening of actual clinical symptoms, or enhancement or improvement of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0105] Generally speaking, the term “tissue” refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.

[0106] As used herein, “cognitive decline” refers to a decrease in one or more areas of mental ability, which can impact daily functioning. For example cognitive decline, includes but is not limited to, memory loss (e.g. behavioral memory loss), failure to acquire new memories, confusion, impaired judgment, personality changes, disorientation, or any combination thereof. A compound that is effective to treat cognitive decline can be thus effective by restoring long term neuronal potentiation (LTP) or long term neuronal depression (LTD) or a balance of synaptic plasticity measured electrophysiologically; inhibiting, treating, and / or abatement of neurodegeneration; inhibiting, treating, and / or abatement of general amyloidosis; inhibiting, treating, abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, and amyloid oligomer binding; inhibiting, treating, and / or abatement of a nonlethal effect of one or more of Abeta species on a neuron cell (such as synapse loss or dysfunction and abnormal membrane trafficking); and any combination thereof. Additionally, that compound can also be effective in treating Abeta related neurodegenerative diseases and disorders including, but not limited to dementia, including but not limited to Alzheimer’s Disease (AD) including mildAlzheimer’s disease, Down’s syndrome, vascular dementia (cerebral amyloid angiopathy and stroke), dementia with Lewy bodies, HIV dementia, Mild Cognitive Impairment (MCI); Age- Associated Memory Impairment (AAMI); Age-Related Cognitive Decline (ARCD), preclinical Alzheimer’s Disease (PC AD); and Cognitive Impairment No Dementia (CIND).

[0107] As used herein, the term “natural ligand” refers to a ligand present in a subject that can bind to a protein, receptor, membrane lipid or other binding partner in vivo or that is replicated in vitro. The natural ligand can be synthetic in origin, but must also be present naturally and without human intervention in the subject. For example, Abeta oligomers are known to exist in human subjects. Therefore the Abeta oligomers found in a subject would be considered natural ligands. The binding of Abeta oligomers to a binding partner can be replicated in vitro using recombinant or synthetic techniques, but the Abeta oligomer would still be considered a natural ligand regardless of how the Abeta oligomer is prepared or manufactured. A synthetic small molecule that can also bind to the same binding partner is not a natural ligand if it does not exist in a subject. For example, isoindoline compounds which are described herein, are not normally present in a subject, and, therefore, would not be considered natural ligands.

[0108] As used herein, the term "cognitive preservation" refers to the maintenance or slowing of decline in cognitive functions, including memory, attention, language, and problemsolving abilities, in individuals at risk of or diagnosed with cognitive impairment or neurodegenerative disorders.

[0109] As used herein, "improving cognition" refers to enhancing or restoring cognitive functions, including memory, attention, language, and problem-solving abilities, in individuals with cognitive impairment or neurodegenerative disorders.

[0110] As used herein, a "therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject, produces a desired therapeutic effect, such as cognitive preservation or improvement, in the treatment of a condition or disorder.

[0111] As used herein, a "pharmaceutically acceptable salt" refers to a salt form of an active compound that retains the biological effectiveness of the free base form of the compound and has acceptable pharmacokinetic properties for use in the body of a subject.

[0112] As used herein, a "fumarate salt" refers to a salt formed between the active compound and fumaric acid, which may possess desirable pharmacological or physicochemical properties.

[0113] As used herein, "mild cognitive impairment" refers to a condition characterized by a slight but noticeable decline in cognitive abilities, particularly memory, that does not significantly interfere with daily activities and does not meet the criteria for dementia.

[0114] As used herein, "mild to moderate cognitive impairment" refers to a range of cognitive decline that encompasses both mild cognitive impairment and the early stages of more significant cognitive decline, but does not reach the severity of advanced dementia.

[0115] As used herein, an "amyloid PET scan" refers to a positron emission tomography imaging technique that uses specific radioactive tracers to detect and visualize amyloid plaques in the brain, which are associated with Alzheimer's disease and other neurodegenerative disorders.

[0116] As used herein, a "cerebrospinal fluid biomarker" refers to a measurable substance in the cerebrospinal fluid that indicates the presence, progression, or characteristics of a neurological condition or disease.

[0117] As used herein, the "Mini-Mental State Examination (MMSE)" refers to a widely used cognitive screening tool that assesses various aspects of cognitive function, including orientation, memory, attention, and language skills, typically scored on a 30-point scale.

[0118] As used herein, "acetylcholinesterase inhibitors" refers to a class of drugs that inhibit the enzyme acetylcholinesterase, thereby increasing the levels of acetylcholine in the brain and potentially improving cognitive function in conditions such as Alzheimer's disease.

[0119] As used herein, "memantine" refers to a specific medication used in the treatment of moderate to severe Alzheimer's disease, which acts as an NMDA receptor antagonist and may help improve cognitive function and behavior.

[0120] As used herein, "significant brain abnormalities" refers to structural or functional changes in the brain that deviate from normal patterns and may be indicative of neurological disorders or conditions.

[0121] As used herein, "primary degenerative dementias" refers to a group of neurological disorders characterized by progressive cognitive decline and brain degeneration, including but not limited to Alzheimer's disease, frontotemporal dementia, and Lewy body dementia.

[0122] As used herein, "neurodegenerative conditions" refers to disorders characterized by the progressive loss of structure or function of neurons, including death of neurons, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

[0123] As used herein, "DSM-V" refers to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, which is a standardized classification system for mental disorders used by mental health professionals.

[0124] As used herein, the "Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11)" refers to a standardized assessment tool used to measure cognitive function in individuals with Alzheimer's disease, typically consisting of 11 tasks that evaluate various aspects of cognition.

[0125] As used herein, the "Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)" refers to a scale used to assess an individual's ability to perform activities of daily living, which is often used to evaluate functional decline in Alzheimer's disease and other dementias.

[0126] As used herein, the "Clinical Global Impression of Change (CGIC)" refers to a rating scale used by healthcare professionals to evaluate the overall change in a patient's condition over time, typically used in clinical trials and patient care.

[0127] As used herein, the "Neuropsychological Test Battery (NTB)" refers to a comprehensive set of standardized tests designed to assess various aspects of cognitive function, including memory, attention, language, and executive function.

[0128] As used herein, "cerebrospinal fluid (CSF) biomarkers" refers to specific molecules or substances present in the cerebrospinal fluid that can be measured to indicate the presence, progression, or characteristics of neurological conditions or diseases.

[0129] As used herein, "neurofilament light chain (NfL)" refers to a protein component of neurons, specifically in axons, that plays a critical role in maintaining the struction and function of nerve cells. Concentrations of NfL can be measured in cerebrospinal fluid or blood and may serve as a biomarker for neuronal damage or degeneration.

[0130] As used herein, "tau" refers to a protein that stabilizes microtubules in neurons and can form abnormal aggregates in various neurodegenerative disorders, including Alzheimer's disease.

[0131] As used herein, "phosphorylated tau" refers to tau protein that has undergone phosphorylation, a process that may contribute to the formation of neurofibrillary tangles in Alzheimer's disease and other tauopathies.

[0132] As used herein, “phosphorylated tau 217” or “pTau-217” or “p-tau217” refers to tau protein that has undergone phospho rylateion at amino acid 217.

[0133] As used herein, "treatment-emergent adverse events (TEAEs)" refers to adverse events that occur or worsen after the initiation of a treatment in a clinical study, which may or may not be related to the treatment itself.

[0134] As used herein, "liver function tests (LFTs)" refers to a group of blood tests that assess various aspects of liver function and may be used to monitor for potential liver-related side effects of medications.

[0135] As used herein, "upper limit of normal (ULN)" refers to the highest value of a physiological measurement that is considered within the normal range for a given population.

[0136] As used herein, "AST" refers to aspartate aminotransferase, an enzyme found primarily in the liver and heart, which may be measured in blood tests to assess liver function or damage.

[0137] As used herein, "ALT" refers to alanine aminotransferase, an enzyme found primarily in the liver, which may be measured in blood tests to assess liver function or damage.

[0138] Human amyloid beta

[0139] Overproduction and accumulation of amyloid beta is a pathologic feature of Alzheimer’s disease. Human amyloid beta (Abeta) is the main component of insoluble amyloid plaques-deposits found in the brain of patients with Alzheimer’s disease. The plaques are composed of fibrillar aggregates of Abeta. Amyloid beta fibrils have been associated with the advanced stages of Alzheimer's disease.

[0140] The cognitive hallmark of early Alzheimer’s disease (AD) is an extraordinary inability to form new memories. Early memory loss is considered a synapse failure caused by soluble A|3 oligomers. These oligomers block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic AD models. It has been hypothesized that early memory loss stems from synapse failure before neuron death and that synapse failure derives from actions of soluble A|3 oligomers rather than fibrils. Lacor et al., Synaptic targeting by Alzheimer ’s-related amyloid oligomers, J. Neurosci. 2004, 24(45):10191-10200.

[0141] Abeta is a cleavage product of an integral membrane protein, amyloid precursor protein (APP), found concentrated in the synapses of neurons. Soluble forms of Abeta are presentin the brains and tissues of Alzheimer’s patients, and their presence correlates with disease progression. Yu et al., 2009, Structural characterization of a soluble amyloid, beta-peptide oligomer, Biochemistry, 48(9): 1870-1877. Soluble amyloid P oligomers have been demonstrated to induce changes in neuronal synapses that block learning and memory.

[0142] Smaller, soluble Ap oligomers interfere with a number of signaling pathways critical for normal synaptic plasticity, ultimately resulting in spine and synapse loss. Selkoe et al., 2008, Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior, Behav Brain Res 192(1): 106-113. Alzheimer’s begins and persists as a synaptic plasticity disease.

[0143] The presence of soluble Ap oligomers is believed to be to be responsible for early cognitive decline in the pre-Alzheimer’s diseased brain. It is known that amyloid beta oligomers bind at neuronal synapses and that sigma-2 receptors are present in significant amounts in neurons and glia.

[0144] Sigma-2 Receptors

[0145] The sigma receptors are multifunctional adapter / chaperone proteins that participate in several distinct protein signaling complexes in a tissue and state-related manner. The sigma-2 receptor is expressed in brain and various peripheral tissues at low levels. (Walker et al., 1990 Sigma receptors: biology and function. Pharmacol. Rev. 42:355-402). Sigma-2 receptors are present in human hippocampus and cortex. The sigma-2 receptor was also previously validated as a biomarker for tumor cell proliferation. (Mach et al., Sigma-2 receptors as potential biomarkers of proliferation in breast cancer. Cancer Res. 57:156-161, 1997).

[0146] Sigma-2 receptors are implicated in many signaling pathways such as heme binding, Cytochrome P450 metabolism, cholesterol synthesis, progesterone signaling, apoptosis and membrane trafficking. Only a subset of sigma receptor binding sites / signaling pathways are relevant to oligomer signaling in AD. No sigma-2 receptor knock-outs are currently available and human mutations in sigma-2 sequence have not been studied in a neurodegeneration context.

[0147] A sigma-2 receptor was recently identified as the progesterone receptor membrane component 1 (PGRMC1) in rat liver by use of a photoaffinity probe WC-21, which irreversibly labels sigma-2 receptors in rat liver. Xu et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nature Communications 2, article number 380, July 5, 2011, incorporated herein by reference. PGRMC1 (progesterone receptor membrane component 1) was identified as the critical 25kDa component of sigma-2 receptor activity inAugust 2011 by Xu et al. PGRMC1 is a single transmembrane protein with no homology to sigma- 1 protein; family members include PGRMC2 and neudesin. PGRMC1 contains a cytochrome b5 heme-binding domain. PGRMC1 is a single transmembrane protein with no homology to S 1 protein; family members include PGRMC2 and neudesin. PGRMC 1 contains a cytochrome b5 heme-binding domain. Endogenous PGRMC 1 ligands include progesterone / steroids, cholesterol metabolites, glucocorticoids, and heme. PGRMC1 functions as chaperone / adapter associated with different protein complexes in different subcellular locations (Cahill 2007. Progesterone receptor membrane component 1: an integrative review. J. Steroid Biochem. Mol. Biol. 105:16-36). PGRMC 1 binds heme with reducing activity, complexes with CYP450 proteins (regulated redox reactions), associates with PAIRBP 1 and mediates progesterone block of apoptosis, and associates with Insig- 1 and SCAP to induce SRE-related gene transcription in response to low cholesterol. The C. elegans homolog VEM1 associates with UNC-40 / DCC to mediate axon guidance. PGRMC 1 contains two SH2 target sequences, an SH3 target sequence, a tyrosine kinase site, two acidophilic kinase sites (CK2), and consensus binding sites for ERK1 and PDK1. PGRMC 1 contains several ITAM sequences involved in membrane trafficking (vesicle transport, clathrin-dependent endocytosis of calveolin-containing pits).

[0148] Sigma-2 receptor therapeutics have reached human Phase II clinical trials for other CNS indications, but not for treatment of AD. Many of the sigma-2 receptor ligands are not very selective and have high affinity for other non-sigma CNS receptors. For example, Cyr-101 / MT- 210 (Cyrenaic Pharmaceuticals; Mitsubishi) is a sigma-2 receptor antagonist in phase Ila clinical trials for schizophrenia, but has multiple other receptor interactions including at 5HT2a, ADRA1, and histamine Hl. Siramesine (Lundbeck, Forest Lu28179) is a sigma-2 receptor agonist that previously was in clinical trials for anxiety, but was discontinued. Sigma- 1 receptor ligands are in clinical trials for various CNS indications. Cutamesine dihydrochloride (AGY SA4503, M’s Science Corp.) is a sigma-1 receptor agonist that was in phase II clinical trials for stroke, and phase II trials for depression. Anavex 2-73 is a sigma- 1 receptor agonist that also acts as at muscarinic cholinergic receptors as M2 / 3 antagonist, Ml agonist, and is an antagonist with respect to various ion channels (NMD AR, Na+, Ca++). Anavex 2-73 entered phase Ila clinical trials for patients with AD and mild cognitive impairment. There are no previous clinical trials with highly selective sigma-2 receptor ligand therapeutics in AD.

[0149] Sigma-2 Antagonists

[0150] While not being bound by theory, it is proposed that the sigma-2 receptor is a receptor for Abeta oligomer in neurons. Various receptors have been proposed in the literature forsoluble Abeta oligomers including prion protein, insulin receptor, beta adrenergic receptor and RAGE (receptor for advanced glycation end products). Lauren, J. et al, 2009, Nature, 457(7233): 1128-1132; Townsend, M. et al, J. Biol. Chem. 2007, 282:33305-33312; Sturchler, E. et al, 2008, J. Neurosci. 28(20):5149-5158. Indeed many investigators believe that Abeta oligomer may bind to more than one receptor protein. Without being bound by theory, on the basis of evidence presented herein, the present inventors postulate an additional receptor for Abeta oligomer located (not necessarily exclusively) in neurons.

[0151] Without being bound by theory, Abeta oligomers are sigma receptor agonists that bind to sigma protein complexes and cause aberrant trafficking and synapse loss. It is demonstrated herein that high affinity sigma-2 ligands that antagonize this interaction and / or sigma receptor function in neurons will compete or otherwise interfere with Abeta oligomers and return neuronal responses to normal. Such ligands are considered functional sigma-2 receptor antagonists and are referred to as such or more simply as sigma-2 receptor antagonists or as sigma- 2 antagonists.

[0152] In some embodiments, the sigma-2 receptor antagonist according to Formula I and / or Formula II, or a pharmaceutically acceptable salt thereof, acts as a functional antagonist in a neuronal cell with respect to inhibiting soluble A|3 oligomer induced synapse loss, and inhibiting soluble A|3 oligomer induced deficits in a membrane trafficking assay; exhibiting high affinity at a sigma-2 receptor; as well as having high selectivity for one or more sigma receptors compared to any other non-sigma receptor; and exhibiting good drug-like properties.

[0153] In some embodiments, a sigma-2 receptor functional antagonist meeting certain in vitro assay criteria detailed herein will exhibit behavioral efficacy, or be predicted to have behavioral efficacy, in one or more relevant animal behavioral models as disclosed in this specification. In some embodiments, behavioral efficacy is determined at 10 mg / kg p.o., or less.

[0154] In some embodiments, the disclosure provides an in vitro assay platform predictive of behavioral efficacy for high affinity sigma-2 receptor ligands. In accordance with the in vitro assay platform, the ligand binds with high affinity to a sigma-2 receptor; acts as a functional antagonist with respect to Abeta oligomer-induced effects in a neuron; inhibits Abeta oligomer- induced synapse loss in a central neuron or reduces Abeta oligomer binding to neurons to inhibit synapse loss; and does not affect trafficking or synapse number in the absence of Abeta oligomer. This pattern of activity in the in vitro assays is termed the “therapeutic phenotype”. The ability of a sigma-2 receptor antagonist to block Abeta oligomer effects in mature neurons without affecting normal function in the absence of Abeta oligomers meets the criteria for the therapeuticphenotype. It is now disclosed that a selective sigma-2 antagonist having a therapeutic phenotype, can block Abeta oligomer-induced synaptic dysfunction.

[0155] In some embodiments, high affinity, selective sigma-2 antagonists are provided having the therapeutic phenotype that also possess the following characteristics are suitable as a therapeutic candidates for treating Abeta oligomer induced synaptic dysfunction in a patient in need thereof: high affinity at sigma receptors; high selectivity for sigma receptors compared to other non-sigma CNS receptors; higher affinity for a sigma-2 receptor, or comparable affinity, for example within an order of magnitude, at sigma-2 and sigma- 1 receptors; selectivity for sigma receptors as opposed to other receptors relevant in the central nervous system and good drug-like properties. Drug-like properties include acceptable brain penetrability(the ability to cross the blood brain barrier), good stability in plasma and good metabolic stability, for example, as measured by exposure to liver microsomes. Without being bound by theory, high affinity sigma- 2 receptor antagonists compete with Abeta oligomers, and / or stop pathological sigma receptor signaling, that leads to Alzheimer’s disease.

[0156] In some embodiments, the antagonist of the disclosure may bind with greater affinity to sigma- 1 receptor than to a sigma-2 receptor but must still behave as a functional neuronal antagonist with respect to blocking or inhibiting an Abeta oligomer-induced effect (Abeta effect).

[0157] In some embodiments, a sigma-2 antagonist having the therapeutic phenotype that also possesses the following characteristics is suitable as a therapeutic candidate for treating Abeta oligomer induced synaptic dysfunction in a patient in need thereof: high affinity at sigma receptors; high selectivity for sigma receptors compared to other non-sigma CNS receptors; high affinity for a sigma-2 receptor, or comparable affinity at sigma-2 and sigma- 1 receptors; and good drug-like properties. Drug-like properties include high brain penetrability, plasma stability, and metabolic stability.

[0158] In some embodiments, in the binding activity studies, an IC50 or Ki value of at most about 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 150 nM, 100 nM, preferably at most about 75 nM, preferably at most about 60 nM, preferably at most about 40 nM, more preferably at most 10 nM, most preferably at most 1 nM indicates a high binding affinity with respect to the sigma receptor binding sites.

[0159] In some embodiments, a sigma-2 receptor antagonist with high affinity (preferably Ki less than about 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 150 nM, 100 nM, 70 nM, 60 nM,50 nM, 30 nM, or 10 nM) at sigma-2 receptors that have greater than about 20-fold, 30-fold, 50- fold, 70-fold, or preferably greater than 100-fold selectivity for sigma receptors compared to other non-sigma CNS or target receptors, and have good drug-like properties including brain penetrability and good metabolic and / or plasma stability, and that possess the therapeutic phenotype, are predicted to have behavioral efficacy and can be used to treat Abeta oligomer- induced synaptic dysfunction in a patient in need thereof.

[0160] As used herein the term “brain penetrability” refers to the ability of a drug, antibody or fragment, to cross the blood-brain barrier. In some embodiments, an animal pharmacokinetic (pK) study, for example, a mouse pharmacokinetic / blood-brain barrier study can be used to determine or predict brain penetrability. In some embodiments various concentrations of drug can be administered, for example at 3, 10 and 30 mg / kg, for example p.o. for 5 days and various pK properties are measured, e.g., in an animal model. In some embodiments, dose related plasma and brain levels are determined. In some embodiments, brain Cmax > 100, 300, 600, 1000, 1300, 1600, or 1900 ng / mL. In some embodiments good brain penetrability is defined as a brain / plasma ratio of > 0.1, > 0.3, > 0.5, > 0.7, > 0.8 , >0.9, preferably >1, and more preferably > 2, >5, or > 10. In other embodiments, good brain penetrability is defined as greater than about 0.1%, 1%, 5%, greater than about 10%, and preferably greater than about 15% of an administered dose crossing the BBB after a predetermined period of time. In certain embodiments, the dose is administered orally (p.o.). In other embodiments, the dose is administered intravenously (i.v.), prior to measuring pK properties. Pharmacokinetic ssays and brain penetrability are described in Example 7.

[0161] As used herein the term “plasma stability” refers to the degradation of compounds in plasma, for example, by enzymes such as hydrolases and esterases. Any of a variety of in vitro assays can be employed. Drugs are incubated in plasma over various time periods. The percent parent compound (analyte) remaining at each time point reflects plasma stability. Poor stability characteristics can tend to have low bioavailability. Good plasma stability can be defined as greater than 50% analyte remaining after 30 min, greater than 50% analyte remaining after 45 minutes, and preferably greater than 50% analyte remaining after 60 minutes.

[0162] As used herein the term “metabolic stability” refers to the ability of the compound to survive first-pass metabolism (intestinal and hepatic degradation or conjugation of a drug administered orally). This can be assessed, for example, in vitro by exposure of the compounds to mouse or human hepatic microsomes. In some embodiments, good metabolic stability refers to a ti / 2 > 5 min, > 10 min, > 15 minutes, > 20 minutes, and preferably > 30 min upon exposure ofa compound to mouse or human hepatic microsomes. In some embodiments, good metabolic stability refers to an Intrinsic Clearance Rate (Clint) of < 300 uL / min / mg, preferably < 200 uL / min / mg, and more preferably < 100 uL / min / mg.

[0163] In some embodiments, excluded are certain compounds of the prior art. In some embodiments, the compounds described in Table 1 are disclosed in WO2013 / 029057 and / or WO20 13 / 029060, each of which is incorporated by reference herein, and are disclaimed with respect to compositions or methods provided herein.

[0165] Isoindoline compounds provided herein act as high affinity, selective sigma-2 functional antagonists having the therapeutic phenotype, and good drug-like properties, and thus can be used to treat Abeta oligomer-induced synaptic dysfunction.

[0166] In certain embodiments, the compositions are provided comprising isoindoline compounds of formula I as selective sigma-2 functional antagonists that have high binding affinity to the sigma receptors. In some embodiments, the sigma receptors include both the sigma-1 and sigma-2 subtypes. See Hellewell, S. B. and Bowen, W. D., Brain Res. 527: 224-253 (1990); and Wu, X.-Z. et al., J. Pharmacol. Exp. Ther. 257: 351-359 (1991). A sigma receptor binding assay which quantitates the binding affinity of a putative ligand for both sigma sites (against3H-DTG, which labels both sites with about equal affinity) is disclosed by Weber et al., Proc. Natl. Acad. Sci (USA) 83: 8784-8788 (1986). Alternatively, [3H]pentozocine may be used to selectively label the sigma- 1 binding site in a binding assay. A mixture of [3H]DTG and unlabeled (+)pentazocine is used to selectively label the sigma-2 site in a binding assay. The disclosure is also directed to compositions comprising certain ligands which are selective for the sigma- 1 and sigma-2 receptors and act as sigma-2 functional antagonists as well as use of these compositions to treat Abeta oligomer-induced synaptic dysfunction. The discovery of such ligands which are selective for one of the two sigma receptor subtypes may be an important factor in identifying compounds which are efficacious in treating central nervous system disorders with minimal side effects.

[0167] In some embodiments, isoindoline compounds of Formula (I) exhibit sigma-2 antagonist activity, high affinity for the sigma-2 receptor, and the ability to block soluble Abeta oligomer binding or Abeta oligomer-induced synaptic dysfunction.

[0168] In some embodiments, the sigma-2 antagonists, are designed to enhance the ability to cross the blood-brain barrier.

[0169] In some embodiments, the specific sigma-2 receptor antagonist compound blocks binding between soluble Abeta oligomers and a sigma-2 receptor.

[0170] In some embodiments, the sigma-2 antagonist compound exhibits high affinity for the sigma-2 receptor.

[0171] Sigma-2 Receptor Ligands for Selection as Sigma-2 Receptor Antagonists

[0172] In some embodiments, sigma-2 receptor antagonists for use in the present disclosure are selected from among sigma-2 receptor ligand compounds that also meet additional selection criteria. Additional criteria are used to select sigma-2 receptor antagonists for use in the present disclosure from among sigma-2 receptor ligands. Additional selection criteria include: acting as a functional antagonist in a neuronal cell with respect to inhibiting soluble A|3 oligomer induced synapse loss, and inhibiting soluble A|3 oligomer induced deficits in a membrane trafficking assay; having high selectivity for one or more sigma receptors compared to any other non-sigma receptor; exhibiting high affinity at a sigma-2 receptor; and exhibiting good drug-like properties including good brain penetrability, good metabolic stability and good plasma stability. In some embodiments, the sigma-2 receptor antagonist is further selected on the basis of exhibiting one or more of the additional following properties: does not affect trafficking or synapse number in the absence of Abeta oligomer; does not induce caspase-3 activity in a neuronal cell; inhibits induction of caspase-3 activity by a sigma-2 receptor agonist; and / or decreases or protects against neuronal toxicity in a neuronal cell caused by a sigma-2 receptor agonist.

[0173] In some embodiments, certain sigma-2 receptor ligand compounds subject to further selection criteria are selected from compounds described herein and can be synthesized according to the methods described herein or in WO 2011 / 014880 (Application No. PCT / US2010 / 044136), WO 2010 / 118055 (Application No. PCT / US2010 / 030130), Application No. PCT / US2011 / 026530, WO 2012 / 106426 (Application No. PCT / US2012 / 023483), WO 2013 / 029057 (Application No. PCT / US2012 / 052572), and WO 2013 / 029060 (Application No. PCT / US2012 / 052578), each of which is incorporated herein by reference in its entirety. Additional options for preparing these compounds are discussed in detail below.

[0174] In some embodiments, the sigma-2 ligand comprises a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: each of Ri and R2 is independently selected from H, Ci-Ce alkyl, or CH2OR'; wherein each R' if present in Ri, and R2 is independently H or Ci-Ce alkyl; each of R3, R4, R5, and Re is independently selected from the group consisting of H, Ci-Ce alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(CI-C6alkyl), OCF3, OCH2CH2OH, O(Ci-C6alkyl)OH, O(Ci-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, Ci-C6haloalkyl, Ci-Ce hydroxyalkyl, Cue alkoxy Ci-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(CI-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(CI-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR, C(O)O(Ci-4alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(Ci-4 alkyl); wherein each R' if present in R3, R4, R5, and Re is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, Ci-Ce haloalkyl; optionally substituted aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, Cue alkoxy, NH(Ci-4 alkyl), and N(Ci-4 alkyl)2, wherein the optionally substituted group is selected from Ci-Ce alkyl or C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R3 and R4 are linked together to form a -O-C1-2 methylene- O- group; or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group;each of R7, Rs, R9, Rio, and R11 is independently selected from the group consisting of H, Ci- C6alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(Ci-C6alkyl), OCF3, OCH2CH2OH, O(CI-C6alkyl)OH, O(Ci-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, Ci-C6haloalkyl, Ci-Ce hydroxyalkyl, C1-6 alkoxy Ci-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(CI-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(CI-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(Ci-4alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(0)NH(CI-4 alkyl); wherein each R' if present in R7, Rs, R9, Rio, and R11 is independently selected from the group consisting of H, CH3, CH2CH3, C3- Ce alkyl, Ci-Ce haloalkyl, aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, Ci-6 alkoxy, NH(Ci-4 alkyl), or N(Ci-4 alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a 4-, 5-, 6-7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, amino, halo, C1-6 alkyl, C 1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R7 and Rs are linked together to form a -O- Ci-2methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a 4-, 5-, 6- 7-or8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or Rs and R9 are linked together to form a -O- Ci-2 methylene-O- group; each n is independently 0, 1, or 2; with the proviso that R7, Rs, R9, Rio, and R11 are not all H; and with the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:

[0175] In some embodiments, the sigma-2 ligand comprises a racemic mixture or an enantiomer of compound of Formula I, wherein Ri, R2, R3, R4, R5, Re, R7, Rs, R9, Rio, and Rn are as described above.

[0176] In some embodiments, an isolated compound is provided according to Formula I:or a pharmaceutically acceptable salt thereof, wherein Ri, R2, R3, R4, R5, Re, R7, Rs, R9, Rio, and R11 are as defined herein, with the proviso that when Ri, R3, FC, R7, Rio and Rn are each H; R2is CH3; Rg is OCH3or Cl; and R9is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3.

[0177] In other embodiments, an isolated compound, or composition thereof, or method comprising administration of, is provided according to Formula I:or a pharmaceutically acceptable salt thereof, wherein Ri, R2, R3, R4, R5, Ri, R7, Rs, R9, Rio, and R11 are as defined herein, with the proviso that a compound according to Formula I wherein Ri, R3, R6, R7, Rio and Rn are each H; R2is CH3; Rgis OCH3or Cl; and R9is OH or Cl; R4 is Cl or CF3, and R5 is Cl or CF3, is not a preferred compound.

[0178] In another embodiment, a pharmaceutical composition is provided for inhibiting an amyloid beta effect on a neuronal cell comprising a compound according to Formula I:or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Ri, R2, R3, R4, R5, s, R7, Rs, R9, Rio, and Rn are as defined herein, with the proviso that when Ri, R3, R6, R7, Rio and Rn are each H; R2is CH3; Rgis OCH3or Cl; and R9is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3.

[0179] In another embodiment, a method / use is provided for inhibiting an amyloid beta effect on a neuronal cell comprising administering an effective amount of a composition comprising a selective sigma-2 receptor antagonist compound according to formula I:or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Ri, R2, R3, R4, R5, R>. R7, Rs, R9, Rio, and Rn are as defined herein, with the proviso that when Ri, R3, R6, R7, Rio and Rn are each H; R2is CH3; Rgis OCH3or Cl; and R9is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3, and wherein the compound or salt thereof is present in the composition in an amount effective to inhibit amyloid beta oligomer binding in said cell; and a pharmaceutically acceptable carrier.

[0180] In some embodiments, the sigma-2 ligand comprises a racemic mixture or an enantiomer of compound of Formula II:wherein R3, R4, Rs, Re, Rs, and R9 are as described herein.

[0181] In another embodiment, a compound, or pharmaceutically acceptable salt thereof, is provided according to Formula III, wherein R3, R4, Rs, Re, R7, Rs, R9, Rio and R11 are as provided herein and wherein each - is independently selected from a single, double or triple bond.

[0182] In some aspects, a compound according to Formula III is selected from:or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the sigma-2 ligand comprises a racemic mixture or an enantiomer of a compound of Formula I, wherein R3, R4, Rs, Re, Rs, and R9 are as described herein.

[0184] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each Rs and R9 is independently selected from the group consisting of OH, C1-6 alkoxy, and hydroxy C1-6 alkoxy.

[0185] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each Rs and R9 is independently selected from OH or NH(Cn 4 alkyl).

[0186] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each Rs and R9 is independently selected from the group consisting of H, halo, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0187] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each Rs and R9 is independently selected from the group consisting of OH, halo, Ci-6 alkoxy and Ci-6 haloalkoxy and each Ri and R2 is independently Ci-6 alkyl.

[0188] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein Ri and R2 are each methyl.

[0189] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein one of Ri and R2 is methyl and the other is H.

[0190] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each of Rs and R9 is independently selected from the group consisting of OH and C1-6 alkoxy and Ri and R2 are each independently methyl.

[0191] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each of Rs and R9 is independently selected from H, halo, and C1-6 haloalkyl, and Ri and R2 are each methyl.

[0192] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each of R8and R9is independently selected from H, halo and Ci- 6 haloalkyl.

[0193] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein R7 and R11 are each H.

[0194] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4, Rs, and Re is independently selected from the group consisting of H, halo, Cue alkyl, Cue haloalkyl and Cue alkoxy.

[0195] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4 and R5 is independently selected from the group consisting of H, halo, C1-6 alkyl, C1-6 haloalkyl and C1-6 alkoxy.

[0196] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4, Rs, and Re is independently selected from the group consisting of H, halo, S(O)nR', C(O)OR’, C(O)N(R’)2, and C(O)R’; wherein each R' if present in R3, R4, Rs, and Re is independently selected from the group consistingof H, CH3, CH2CH3, C3-C6 alkyl, Ci-Ce haloalkyl, or optionally Ci-Ce alkyl or C2-C7 acyl substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocycloalkyl, and heteroaryl; and n is 2.

[0197] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4 and Rs is independently selected from the group consisting of H, halo, S(O)nR', and C(O)R’; each R' if present in R3, R4, Rs, and Re is independently selected from the group consisting of CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin- 1-yl, piperidin-l-yl, and morpholinyl-4-yl; and where n is 2.

[0198] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4 and R5 is independently selected from the group consisting of H, halo, S(O)nR', and C(O)R’; each R' if present in R3, R4, Rs, and Re is independently selected from the group consisting of CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin- 1-yl, piperidin-l-yl, and morpholinyl-4-yl; each Rs and R9 is independently selected from the group consisting of OH, halo, Cue alkoxy and Cue haloalkoxy; Ri and R2 are each methyl; and n is 2.

[0199] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein R3 and R4 or R4 and Rs together with the C atom to which they are attached form a 6-membered cycloalkyl, or a heterocycloalkyl, aryl or heteroaryl ring.

[0200] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein R3 and R4 or R4 and Rs are O, and are linked together to form a -O-C1-2 methylene-O- group.

[0201] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R2and R3is independently selected from the group consisiting of H, OH, halo, C1-6 alkoxy and C1-6 haloalkyl.

[0202] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula II, wherein each R3 and R4 is independently selected from the groupconsisting of H, Cl, F, -OMe, -CF3, S(O)nR', and C(O)R’; wherein each R' if present in R7, Rs, R9, Rio, and R11 is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin- 1-yl, piperidin-l-yl, and morpholinyl-4-yl; each Rs and R9 is independently selected from OH or C1-6 alkoxy; and n is 2.

[0203] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R2and R3is independently selected from the group consisting of H, OH, Cl, F, -OMe, and -CF3, each R7and R8is independently selected from H or C1-6 alkyl, R9is H, and each R5and R6is independently selected from H or C1-6 haloalkyl.

[0204] Preferred salts for use in the disclosure include the hydrochloride salts of the above compounds.

[0205] These have been synthesized in accordance with general methods provided herein and specific synthetic examples with any additional steps being well within the skill in the art. Several of these compounds have been tested in various assays as detailed herein and have been found active. Tested compounds also display increased bioavailability by reference to compounds disclosed in WO 2010 / 110855.

[0206] In some embodiments, each of the general formulae above may contain a proviso to remove one or more of the following compounds:

[0207] Compounds according to Formula I and / or Formula II have been synthesized in accordance with general methods provided herein and specific synthetic examples with any additional steps being well within the skill in the art. Several of these compounds have been tested in various assays as detailed herein and have been found active. Tested compounds also display increased bioavailability by reference to compounds disclosed in WO 2010 / 110855, incorporated herein by reference.

[0208] As used herein, the term “hydrogen bond acceptor group” refers to a group capable of accepting a hydrogen bond. Examples of hydrogen bond acceptor groups are known and include, but are not limited to, alkoxy groups, oxazolidin-2-one groups, -O-C(O)-N-; -C(O)-N-; - O-; the hetero atom (e.g. oxygen) in a cycloheteroalkyl; -N-SO2- and the like. The groups can be bound in either direction and can be connected to another carbon or heteroatom. A hydrogen bond acceptor group can also be present in or near a hydrophobic aliphatic group. For example, a tetrahydrofuran group comprises both a hydrogen bond acceptor group and a hydrophobic aliphatic group. The oxygen present in the tetrahydro furan ring acts as a hydrogen bond acceptor and the carbons in the tetrahydro furan ring act as the hydrophobic aliphatic group.

[0209] As used herein, the term “hydrophobic aliphatic group” refers to a carbon chain or carbon ring. The carbon chain can be present in a cycloheteroalkyl, but the hydrophobic aliphatic group does not include the heteroatom. The tetrahydrofuran example provided above is one such example, but there are many others. In some embodiments, the hydrophobic aliphatic group is an optionally substituted C1-C6 alkyl, cycloalkyl, or C1-C6 carbons of a heterocycloalkyl. A “hydrophobic aliphatic group” is not a hydrophobic aromatic group.

[0210] As used herein, the term “positive ionizable group” refers to an atom or a group of atoms present in a structure that can be positively charged under certain conditions such as biological conditions present in solution or in a cell. In some embodiments, the positive ionizable group is a nitrogen. In some embodiments, the positive ionizable group is a nitrogen present in a cyclohetero alkyl ring. For example, in a piperazine group, the two nitrogens would be considered two positive ionizable groups. However, in some embodiments, the carbons linked to a positive ionizable group are not considered a hydrophobic aliphatic group. In some embodiments, the positive ionizable group is a nitrogen containg ring. Examples of nitrogen containing rings include, but are not limited to, piperazine, piperadine, triazinane, tetrazinane, and the like. In some embodiments with respect to the positive ionizable group, a nitrogen containing ring comprises 1, 2, 3, or 4 nitrogens. In some embodiments, the positive ionizable group is not the nitrogen present in a -N-SO2- group

[0211] In some embodiments, a group comprises both a hydrogen bond acceptor and a positive ionizable group. For example, a morpholine group comprises both a hydrogen bond acceptor in the oxygen group and a positive ionizable group in the nitrogen.

[0212] As used herein, the term “hydrogen bond donor” refers to a group that is capable of donating a hydrogen bond. Examples of a hydrogen bond donor group include, but are not limited to, -OH, and the like.Salts, solvates, stereoisomers, derivatives, prodrugs and active metabolites of the novel compounds.

[0213] The disclosure further encompasses salts, solvates, stereoisomers, prodrugs and active metabolites of the compounds of any of the formulae above.

[0214] The term “salts” can include acid addition salts or addition salts of free bases. Preferably, the salts are pharmaceutically acceptable. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, or hydrobromic, hydroiodic, hydrofluoric, phosphorous, as well as salts derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids. Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, et al. “Pharmaceutical Salts,” J. Pharma. Sci. 1977;66:1).

[0215] The acid addition salts of the compounds of any of the formulae above may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubilityin polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the disclosure.

[0216] Also included are both total and partial salts, that is to say salts with 1, 2 or 3, preferably 2, equivalents of base per mole of acid of a, e.g., formula I compound or salt, with 1, 2 or 3 equivalents, preferably 1 equivalent, of acid per mole of base of a any of the formulae above compound.

[0217] For the purposes of isolation or purification it is also possible to use pharmaceutically unacceptable salts. However, only the pharmaceutically acceptable, non- toxic salts are used therapeutically and they are therefore preferred.

[0218] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0219] The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.

[0220] Compounds of the disclosure may have both a basic and an acidic center and may therefore be in the form of zwitterions or internal salts.

[0221] Typically, a pharmaceutically acceptable salt of a compound of any of the formulae above may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. For example, an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of a compound of any of the formulae above and the resulting mixture evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, a compound of any of the formulae above may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent. The resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.

[0222] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they areprecipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compound of the disclosure are within the scope of the disclosure. The salts of the compound of any of the formulae above may form solvates (e.g., hydrates) and the disclosure also includes all such solvates. The meaning of the word "solvates" is well known to those skilled in the art as a compound formed by interaction of a solvent and a solute (i.e., solvation). Techniques for the preparation of solvates are well established in the art (see, for example, Brittain. Polymorphism in Pharmaceutical solids. Marcel Decker, New York, 1999.).

[0223] The disclosure also encompasses N-oxides of the compounds of formulas I. The term "N-oxide" means that for heterocycles containing an otherwise unsubstituted sp2N atom, the N atom may bear a covalently bound O atom, i.e., -N->0. Examples of such N-oxide substituted heterocycles include pyridyl N-oxides, pyrimidyl N-oxides, pyrazinyl N-oxides and pyrazolyl N- oxides.

[0224] Compounds of any of the formulae above may have one or more chiral centers and, depending on the nature of individual substituents, they can also have geometrical isomers. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has a chiral center, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R— and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomer respectively). A chiral compound can exist as either an individual enantiomer or as a mixture of enantiomers. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. A mixture containing unequal portions of the enantiomers is described as having an “enantiomeric excess” (ee) of either the R or S compound. The excess of one enantiomer in a mixture is often described with a % enantiomeric excess (% ee) value determined by the formula:% ee = (R) - (S) / (R) + (S)

[0225] The ratio of enantiomers can also be defined by “optical purity” wherein the degree at which the mixture of enantiomers rotates plane polarized light is compared to the individual optically pure R and S compounds. Optical purity can be determined using the following formula:Optical purity = enant.ma70r / (enant.ma70r+ enant.m™or)

[0226] The compounds can also be a substantially pure (+) or (-) enantiomer of the compounds described herein. In some embodiments, a composition comprising a substantially pure enantiomer comprises at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of one enantiomer. In some embodiments, a composition comprising a substantially pure enantiomer is at least 99.5% one enantiomer. In some embodiments, the composition comprises only one enantiomer of a compound described herein.

[0227] The disclosure encompasses all individual isomers of the compounds of any of the formulae above. The description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Methods for the determination of stereochemistry and the resolution or stereotactic synthesis of stereoisomers are well-known in the art. Specifically, there is a chiral center shown in the compounds of any of the formulae above which gives rise to one set of enantiomers. Additional chiral centers may be present depending on the substituents.

[0228] For many applications, it is preferred to carry out stereoselective syntheses and / or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions. Those of skill in the art will further recognize that disclosure compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.

[0229] Diastereomers differ in both physical properties and chemical reactivity. A mixture of diastereomers can be separated into enantiomeric pairs based on solubility, fractional crystallization or chromatographic properties, e.g., thin layer chromatography, column chromatography or HPLC.

[0230] Purification of complex mixtures of diastereomers into enantiomers typically requires two steps. In a first step, the mixture of diastereomers is resolved into enantiomeric pairs, as described above. In a second step, enantiomeric pairs are further purified into compositions enriched for one or the other enantiomer or, more preferably resolved into compositions comprising pure enantiomers. Resolution of enantiomers typically requires reaction or molecular interaction with a chiral agent, e.g., solvent or column matrix. Resolution may be achieved, for example, by converting the mixture of enantiomers, e.g., a racemic mixture, into a mixture of diastereomers by reaction with a pure enantiomer of a second agent, i.e., a resolving agent. Thetwo resulting diastereomeric products can then be separated. The separated diastereomers are then reconverted to the pure enantiomers by reversing the initial chemical transformation.

[0231] Resolution of enantiomers can also be accomplished by differences in their non- covalent binding to a chiral substance, e.g., by chromatography on homochiral adsorbants. The noncovalent binding between enantiomers and the chromatographic adsorbant establishes diastereomeric complexes, leading to differential partitioning in the mobile and bound states in the chromatographic system. The two enantiomers therefore move through the chromatographic system, e.g., column, at different rates, allowing for their separation.

[0232] Chiral resolving columns are well known in the art and are commercially available (e.g., from MetaChem Technologies Inc., a division of ANSYS Technologies, Inc., Lake Forest, CA). Enantiomers can be analyzed and purified using, for example, chiral stationary phases (CSPs) for HPLC. Chiral HPLC columns typically contain one form of an enantiomeric compound immobilized to the surface of a silica packing material.

[0233] D-phenylglycine and L-leucine are examples of Type I CSPs and use combinations of 7i- 7i interactions, hydrogen bonds, dipole-dipole interactions, and steric interactions to achieve chiral recognition. To be resolved on a Type I column, analyte enantiomers must contain functionality complementary to that of the CSP so that the analyte undergoes essential interactions with the CSP. The sample should preferably contain one of the following functional groups: 7i - acid or n -base, hydrogen bond donor and / or acceptor, or an amide dipole. Derivatization is sometimes used to add the interactive sites to those compounds lacking them. The most common derivatives involve the formation of amides from amines and carboxylic acids.

[0234] The MetaChiral ODM™ is an example of a type II CSP. The primary mechanisms for the formation of solute-CSP complexes is through attractive interactions, but inclusion complexes also play an important role. Hydrogen bonding, 71 - 71 interactions, and dipole stacking are important for chiral resolution on the MetaChiral™ ODM. Derivatization maybe necessary when the solute molecule does not contain the groups required for solute-column interactions. Derivatization, usually to benzylamides, may be required for some strongly polar molecules like amines and carboxylic acids, which would otherwise interact strongly with the stationary phase through non-specific-stereo interactions.

[0235] Where applicable, compounds of any of the formulae above can be separated into diastereomeric pairs by, for example, separation by column chromatography or TLC on silica gel. These diastereomeric pairs are referred to herein as diastereomer with upper TLC Rf; anddiastereomer with lower TLC Rf. The diastereomers can further be enriched for a particular enantiomer or resolved into a single enantiomer using methods well known in the art, such as those described herein.

[0236] The relative configuration of the diastereomeric pairs can be deduced by the application of theoretical models or rules (e.g. Cram’s rule, the Felkin-Ahn model) or using more reliable three-dimensional models generated by computational chemistry programs . In many instances, these methods are able to predict which diastereomer is the energetically favored product of a chemical transformation. As an alternative, the relative configuration of the diastereomeric pairs can be indirectly determined by discovering the absolute configurations of a single enantiomer in one (or both) of the diastereomeric pair(s).

[0237] The absolute configuration of the stereocenters can be determined by very well known method to those skilled in the art (e.g. X-Ray diffraction, circular dichroism). Determination of the absolute configuration can be useful also to confirm the predictability of theoretical models and can be helpful to extend the use of these models to similar molecules prepared by reactions with analogous mechanisms (e.g. ketone reductions and reductive amination of ketones by hydrides).

[0238] The disclosure may also encompass stereoisomers of the Z-E type, and mixtures thereof due to R2-R3 substituents to the double bond not directly linked to the ring. Additional Z- E stereoisomers are encountered when m is not 1 and m and n are different. The Cahn-Ingold- Prelog priority rules are applied to determine whether the stereoisomers due to the respective position in the plane of the double bond of the doubly bonded substituents are Z or E. The stereoisomer is designated as Z (zusammen = together) if the 2 groups of highest priority lie on the same side of a reference plane passing through the C=C bond. The other stereoisomer is designated as E (entgegen = opposite).

[0239] Mixture of stereoisomers of E-Z type can be separated (and / or characterized) in their components using classical method of purification that are based on the different chemico- physical properties of these compounds. Included in these method are fractional crystallization, chromatography carried out by low, medium or high pressure techniques, fractional distillation and any other method very well known to those skilled in the art.

[0240] The disclosure also encompasses prodrugs of the compounds of any of the formulae above, i.e., compounds which release an active drug according to any of the formulae above in vivo when administered to a mammalian subject. A prodrug is a pharmacologicallyactive or more typically an inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. Prodrugs of a compound of any of the formulae above are prepared by modifying functional groups present in the compound of any of the formulae above in such a way that the modifications may be cleaved in vivo to release the parent compound. In vivo, a prodrug readily undergoes chemical changes under physiological conditions (e.g., are hydrolyzed or acted on by naturally occurring enzyme(s)) resulting in liberation of the pharmacologically active agent. Prodrugs include compounds of any of the formulae above wherein a hydroxy, amino, or carboxy group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino or carboxy group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives) of compounds of any of the formulae above or any other derivative which upon being brought to the physiological pH or through enzyme action is converted to the active parent drug. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the art (see, for example, Bundgaard. Design of Prodrugs. Elsevier, 1985).

[0241] Prodrugs may be administered in the same manner as the active ingredient to which they convert or they may be delivered in a reservoir form, e.g., a transdermal patch or other reservoir which is adapted to permit (by provision of an enzyme or other appropriate reagent) conversion of a prodrug to the active ingredient slowly over time, and delivery of the active ingredient to the patient.

[0242] Unless specifically indicated, the term “active ingredient” is to be understood as referring to a compound of any of the formulae above as defined herein.

[0243] The disclosure also encompasses metabolites. “Metabolite” of a compound disclosed herein is a derivative of a compound which is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound which is formed when the compound is metabolized. The term “metabolized” refers to the sum of the processes by which a particular substance is changed in the living body. In brief, all compounds present in the body are manipulated by enzymes within the body in order to derive energy and / or to remove them from the body. Specific enzymes produce specific structural alterations to the compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996), pages 11-17.Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art.Use of the Sigma-2 Receptor Antagonists

[0244] In some embodiments, the disclosure provides methods of inhibiting synapse number decline or membrane trafficking abnormalities associated with exposure of a neuronal cell to Abeta species by administration of a sigma-2 receptor antagonist. The disclosure also provides methods for treating cognitive decline and / or a neurodegenerative disease, e.g. Alzheimer’s disease or mild cognitive impairment (MCI) in a patient comprising administering to the patient a sigma-2 antagonist described herein, e.g., those encompassed by any of the formulae described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of inhibiting, or treating, cognitive decline and / or a neurodegenerative disease, e.g. Alzheimer’s disease comprises inhibiting, or treating one or more symptoms of cognitive decline selected from the group consisting of memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. In some embodiments, the method comprises inhibiting, or treating, diseases or disorders or conditions mediated by or associated with Abeta oligomers. In some embodiments, the method of inhibiting, or treating, cognitive decline and / or a neurodegenerative disease, e.g. Alzheimer’s disease, comprises one or more of: (i) restoration of long term potentiation (LTP), long term depression (LTD) or synaptic plasticity detectable by electrophysiological measurements or any of the other negative changes in cognitive function as mentioned in the definition of the term above; and / or (ii) inhibiting, or treating, neurodegeneration; and / or (iii) inhibiting, or treating, general amyloidosis; and / or (iv) inhibiting, or treating, one or more of amyloid production, amyloid assembly, amyloid aggregation, and amyloid oligomer binding, and amyloid deposition; and / or (v) inhibiting, treating, and / or abating an effect, notably a nonlethal effect, of one or more of Abeta oligomers on a neuron cell. In some embodiments, the method of inhibiting, treating, and / or abating cognitive decline and / or a neurodegenerative disease, e.g. Alzheimer’s disease comprises inhibiting, treating, and / or abating one or more of amyloid production, amyloid assembly, the activity / effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation, amyloid binding, and amyloid deposition. In some embodiments, the method of inhibiting, treating, and / or abating cognitive decline and / or a neurodegenerative disease, e.g. Alzheimer’s disease comprises inhibiting, treating, and / or abating one or more of the activity / effect of one or more of Abeta oligomers on a neuron cell.

[0245] In some embodiments, the activity / effect of one or more of Abeta oligomers on a neuron cell, amyloid aggregation and amyloid binding is the effect of Abeta oligomers on membrane trafficking or synapse number. In some embodiments, the sigma-2 antagonist inhibits the Abeta oligomer effect on membrane trafficking or synapse number or Abeta oligomer binding.

[0246] In some embodiments, the disclosure provides methods of treating a proteopathic disease associated with Abeta oligomer toxicity, specifically nonlethal Abeta oligomer effects. In some embodiments, the method comprises contacting a subject with such a proteopathic disease with a sigma-2 antagonist of the disclosure or a composition containing the same that binds the sigma-2 receptor.

[0247] In some embodiments, the proteopathic disease is a CNS proteopathy, characterized by an increase in Abeta protein, such as MCI, Down’s Syndrome, macular degeneration or Alzheimer’s disease, and the like.

[0248] In some embodiments, the disclosure provides methods of treating one or more mild cognitive impairment (MCI), or dementia by administering a sigma-2 antagonist in accordance with the disclosure. In some embodiments, the disclosure provides methods of treating MCI, and dementia.

[0249] In some embodiments, the disclosure provides methods of treating an individual with a sigma-2 antagonist according to the disclosure to restore, partially or totally, the subject’s cells to a normal phenotype in terms of functions affected adversely by Abeta species, such as Abeta oligomers. Examples are synaptic number reduction and membrane trafficking abnormalities, which can be measured by various methods including assays described herein. The normal phenotype can be, for example, normal membrane trafficking. In some embodiments, the normal phenotype is normal cognitive ability. The “normal” phenotype can be determined by comparing a subject’s results with a sample of normal subjects. The sample may be as small as 1 subject or 1 sample or may be more than 10 samples or subjects and the norm is an average that is calculated based upon a plurality of subjects.

[0250] In some embodiments, the method comprises administering to a subject afflicted with cognitive decline or with a neurodegenerative disease a compound or composition that binds a sigma-2 protein and inhibits a beta-amyloid pathology. In some embodiments, the beta-amyloid pathology is a membrane trafficking defect, a decrease in synapse number, a decrease in dendritic spine number, a change in dendritic spine morphology, a change in LTP, a change in LTD, a defectin measures of memory and learning in an animal, or any combination thereof, and the like. The foregoing uses result from evidence adduced by the inventors as follows:

[0251] Evaluation of Behavioral Efficacy: Abeta oligomer-induced memory deficits in mouse fear conditioning is a model established in the laboratory of Dr. Ottavio Arancio of Columbia University (Puzzo 2008). Several pharmaceutical companies use this same model in their discovery efforts. Contextual fear conditioning is an accepted model of associative memory formation which correlates to human cognitive function and specifically the creation of new memories (Delgado 2006). Abeta oligomers are injected into the hippocampus of wild-type animals immediately before conditioning training and memory is assessed via freezing behavior after 24 hours. This model system was chosen because intrahippocampal administration of oligomers allows rapid comparative assessment of compound activity and off-target toxicity.

[0252] Compounds also can be tested in vivo in two transgenic Alzheimer’s models to show the compound’s effect in reversing Abeta oligomer-associated memory loss. These behavioral studies collectively demonstrated that sigma-2 antagonist compounds cause improvement in learning and memory in two different behavioral tasks, with two different models of Alzheimer’s disease, in both genders and following short or long-term administration and demonstrate that the in vitro assays correlate with in vivo activity.

[0253] As discussed herein, evidence suggests that Abeta oligomer-mediated reduction in neuronal surface receptor expression mediated by membrane trafficking are the basis for oligomer inhibition of electrophysiological measures of synaptic plasticity (LTP) and thus learning and memory (See Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37; and Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMP AR removal underlies Abeta oligomer-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831 -43). Measuring membrane trafficking rate changes induced by oligomers via formazan morphological shifts has been used in cell lines to discover Abeta oligomer-blocking drugs [Maezawa I, Hong HS, Wu HC, Battina SK, Rana S, Iwamoto T, Radke GA, Pettersson E, Martin GM, Hua DH, Jin LW. A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-beta oligomeric complexes. J Neurochem. 2006 Jul;98(l):57-67; Liu Y, Schubert D. Cytotoxic amyloid peptides inhibit cellular 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction by enhancing MTT formazan exocytosis. J Neurochem. 1997 Dec;69(6):2285-93; Liu Y, Dargusch R, Banh C, Miller CA, Schubert D. Detecting bioactive amyloid beta peptide species in Alzheimer's disease. JNeurochem. 2004 Nov;91(3):648-56; Liu Y, Schubert D. Treating Alzheimer's disease by inactivating bioactive amyloid beta peptide. Curr Alzheimer Res. 2006 Apr;3(2): 129-35; Rana S, Hong HS, Barrigan L, Jin LW, Hua DH. Syntheses of tricyclic pyrones and pyridinones and protection of Abeta-peptide induced MC65 neuronal cell death. Bioorg Med Chem Lett. 2009 Feb 1 ; 19(3):670-4. Epub 2008 Dec 24; and Hong HS, Maezawa I, Budamagunta M, Rana S, Shi A, Vassar R, Liu R, Lam KS, Cheng RH, Hua DH, Voss JC, Jin LW. Candidate anti-Abeta fluorene compounds selected from analogs of amyloid imaging agents. Neurobiol Aging. 2008 Nov 18. (Epub ahead of print)] that lower Abeta brain levels in rodents in vivo [Hong HS, Rana S, Barrigan L, Shi A, Zhang Y, Zhou F, Jin LW, Hua DH. Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo. J Neurochem. 2009 Feb;108(4):1097-l 108]. Accordingly, the foregoing tests have established relevance in identifying compounds to treat early Alzheimer’s disease and mild cognitive impairment.

[0254] In some embodiments, a compound of any of the formulae above has an IC50 value of less than lOOpM, 50 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, 500 nM, 100 nM, 50 nM, or 10 nM with respect to inhibition of one or more of the effect of Abeta oligomers on neurons (such as neurons in the brain), amyloid assembly or disruption thereof, and amyloid (including amyloid oligomer) binding, and amyloid deposition. In some embodiments, the compound has an IC50 value of less than lOOpM, 50 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, 500 nM, 100 nM, 50 nM, or 10 nM with respect to inhibition of the activity / effect of Abeta species such as oligomers on neurons (such as central nervous system neurons).

[0255] In some embodiments, percentage inhibition by the compound of the disclosure of one or more of the effects of Abeta species such as oligomers on neurons (such as neurons in the brain), such as amyloid (including amyloid oligomer) binding to synapses, and abnormalities in membrane trafficking mediated by Abeta oligomer was measured at a concentration of from 10 nM to 10 pM. In some embodiments, the percentage inhibition measured is about 1% to about 20%, about 20% to about 50%, about 1% to about 50%, or about 1% to about 80%. Inhibition can be assessed for example by quantifying synapse number of a neuron prior to and after exposure to an amyloid beta species or quantifying the number of synapses in the presence of both of a sigma-2 antagonist and the Abeta species wherein the sigma-2 antagonist is simultaneous with, or precedes or follows, Abeta species exposure. As another example, inhibition can be assessed by determining membrane trafficking and comparing one or more parameters that measure exocytosis rate and extent, endocytosis rate and extent, or other indicators of cell metabolism in the presence and absence of an Abeta species and in the presence and absence of a sigma-2antagonist according to the disclosure. The present inventors have adduced biochemical assay evidence that compounds of the disclosure also inhibit amyloid aggregation (data not shown).

[0256] In some embodiments, the compounds described herein bind specifically to a sigma-2 receptor. A compound that binds specifically to a specific receptor refers to a compound that has a preference for one receptor over another. For example, although a compound may be capable of binding both sigma- 1 and sigma-2 receptor, a compound can be said to be specific for a sigma-2 receptor when it binds with a binding affinity that is at least 10% greater than to the sigma- 1 receptor. In some embodiments, the specificity is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 1000% greater for one binding partner (e.g. receptor) than a second binding partner.

[0257] In some embodiments, the disclosure provides methods of measuring betaamyloid-associated cognitive decline in an animal using a labeled sigma-2 ligand. In some embodiments, the method comprises contacting the animal with a labeled sigma-2 ligand according to the disclosure and measuring sigma-2 activity or expression. In some embodiments, the method comprises comparing the sigma-2 activity or expression in the animal with an animal known to have beta-amyloid induced cognitive decline. If the activity or expression is the same as the animal known to have beta-amyloid induced cognitive decline the animal is said to have the same level of cognitive decline. The animals can be ranked according the similarities in known activity or expression of various stages of beta amyloid induced cognitive decline. Any of the sigma-2 ligands described herein can be labeled so that the labeled sigma-2 ligand can be used in vivo.

[0258] In determining whether a compound of any of the formulae above and other compounds described as sigma-2 antagonists above is effective in treating the various conditions described herein, in vitro assays can be used. The in vitro assays have been correlated with an in vivo effect using Compound II For example, if a compound of formulae III-IV which bears structural similarity to compound II is active, for example, in the in vitro assays described herein, it can also be used in vivo to treat or ameliorate the conditions described herein including inhibiting or restoring synapse loss, modulating a membrane trafficking change in neuronal cells, protecting against or restoring memory loss, and treating cognitive decline conditions, diseases and disorders such as MCI and Alzheimer’s disease. The assays are based, in part, on the amyloid beta oligomers and their function in binding to neurons at the synapses and the effect that amyloid beta oligomers have on neurons in vitro. In some embodiments, an Abeta oligomer receptor in neurons which the present inventors believe includes a sigma-2 protein is contacted with an amyloid betaassembly as described herein and a compound according to Formula I, II, or III that binds to the sigma-2 protein will inhibit the binding of the amyloid beta assembly to the receptor. In competitive radioligand binding assays the present inventors have shown that the present compounds are specific for the sigma-2 receptor. The inventors have also shown that the compounds of the disclosure inhibit binding of Abeta oligomers to their heretofore unidentified receptor on the surface of neurons. In some embodiments, methods are provided to determine a compound of any above formula’s sigma-2 ligand efficacy in neuronal signaling. In some embodiments, the method comprises contacting a cell, such as but not limited to, a primary neuron, with a sigma-2 ligand and measuring neuronal function. In some embodiments, the cell is contacted in vitro. In some embodiments the cell is contacted in vivo. The neuronal activity can be signaling activity, electrical activity, the production or release of synaptic proteins, and the like. A sigma-2 antagonist that enhances or restores the signaling is identified as a compound that is effective in modulating neuronal activity. In some embodiments, the cell is derived from a pathological sample. In some embodiments, the cell is derived from a subject having a neurodegenerative disease. In some embodiments, the neurodegenerative disease is MCI or Alzheimer’s Disease, especially mild Alzheimer’s disease.Receptor Binding Assays and Compound Screening

[0259] In some embodiments, a test compound is contacted with the cell or cell membrane to determine if the test compound can bind to the sigma-2 receptor. In some embodiments, the test compound is dissolved in a carrier or vehicle, such as but not limited to, dimethyl sulfoxide. In some embodiments, the cells are cultured until confluent. In some embodiments, upon confluence, the cells can be detached by gentle scraping. In some embodiments, the cells are detached by trypsinization, or any other suitable detachment means.

[0260] In some embodiments, the binding of the test compound to the sigma-2 receptor can be determined by, for example, a competitive radioligand binding assay. Radioligand binding assays can be carried out on intact cells stably expressing human receptors or a tissue source. The detached cells or tissue can, for example, be washed, centrifuged, and / or resuspended in a buffer. The test compound can be radiolabeled according to any method including, but not limited to, those described herein. The radioligand can be used at a fixed concentration of 0.1 pCi in the absence and presence of various concentrations (the range can be, for example, 1O1O-1O3M OR 10n-104M of competing drugs. The drugs can be added to the tissue or cells (~ e.g., 50,000 cells) in a buffer and allowed to incubate. Nonspecific binding can be determined in the presence of broad spectrum activators or inhibitors or functional agonists or antagonists for each receptorsubtype (for example, for sigma receptors, in the presence of e.g., 10 pM of an appropriate ligand for each receptor). Reactions can be terminated by rapid filtration, which can be followed by washes with ice-cold buffer twice. Radioactivity on the dried filter discs can be measured using any method, including but not limited to, a liquid scintillation analyzer. The displacement curves can be plotted and the Ki values of the test ligands for the receptor subtypes cam be determined using, for example, GraphPad Prism (GraphPad Software Inc., San Diego, CA). The percentage specific binding can be determined by dividing the difference between total bound (disintegrations per minute) and nonspecific bound (disintegrations per minute) by the total bound (disintegrations per minute).

[0261] In some embodiments, for binding studies in cell lines or tissues sources, varying concentrations of each drug were added in duplicate within each experiment, and the individual IC50 values were determined using, for example, GraphPad Prism software. The Ki value of each ligand can be determined according to the equation described by Cheng and Prusoff (1973), and final data can presented as pKi ± S.E.M., where in some embodiments, the number of tests is about 1-6.

[0262] In some embodiments, the method further comprises determining whether a compound that binds to a sigma-2 receptor acts as a functional antagonist at a sigma-2 receptor by inhibiting soluble A|3 oligomer induced neurotoxicity with respect to inhibiting soluble A|3 oligomer induced synapse loss, and inhibiting soluble A|3 oligomer induced deficits in a membrane trafficking assay. In some embodiments the method further determining that the sigma-2 receptor antagonist does not affect trafficking or synapse number in the absence of Abeta oligomer; does not induce caspase-3 activity in a neuronal cell; inhibits induction of caspase-3 activity by a sigma-2 receptor agonist; and / or decreases or protects against neuronal toxicity in a neuronal cell caused by a sigma-2 receptor agonist.

[0263] The testing can also include a functional assay to determine the effect of the test compound on the function of the binding partner, which can be, but is not limited to sigma-2 receptor. A variety of standard assay technologies can be used. For example, methods can be used to measure functional agonist-like or antagonist-like activity of compounds in living cells or tissues. Methods include, but are not limited to, TR-FRET to determine cAMP concentration and IP1 levels, real time fluorescence to monitor calcium flux, cellular dielectric spectroscopy to measure impedance modulation, ileum contraction, or tumor cell apoptosis. The specificity of the test compound can also be determined by, for example, determining if the compound binds to Sigma- 1 receptor, Sigma-2 receptor, neither, or both. A method for determining if a testcompound binds to a Sigma- 1 receptor is described in Ganapathy, M.E et al. (1999) J. Pharmacol. Exp. Ther., 289: 251-260, which is hereby incorporated by reference in its entirety. A method for determining if a test compound binds to a Sigma- 1 receptor is described in Bowen, W.D et al. (1993) Mol. Neuropharmacol., 3: 117-126, which is hereby incorporated by reference in its entirety, and also Xu, J. et al, Nature Communications, 2011, 2:380 DOI:10.1038 / ncomms 1386 which is also hereby incorporated by reference here in its entirety.

[0264] In various embodiments, the disclosure provides assay protocols for identification of a selective, high affinity sigma-2 receptor ligands that can act as a functional antagonist at a sigma-2 receptor by inhibiting soluble Ap oligomer-induced neurotoxicity with respect to inhibiting soluble Ap oligomer induced synapse loss, that inhibits soluble Ap oligomer induced deficits in a membrane trafficking assay, that does not affect trafficking or synapse number in the absence of Abeta oligomer; and that exhibits good drug like properties as described herein such that the selective, high affinity sigma-2 receptor antagonist compound thus identified can be used to treat soluble Ap oligomer-induced synaptic dysfunction in vivo.

[0265] In some embodiments, the disclosure provides methods of determining whether a subject should be treated with a sigma-2 antagonist, wherein the subject is suspected of having cognitive decline or a neurodegenerative disease or other condition, disease or disorder described herein. In some embodiments, the method comprises contacting a sample derived from the patient with a sigma-2 antagonist and determining whether the sigma-2 modulating compound inhibits or ameliorates a beta-amyloid pathology present in the sample, wherein a sample that shows inhibition or amelioration of the beta-amyloid pathology present in the sample indicates that the subject should be treated with a sigma-2 antagonist.

[0266] Additionally, the disclosure includes methods to identify sigma-2 antagonists that inhibit an Ap oligomer induced reduction in synapse number, and the like. In some embodiments, the methods can be used to identify sigma-2 antagonists for treating a beta-amyloid pathology. In some embodiments, the methods are used to determine the efficacy of a treatment to treat a betaamyloid pathology. In some embodiments, the beta-amyloid pathology is a defect in membrane trafficking, synaptic dysfunction, memory and learning defect in an animal, reduction in synapse number, change in dendritic spine length or spine morphology, a defect in LTP, or an increase in the phosphorylation of Tau protein.Amyloid Beta as Used in the Present Disclosure

[0267] Human amyloid P is the cleavage product of an integral membrane protein, amyloid precursor protein (APP), found concentrated in the synapses of neurons. Amyloid P selfassociates to form metastable, oligomeric assemblies. At higher concentrations, Abeta will polymerize and assemble into linear-shaped fibrils, facilitated by lower pH. It is not presently clear whether fibrils are formed from oligomers. Amyloid P oligomers have been demonstrated to cause Alzheimer’s disease in animal models by inducing changes in neuronal synapses that block learning and memory, and amyloid P fibrils have long been associated with the advanced stages Alzheimer’s disease in animals and humans. In fact, the modem working hypothesis for Alzheimer’s disease, and one that has gained a lot of support, is that Abeta assemblies and notably Abeta oligomers are at the center of early pathology associated with Alzheimer’s as well as of pathologies associated with less grave dementias, such as MCI and mild AD. Cleary, James P. et al. “Natural oligomers of the amyloid-P protein specifically disrupt cognitive function.” Nature Neuroscience Vol. 8 (2005): 79 - 84; Klyubin, I. et al. “Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization.” J Neurosci. Vol. 28 (2008): 4231-4237. However, very little is known about how oligomers form and the structural state of the oligomer. For example, the number of amyloid P subunits that associate to form the oligomer is currently unknown, as is the structural form of the oligomers, or which residues are exposed. There is evidence to suggest that more than one structural state of oligomer is neuroactive. Reed, Jess D. et al. “MALDI-TOF mass spectrometry of oligomeric food polyphenols.” Phytochemistry 66:18 (September 2005): 2248-2263; Cleary, James P. et al. “Natural oligomers of the amyloid-P protein specifically disrupt cognitive function.” Nature Neuroscience Vol. 8 (2005): 79 - 84.

[0268] Amyloid P has affinity for many proteins found in the brain, including ApoE and ApoJ. However, it is unclear whether chaperones or other proteins form associations with the protein that can affect its final structural state and / or its neuroactivity.

[0269] Soluble Abeta peptide is likely to play a key role during early stages of AD by perturbing synaptic dusfunction and cognitive processes. For example, Origlia et al. showed soluble Abeta (Abeta 42) impairs long term potentiation (LTP) in the entorhinal cortex through neuronal receptor for advanced glycation end products (RAGE)-mediated activation of p38MAPK. Origlia et al. 2008, Receptor for advanced glycation end product-dependnet activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J. Neuroscience 28(13):3521 -3530, incorporated herein by reference.

[0270] Synaptic dysfunction is involved in early stages of Alzheimer’s disease. Amyloid beta peptides have been shown to alter synaptic function. Puzzo et al reported that a synthetic fibrillar form of Abeta impairs the late protein synthesis dependent phase of LTP without affecting the early protein synthesis phase. The report is consistent with earlier reports that Abeta oligomers are highly toxic to cells and involved in synaptic dysfunction. Puzzo et al., 2006, Curr Alzheimer’s Res 3(3): 179-183, which isincorporated herein by reference. Abeta has been found to markedly impair hippocampal long-term potentiation(LTP) by various second messenger cascades including a nitric oxide cascade. NO / cGMP / cGK / CREB. Puzzo et al., J Neurosci. 2005, In some embodiments, the disclosure provides compositions and methods comprising sigma-2 receptor antagonists for inhibiting amyloid beta oligomer-induced synaptic dysfunction of a neuronal cell; and inhibiting suppression of hippocampal long term potention caused by exposure of neurons to Abeta oligomers.

[0271] Any form of amyloid P may be used in the practice of the screening methods and of the assays according to the disclosure, including amyloid P monomers, oligomers, fibrils, as well as amyloid P associated with proteins (“protein complexes”) and more generally amyloid P assemblies. For example, screening methods can employ various forms of soluble amyloid P oligomers as disclosed, for example, in U.S. patent application serial number 13 / 021,872; U.S. Patent Publication 2010 / 0240868; International Patent Application WO / 2004 / 067561; International Patent Application WG / 2010 / 011947; U.S. Patent Publication 20070098721; U.S. Patent Publication 20100209346; International Patent Application WG / 2007 / 005359; U.S. Patent Publication 20080044356; U.S. Patent Publication 20070218491; WO / 2007 / 126473; U.S. Patent Publication 20050074763; International Patent Application WO / 2007 / 126473, International Patent Application WO / 2009 / 048631, and U.S. Patent Publication 20080044406, U.S. Patent No. 7,902,328 and U.S. Patent No. 6,218,506, each of which is incorporated herein by reference.

[0272] Amyloid P forms, including monomers or oligomers of amyloid P may be obtained from any source. For example, in some embodiments, commercially available amyloid P monomers and / or amyloid P oligomers may be used in the aqueous solution, and in other embodiments, amyloid P monomers and / or amyloid P oligomers that are used in the aqueous protein solution can be isolated and purified by the skilled artisan using any number of known techniques. In general, the amyloid P monomers and / or amyloid P oligomers used in the preparation of the aqueous solution of proteins and amyloid P of various embodiments may be soluble in the aqueous solution. Therefore, both the proteins of the aqueous solution and the amyloid P may be soluble.

[0273] The amyloid P added may be of any isoform. For example, in some embodiments, the amyloid P monomers may be amyloid P 1-42, and in other embodiments the amyloid P monomers may be amyloid P 1-40. In still other embodiments, the amyloid P may be amyloid P 1-39 or amyloid P 1-41. Hence, the amyloid P of various embodiments may encompass any C- terminal isoform of amyloid p. Yet other embodiments include amyloid P in which the N- terminus has been frayed, and in some embodiments, the N-terminus of any of amyloid P C- terminal isomers described above may be amino acid 2, 3, 4, 5, or 6. For example, amyloid P 1- 42 may encompass amyloid P 2-42, amyloid P 3-42, amyloid P 4-42, or amyloid P 5-42 and mixtures thereof, and similarly, amyloid P 1-40 may encompass amyloid P 2-40, amyloid P 3-40, amyloid P 4-40, or amyloid P 5-40.

[0274] The amyloid P forms used in various embodiments may be wild type, i.e. having an amino acid sequence that is identical to the amino acid sequence of amyloid P synthesized in vivo by the majority of the population, or in some embodiments, the amyloid P may be a mutant amyloid p. Embodiments are not limited to any particular variety of mutant amyloid p. For example, in some embodiments, the amyloid P introduced into the aqueous solution may include a known mutation, such as, for example, amyloid P having the “Dutch” (E22Q) mutation or the “Arctic” (E22G) mutation. Such mutated monomers may include naturally occurring mutations such as, for example, forms of amyloid P isolated from populations of individuals that are predisposed to, for example, Alzheimer’s disease, familial forms of amyloid p. In other embodiments, mutant amyloid P monomers may be synthetically produced by using molecular techniques to produce an amyloid P mutant with a specific mutation. In still other embodiments, mutant amyloid P monomers may include previously unidentified mutations such as, for example, those mutants found in randomly generated amyloid P mutants. The term “amyloid P” as used herein is meant to encompass both wild type forms of amyloid P as well as any of the mutant forms of amyloid p.

[0275] In some embodiments, the amyloid P in the aqueous protein solution may be of a single isoform. In other embodiments, various C-terminal isoforms of amyloid P and / or various N-terminal isoforms of amyloid P may be combined to form amyloid P mixtures that can be provided in the aqueous protein solution. In yet other embodiments, the amyloid P may be derived from amyloid precursor protein (APP) that is added to the protein containing aqueous solution and is cleaved in situ, and such embodiments, various isoforms of amyloid P may be contained within the solution. Fraying of the N-terminus and / or removal of C-terminal amino acids may occurwithin the aqueous solution after amyloid P has been added. Therefore, aqueous solutions prepared as described herein may include a variety of amyloid P isoforms even when a single isoform is initially added to the solution.

[0276] The amyloid P monomers added to the aqueous solution may be isolated from a natural source such as living tissue, and in other embodiments, the amyloid P may be derived from a synthetic source such as transgenic mice or cultured cells. In some embodiments, the amyloid P forms, including monomers, oligomers, or combinations thereof are isolated from normal subjects and / or patients that have been diagnosed with cognitive decline or diseases associated therewith, such as, but not limited to, Alzheimer’s disease. In some embodiments, the amyloid P monomers, oligomers, or combinations thereof are Abeta assemblies that have been isolated from normal subjects or diseased patients. In some embodiments, the Abeta assemblies are high molecular weight, e.g. greater than lOOKDa. In some embodiments, the Abeta assemblies are intermediate molecular weight, e.g. 10 to lOOKDa. In some embodiments, the Abeta assemblies are less than 10 kDa.

[0277] The amyloid P oligomers of some embodiments may be composed of any number of amyloid P monomers consistent with the commonly used definition of “oligomer.” For example, in some embodiments, amyloid P oligomers may include from about 2 to about 300, about 2 to about 250, about 2 to about 200 amyloid P monomers, and in other embodiments, amyloid P oligomers may be composed from about 2 to about 150, about 2 to about 100, about 2 to about 50, or about 2 to about 25, amyloid P monomers. In some embodiments, the amyloid P oligomers may include 2 or more monomers. The amyloid P oligomers of various embodiments may be distinguished from amyloid P fibrils and amyloid P protofibrils based on the confirmation of the monomers. In particular, the amyloid P monomers of amyloid P oligomers are generally globular consisting of P-pleated sheets whereas secondary structure of the amyloid P monomers of fibrils and protofibrils is parallel P-sheets.Identification of subjects having or at risk of having Alzheimer’s Disease

[0278] Alzheimer's disease (AD) is defined histologically by the presence of extracellular P-amyloid (AP) plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. Various diagnostic and prognostic biomarkers are known in the art, such as magnetic resonance imaging, single photon emission tomography, FDG PET, PiB PET, CSF tau and Abeta analysis, as well as available data on their diagnostic accuracy are discussed in Alves et al., 2012, Alzheimer’sdisease: a clinical practice-oriented review, Frontiers in Neurology, April, 2012, vol 3, Article 63, 1-20, which is incorporated herein by reference.

[0279] The diagnosis of dementia, along with the prediction of who will develop dementia, has been assisted by magnetic resonance imaging and positron emission tomography (PET) by using [(18)F]fluorodeoxyglucose (FDG). These techniques are not specific for AD. See, e.g.,Vallabhajosula S. Positron emission tomography radiopharmaceuticals for imaging brain Beta-amyloid. Semin Nucl Med. 2011 Jul;41(4):283-99. Another PET ligand recently FDA approved for imaging moderate to frequent amyloid neuritic plaques in patients with cognitive impairment is Florbetapir F 18 injection, (4-((lE)-2-(6-{2-(2-(2- (18F)fluoroethoxy)ethoxy)ethoxy}pyridin-3-yl)ethenyl)-N- methylbenzenamine, AMYVID®, Lilly). Florbetapir binds specifically to fibrillar Abeta, but not to neurofibrillary tangles. See,e.g., Choi SR, et al., Correlation of amyloid PET ligand florbetapir F 18 binding with Af aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis Assoc Disord. 2012 Jan;26(l):8-16. The PET ligand florbetapir suffers from low specificity with respect to qualitative visual assessment of the PET scans. Camus et al., 2012, Eur J Nucl Med Mol Imaging 39:621- 631. However, many people with neuritic plaques seem cognitively normal.

[0280] CSF markers for Alzheimer’s disease include total tau, phosphor-tau and Abeta42. See, for example, Andreasen , Sjogren and Blennow, World J Biol Psyciatry, 2003, 4(4): 147-155, which is incorporated herein by reference. Reduced CSF levels of the 42 amino acid form of Abeta (Abeta42) and increased CSF levels of total tau in AD have been found in numerous studies. In addition, there are known genetic markers for mutations in the APP gene useful in the identification of subjects at risk for developing AD. See, for example, Goate et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease, Nature, 349, 704-706, 1991, which is incorporated herein by reference. In embodiments, any knowndiagnostic or prognostic method can be employed to identify a subject having or at risk of having Alzheimer’s disease. Pharmaceutical Compositions Comprising a Sigma-2 Receptor Antagonist

[0281] The sigma-2 receptor antagonist compounds provided herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0282] Thus, another embodiment of the disclosure comprises pharmaceutical compositions comprising a pharmaceutically acceptable excipient or diluent and a therapeuticallyeffective amount of a sigma-2 receptor antagonist compound of the disclosure, including an enantiomer, diastereomer, N-oxide or pharmaceutically acceptable salt thereof.

[0283] While it is possible that a compound may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, e.g., wherein the active agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

[0284] Accordingly, in one aspect, the disclosure provides a pharmaceutical composition comprising at least one compound, antibody or fragment, of any of the formulae above and other compounds described as sigma-2 receptor antagonists above described above or a pharmaceutically acceptable derivative (e.g., a salt or solvate) thereof, and, optionally, a pharmaceutically acceptable carrier. In particular, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any of the formulae above or a pharmaceutically acceptable derivative thereof, and, optionally, a pharmaceutically acceptable carrier.Combinations

[0285] For the compositions and methods of the disclosure, a compound of any of the formulae above and other compounds described as sigma-2 receptor antagonists above described above may be used in combination with other therapies and / or active agents.

[0286] In some embodiments, the sigma-2 antagonist compound can be combined with one or more of a cholinesterase inhibitor, an N-methyl-D-aspartate (NMD A) glutamate receptor antagonist, a beta-amyloid specific antibody, a beta-secretase 1 (BACE1, beta-site amyloid precursor protein cleaving enzyme 1) inhibitor, a tumor necrosis factor alpha (TNF alpha) modulator, an intravenous immunoglobulin (IVIG), or a prion protein antagonist. In some embodiments the sigma-2 receptor antagonist is combined with a cholinesterase inhibitor selected from tacrine (COGNEX®; Sciele), donepezil (ARICEPT®; Pfizer), rivastigmine (EXELON®; Novartis), or galantamine (RAZADYNE®; Ortho-McNeil-Janssen). In some embodiments, the sigma-2 receptor antagonist is combined with a TNF alpha modulator that is perispinal etanercept (ENBREL®, Amgen / Pfizer). In some embodiments, the sigma-2 receptor antagonist is combined with a beta-amyloid specific antibody selected from bapineuzumab (Pfizer), solanezumab (Lilly), PF-04360365 (Pfizer), GSK933776(GlaxoSmithKline), Gammagard (Baxter) or Octagam (Octapharma). In some embodiments, the sigma-2 receptor antagonist is combined with an NMDA receptor antagonist that is memantine (NAMENDA®;Forest). In some embodiments, the BACE1 inhibitor is MK-8931 (Merck). In some embodiments, the sigma-2 receptor antagonist is combined with IVIG as described in Magga et al., J Neuroinflam 2010, 7:90, Human intravenous immunoglobulin provides protection against Ab toxicity by multiple mechanisms in a mouse model of Alzheimer’s disease, and Whaley et al., 2011, Human Vaccines 7:3, 349-356, Emerging antibody products and Nicotiana manufacturing; each of which is incorporated herein by reference. In some embodiments, the sigma-2 receptor antagonist is combined with a prion protein antagonist as disclosed in Strittmatter et al., US 2010 / 0291090, which is incorporated herein by reference.

[0287] Accordingly, the disclosure provides, in a further aspect, a pharmaceutical composition comprising at least one compound of any of the formulae above or a pharmaceutically acceptable derivative thereof, a second active agent, and, optionally a pharmaceutically acceptable carrier.

[0288] When combined in the same formulation it will be appreciated that the two or more compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

[0289] Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

[0290] With respect to combinations including biologies such as monoclonal antibodies or fragments, suitable excipients will be employed to prevent aggregation and stabilize the antibody or fragment in solution with low endotoxin, generally for parenteral, for example, intravenous, administration. For example, see Formulation and Delivery Issues for Monoclonal Antibody Therapeutics, Daugherty et al., in Current Trends in Monoclonal Antibody Development and Manufacturing, Part 4, 2010, Springer, New York pp 103-129.

[0291] The compounds of the disclosure may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the disclosure may be prepared by processes known in the art, for example see WO 02 / 00196 (SmithKline Beecham).Routes of Administration and Unit Dosage Forms

[0292] The routes for administration (delivery) include, but are not limited to, one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), parenteral (e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intracerebroventricular, or other depot administration etc. Administration of an antibody or fragment will generally be by parenteral means.

[0293] Therefore, the compositions of the disclosure include those in a form especially formulated for, the mode of administration. In certain embodiments, the pharmaceutical compositions of the disclosure are formulated in a form that is suitable for oral delivery. For example compound CB and compound CF are sigma-2 receptor antagonist compounds that are orally bioavailable in animal models and have been administered orally once per day and shown efficacy in a fear conditioning model. Orally bioavailable compounds as described herein can be prepared in an oral formulation. In some embodiments, the sigma-2 antagonist compound is an orally bioavailable compound, suitable for oral delivery. In other embodiments, the pharmaceutical compositions of the disclosure are formulated in a form that is suitable for parenteral deliveryin some embodiments, the sigma-2 receptor antagonist compound is an antibody or fragment thereof, wherein the antibody or fragment is formulated in a parenteral composition. For example, an anti-sigma-2 receptor antibody such as an anti-PGRMCl antibody that blocks binding of Abeta oligomers to the sigma-2 receptor can be formulated for parenteral delivery.

[0294] The compounds of the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine and the disclosure therefore includes within its scope pharmaceutical compositions comprising a compound of the disclosure adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers. Acceptable carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s).

[0295] There may be different composition / formulation requirements depending on the different delivery systems. It is to be understood that not all of the compounds need to be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes. By way of example, the pharmaceutical composition of the disclosure may be formulated to be delivered using a minipump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by multiple routes.

[0296] The combination of a compound provided herein and an antibody or antibody fragment molecule can be formulated and administered by any of a number of routes and are administered at a concentration that is therapeutically effective in the indication or for the purpose sought. To accomplish this goal, the antibodies may be formulated using a variety of acceptable excipients known in the art. Typically, the antibodies are administered by injection, for example, intravenous injection. Methods to accomplish this administration are known to those of ordinary skill in the art. For example, Gokarn et al., 2008, J Pharm Sci 97(8):3051-3066, incorporated herein by reference, describe various high concentration antibody self buffered formulations. For example, monoclonal antibodies in self buffered formulation at e.g., 50 mg / mL mAb in 5.25% sorbitol, pH 5.0 or 60 mg / mL mAb in 5% sorbitol, 0.01% polysorbate 20, pH 5.2; or conventional buffered formulations, for example, 50 mg / mL mAbl in 5.25% sorbitol, 25 or 50 rnM acetate, glutamate or succinate, at pH 5.0; or 60 mg / mL in 10 mM acetate or glutamate, 5.25% sorbitol, 0.01% polysorbate 20, pH 5.2; other lower concentration formulations can be employed as known in the art.

[0297] Because the preferred sigma-2 receptor antagonist compounds of the disclosure cross the blood brain barrier they can be administered in a variety of methods including for example systemic (e.g., by iv, SC, oral, mucosal, transdermal route) or localized methods (e.g., intracranially). Where the compound of the disclosure is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile. For example, the sigma-2 antagonist compounds selected from the sigma-2 ligands and prepared for oral administration described above may be coated with an enteric coating layer. The enteric coating layer material may be dispersed or dissolved in either water or in a suitable organic solvent. As enteric coating layer polymers, one or more, separately or in combination, of the following can be used; e.g. , solutions or dispersions of methacrylic acidcopolymers, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating layer polymer(s). For environmental reasons, an aqueous coating process may be preferred. In such aqueous processes methacrylic acid copolymers are most preferred.

[0298] Where appropriate, the pharmaceutical compositions can be administered by inhalation, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For buccal or sublingual administration the compositions maybe administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

[0299] Where the composition of the disclosure is to be administered parenterally, such administration includes without limitation: intravenously, intraarterially, intrathecally, intraventricularly, intracranially, intramuscularly or subcutaneously administering the compound of the disclosure; and / or by using infusion techniques. Antibodies or fragments are typically administered parenterally, for example, intravenously.

[0300] Pharmaceutical compositions suitable for injection or infusion may be in the form of a sterile aqueous solution, a dispersion or a sterile powder that contains the active ingredient, adjusted, if necessary, for preparation of such a sterile solution or dispersion suitable for infusion or injection. This preparation may optionally be encapsulated into liposomes. In all cases, the final preparation must be sterile, liquid, and stable under production and storage conditions. To improve storage stability, such preparations may also contain a preservative to prevent the growth of microorganisms. Prevention of the action of micro-organisms can be achieved by the addition of various antibacterial and antifungal agents, e.g. , paraben, chlorobutanol, or acsorbic acid. In many cases isotonic substances are recommended, e.g., sugars, buffers and sodium chloride to assure osmotic pressure similar to those of body fluids, particularly blood. Prolonged absorption of such injectable mixtures can be achieved by introduction of absorption-delaying agents, such as aluminum monostearate or gelatin.

[0301] Dispersions can be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof. The liquid carrier or intermediate can be a solvent or liquid dispersive medium that contains, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol or the like), vegetable oils, non-toxic glycerine esters and suitablemixtures thereof. Suitable flowability may be maintained, by generation of liposomes, administration of a suitable particle size in the case of dispersions, or by the addition of surfactants.

[0302] For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

[0303] Sterile injectable solutions can be prepared by mixing a compound of formulas I, with an appropriate solvent and one or more of the aforementioned carriers, followed by sterile filtering. In the case of sterile powders suitable for use in the preparation of sterile injectable solutions, preferable preparation methods include drying in vacuum and lyophilization, which provide powdery mixtures of the sigma-2 receptor antagonists and desired excipients for subsequent preparation of sterile solutions.

[0304] The compounds according to the disclosure may be formulated for use in human or veterinary medicine by injection (e.g., by intravenous bolus injection or infusion or via intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative. The compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, solubilizing and / or dispersing agents. Alternatively the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0305] The compounds of the disclosure can be administered in the form of tablets, capsules, troches, ovules, elixirs, solutions or suspensions, for immediate-, delayed-, modified-, sustained-, pulsed-or controlled-release applications.

[0306] The compounds of the disclosure may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, or suspensions, or a dry powder for reconstitution with water or other suitable vehicle before use. Solid compositions such as tablets, capsules, lozenges, troches, pastilles, pills, boluses, powder, pastes, granules, bullets or premix preparations may also be used. Solid and liquid compositions for oral use may be prepared according to methods well-known in the art.Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

[0307] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.

[0308] Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

[0309] The compositions may be administered orally, in the form of rapid or controlled release tablets, microparticles, mini tablets, capsules, sachets, and oral solutions or suspensions, or powders for the preparation thereof. Oral preparations may optionally include various standard pharmaceutical carriers and excipients, such as binders, fdlers, buffers, lubricants, glidants, dyes, disintegrants, odorants, sweeteners, surfactants, mold release agents, antiadhesive agents and coatings. Some excipients may have multiple roles in the compositions, e.g., act as both binders and disintegrants.

[0310] Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the disclosure include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and crosslinked polyvinylpyrrolidone.

[0311] Examples of pharmaceutically acceptable binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthine resin, alginates, magnesium-aluminum silicate, polyethylene glycol or bentonite.

[0312] Examples of pharmaceutically acceptable fillers for oral compositions include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate and calcium sulphate.

[0313] Examples of pharmaceutically acceptable lubricants useful in the compositions of the disclosure include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulphate, magnesium lauryl sulphate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.

[0314] Examples of suitable pharmaceutically acceptable odorants for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions.

[0315] Examples of suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.

[0316] Examples of useful pharmaceutically acceptable coatings for the oral compositions, typically used to facilitate swallowing, modify the release properties, improve the appearance, and / or mask the taste of the compositions include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.

[0317] Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.

[0318] Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.

[0319] Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulphate and polysorbates.

[0320] Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0321] As indicated, the compounds of the disclosure can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichloro fluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134AT) or 1, 1,1, 2, 3,3,3- heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.

[0322] Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0323] For topical administration by inhalation the compounds according to the disclosure may be delivered for use in human or veterinary medicine via a nebulizer.

[0324] The pharmaceutical compositions of the disclosure may contain from 0.01 to 99% weight per volume of the active material. For topical administration, for example, the composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active material.

[0325] The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0326] The pharmaceutical composition or unit dosage form of the disclosure may be administered according to a dosage and administration regimen defined by routine testing in the light of the guidelines given above in order to obtain optimal activity while minimizing toxicity or side effects for a particular patient. However, such fine tuning of the therapeutic regimen is routine in the light of the guidelines given herein.

[0327] The dosage of the compounds of the disclosure may vary according to a variety of factors such as underlying disease conditions, the individual’s condition, weight, sex and age, and the mode of administration. An effective amount for treating a disorder can easily be determined by empirical methods known to those of ordinary skill in the art, for example by establishing a matrix of dosages and frequencies of administration and comparing a group of experimental unitsor subjects at each point in the matrix. The exact amount to be administered to a patient will vary depending on the state and severity of the disorder and the physical condition of the patient. A measurable amelioration of any symptom or parameter can be determined by a person skilled in the art or reported by the patient to the physician. It will be understood that any clinically or statistically significant attenuation or amelioration of any symptom or parameter of urinary tract disorders is within the scope of the disclosure. Clinically significant attenuation or amelioration means perceptible to the patient and / or to the physician.

[0328] The amount of the compound to be administered can range between about 0.01 and about 25 mg / kg / day, usually between about 0.1 and about 10 mg / kg / day and most often between 0.2 and about 5 mg / kg / day. It will be understood that the pharmaceutical formulations of the disclosure need not necessarily contain the entire amount of the compound that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of divided doses of such pharmaceutical formulations.

[0329] In a preferred embodiment of the disclosure, the compounds I are formulated in capsules or tablets, usually containing 10 to 200 mg of the compounds of the disclosure, and are preferably administered to a patient at a total daily dose of 10 to 300 mg, preferably 20 to 150 mg and most preferably about 50 mg.

[0330] A pharmaceutical composition for parenteral administration contains from about 0.01% to about 100% by weight of the active compound of the disclosure, based upon 100% weight of total pharmaceutical composition.

[0331] Generally, transdermal dosage forms contain from about 0.01% to about 100% by weight of the active compound versus 100% total weight of the dosage form.

[0332] The pharmaceutical composition or unit dosage form may be administered in a single daily dose, or the total daily dosage may be administered in divided doses. In addition, co-administration or sequential administration of another compound for the treatment of the disorder may be desirable. To this purpose, the combined active principles are formulated into a simple dosage unit.Synthesis of the Compounds

[0333] Compounds of formulas I and II and enantiomers, diastereomers, N-oxides, and pharmaceutically acceptable salts thereof, may be prepared by the general methods outlined in, for example, WO2013 / 029057, incorporated herein by reference, or as described hereinafter, said methods constituting a further aspect of the disclosure.

[0334] It will be appreciated by those skilled in the art that it may be desirable to use protected derivatives of intermediates used in the preparation of the compounds. Protection and deprotection of functional groups may be performed by methods known in the art (see, for example, Green and Wuts Protective Groups in Organic Synthesis. John Wiley and Sons, New York, 1999.). Hydroxy or amino groups may be protected with any hydroxy or amino protecting group. The amino protecting groups may be removed by conventional techniques. For example, acyl groups, such as alkanoyl, alkoxycarbonyl and aroyl groups, may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions. Arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl) may be cleaved by hydrogenolysis in the presence of a catalyst such as palladium-on-charcoal.

[0335] The synthesis of the target compounds is completed by removing any protecting groups which may be present in the penultimate intermediates using standard techniques, which are well-known to those skilled in the art. The deprotected final products are then purified, as necessary, using standard techniques such as silica gel chromatography, HPLC on silica gel and the like, or by recrystallization.METHODS OF USE

[0336] In embodiments, the techniques described herein relate to a method of inducing cognitive preservation in a subject, including administering to the subject a therapeutically effective amount of a compound of formula:

[0337] pharmaceutically acceptable salt thereof.

[0338] In embodiments, the techniques described herein relate to a method of improving cognition in a subject, including administering to the subject a therapeutically effective amount of a compound of formula:

[0339] pharmaceutically acceptable salt thereof.

[0340] In embodiments, the techniques described herein relate to a method of treating Alzheimer's disease in a subject, including administering to the subject a therapeutically effective amount of a compound of formula:

[0341] pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the pharmaceutically acceptable salt is a fumarate salt.

[0343] In any embodiment described herein, the subject may have reduced plasma levels of Tau protein phosphorylated at amino acid 217 (pTau-217). In any embodiment described herein, the subject may have reduced plasma levels of phosphorylated Tau 217. In some embodiments, the reduced plastma levels of pTau-217 are detected prior to administration of the compound or pharmaceutically acceptable salt thereof. In some embodiments, a reduced plasma level of pTau-217 is a plasma concentration below the median of 1.0 pg / mL. In some embodiments, a reduced plasma level of pTau-217 is about 50% of the average concentration of all patients. In some embodiments, a reduced plasma level of pTau-217 is about 30%, about 40%, about 50%, about 60%, about 70% of the average concentration of all patients and any range between any two of these values. In some embodiments, a reduced plasma leve of pTau-217 is about 30% to about 70%, about 40% to about 60%, about 30% to about 50%, about 40% to about 70% of the average concentration of all patients and any value within these ranges.

[0344] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject is diagnosed with Alzheimer's disease.

[0345] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject is diagnosed with mild cognitive impairment.

[0346] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject is diagnosed with mild to moderate cognitive impairment.

[0347] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has a positive amyloid PET scan or cerebrospinal fluid biomarker consistent with Alzheimer's disease.

[0348] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has a Mini-Mental State Examination (MMSE) score between 18 and 26.

[0349] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has a mini-mental state examination (MMSE) score between about 22-26.

[0350] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has an MMSE score greater than, or equal to 24.

[0351] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject is aged less than 50 years. In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject is aged between 50 and 80 years.

[0352] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has undergone magnetic resonance imaging (MRI) that shows no significant abnormality.

[0353] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with major depressive disorder, schizophrenia, bipolar disorder, or combinations thereof.

[0354] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject is on a stable regimen of acetylcholinesterase inhibitors or memantine.

[0355] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject meets all of the following criteria: a) has been diagnosed with Alzheimer's disease; b) has a positive amyloid PET scan or cerebrospinal fluid biomarker consistent with Alzheimer's disease; c) has a Mini-Mental State Examination (MMSE) score between 18 and 26, inclusive; d) has undergone magnetic resonance imaging (MRI) that shows no significant abnormality; e) has not been diagnosed with major depressive disorder, schizophrenia, bipolar disorder, or combinations therof; and f) is on a stable regimen of acetylcholinesterase inhibitors or memantine, or is not taking such medications.

[0356] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject does not have significant brain abnormalities as determined by magnetic resonance imaging (MRI).

[0357] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein significant brain abnormalities include prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, or space-occupying lesions.

[0358] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with other primary degenerative dementias.

[0359] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein other primary degenerative dementias include dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Creutzfeldt- Jakob Disease, Down syndrome, or combinations thereof.

[0360] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with other neurodegenerative conditions.

[0361] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein other neurodegenerative conditions include Parkinson's disease, amyotrophic lateral sclerosis, or combinations thereof.

[0362] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with a seizure disorder.

[0363] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with an infectious, metabolic, or systemic diseases affecting the central nervous system.

[0364] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the infectious, metabolic, or systemic diseases affecting the central nervous system include syphilis, present hypothyroidism, or present vitamin B12 or folate deficiency.

[0365] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with a current DSM-V diagnosis of active major depression, schizophrenia, bipolar disorder, or combinations thereof.

[0366] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein subjects with depressive symptoms successfully managed by a stable dose of an antidepressant are not excluded.

[0367] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the subject has not been diagnosed with a clinically significant, advanced, or unstable disease that may interfere with outcome evaluations.

[0368] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the compound is administered orally.

[0369] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the compound is administered for about 6 months.

[0370] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the compound is administered for at least about 6 months.

[0371] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

[0372] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is about 100 mg.

[0373] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is about 200 mg.

[0374] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is about 300 mg.

[0375] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

[0376] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is a total daily dose of about 100 mg.

[0377] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is a total daily dose of about 200 mg.

[0378] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the therapeutically effective amount is a total daily dose about 300 mg.

[0379] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the total daily dose is administered for about 6 months.

[0380] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the total daily dose is administered for at least about 6 months.

[0381] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in a reduction in the rate of cognitive decline compared to placebo.

[0382] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to placebo. In some embodiments, administering the compound results in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment. In some embodiments, administering the compound results in maintenance of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment.

[0383] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in an improvement in the Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) score compared to placebo. In some embodiments, administering the compound results in an improvement in the Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) score compared to the start of treatment. In some embodiments, administering the compound results in maintenance of the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS- ADL) score compared to the start of treatment.

[0384] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in an improvement in the Clinical Global Impression of Change (CGIC) score compared to placebo. In some embodiments, administering the compound results in an improvement in the Clinical Global Impression ofChange (CGIC) score compared to the start of treatment. In some embodiments, administering the compound results in maintenance of the Clinical Global Impression of Change (CGIC) score compared to the start of treatment.

[0385] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in an improvement in the Neuropsychological Test Battery (NTB) score compared to placebo. In some embodiments, administering the compound results in an improvement in the Neuropsychological Test Battery (NTB) score compared to the start of treatment. In some embodiments, administering the compound results in maintenance of the Neuropsychological Test Battery (NTB) score compared to the start of treatment.

[0386] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in an improvement in the MiniMental State Examination (MMSE) score compared to placebo. In some embodiments, administering the compound results in an improvement in the Mini-Mental State Examination (MMSE) score compared to the start of treatment. In some embodiments, administering the compound results in maintenance of the Mini-Mental State Examination (MMSE) score compared to the start of treatment.

[0387] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering the compound results in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease. In some embodiments, administering the compound results in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease compared to the start of treatment.

[0388] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the one or more CSF biomarkers are neurofllament light chain (NfL), amyloid beta (Abeta), tau, and phosphorylated tau.

[0389] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administration results in a reduction in the concentration of NfL compared to a placebo. In some embodiments, administration results in a reduction in the concentration of NfL compared to the start of treatment.

[0390] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the Abeta is Abeta 40 or Abeta 42.

[0391] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administration results in a reduction in the concentration of Abeta 42 compared to a placebo. In some embodiments, administration results in a reduction in the concentration of Abeta 42 compared to the start of treatment.

[0392] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering a therapeutically effective amount of the compound results in a reduction in the Alzheimer's Disease Assessment Score (ADAS-COG) score of a subject as compared to the ADAS-COG score of the subject before treatment.

[0393] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein administering a therapeutically effective amount of the compound results in at a least 3 point reduction in the Alzheimer's Disease Assessment Score (ADAS-COG) score of a subject.

[0394] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein an incidence of treatment-emergent adverse events (TEAEs) is comparable to placebo.

[0395] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the method further includes monitoring liver function tests (LFTs) during treatment.

[0396] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein less than about 20% of patients treated with 300 mg CT 1812 experience LFT elevations >3x upper limit of normal (ULN) for AST or ALT.

[0397] In some embodiments, the techniques described herein relate to any embodiment described herein, wherein the liver function tests return to normal after cessation of treatment with the compound.FURTHER EMBODIMENTS

[0398] Clause 1. A method of inducing cognitive preservation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula: or a pharmaceutically acceptable salt thereof.

[0399] Clause 2. A method of improving cognition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula: or a pharmaceutically acceptable salt thereof.

[0400] Clause 3. A method of treating Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula: or a pharmaceutically acceptable salt thereof.

[0401] Clause 4. The method of any one of clauses 1 to 3, wherein the pharmaceutically acceptable salt is a fumarate salt.

[0402] Clause 5. The method of any one of clauses 1 to 4, wherein the subject has reduced plasma levels of Tau protein phosphorylated at amino acid 217 (pTau-217).

[0403] Clause 6. The method of clause 5, wherein the reduced plasma levels of pTau-217 are detected prior to administration of the compound or pharmaceutically acceptable salt thereof.

[0404] Clause 7. The method of any one of clauses 1 to 6, wherein the subject is diagnosed with Alzheimer's disease.

[0405] Clause 8. The method of any one of clauses 1 to 6, wherein the subject is diagnosed with mild cognitive impairment.

[0406] Clause 9. The method of any one of clauses 1 to 6, wherein the subject is diagnosed with mild to moderate cognitive impairment.

[0407] Clause 10. The method of any one of clauses 1 to 9, wherein the subject has a positive amyloid PET scan or cerebrospinal fluid biomarker consistent with Alzheimer's disease.

[0408] Clause 11. The method of any one of clauses 1 to 10, wherein the subject has a Mini-Mental State Examination (MMSE) score between 18 and 26.

[0409] Clause 12. The method of any one of clauses 1 to 11, wherein the subject has a mini-mental state examination (MMSE) score between about 22-26. 13. The method of any one of claims 1 to 12, wherein the subject has an MMSE score greater than, or equal to 24.

[0410] Clause 14. The method of any one of clauses 1 to 13, wherein the subject is aged less than 50 years. 15. The method of any one of claims 1 to 14, wherein the subject is aged between 50 and 80 years.

[0411] Clause 16. The method of any one of clauses 1 to 15, wherein the subject has not been diagnosed with major depressive disorder, schizophrenia, bipolar disorder, or any combination thereof.

[0412] Clause 17. The method of any one of clauses 1 to 16, wherein the subject is on a stable regimen of acetylcholinesterase inhibitors, memantine, or a combination thereof.

[0413] Clause 18. The method of any one of clauses 1 to 17, wherein the subject meets all of the following criteria: a) has been diagnosed with Alzheimer's disease; b) has a positive amyloid PET scan or cerebrospinal fluid biomarker consistent with Alzheimer's disease; c) has a MiniMental State Examination (MMSE) score between 18 and 26, inclusive; d) has undergone magnetic resonance imaging (MRI) that shows no significant abnormality; e) has not been diagnosed with major depressive disorder, schizophrenia, bipolar disorder, or combinations thereof; and f) is on a stable regimen of acetylcholinesterase inhibitors or memantine, or is not taking such medications.

[0414] Clause 19. The method of any one of clauses 1 to 18, wherein the subject does not have significant brain abnormalities as determined by magnetic resonance imaging (MRI).

[0415] Clause 20. The method of any one of clauses 1 to 19, wherein significant brain abnormalities include prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, or space-occupying lesions.

[0416] Clause 21. The method of any one of clauses 1 to 20, wherein the subject has not been diagnosed with other primary degenerative dementias.

[0417] Clause 22. The method of any one of clauses 1 to 21, wherein other primary degenerative dementias include dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Creutzfeldt-Jakob Disease, Down syndrome, or combinations thereof.

[0418] Clause 23. The method of any one of clauses 1 to 22, wherein the subject has not been diagnosed with other neurodegenerative conditions.

[0419] Clause 24. The method of any one of clauses 1 to 23, wherein other neurodegenerative conditions include Parkinson's disease, amyotrophic lateral sclerosis, or combinations thereof.

[0420] Clause 25. The method of any one of clauses 1 to 24, wherein the subject has not been diagnosed with a seizure disorder.

[0421] Clause 26. The method of any one of clauses 1 to 25, wherein the subject has not been diagnosed with infectious, metabolic, systemic diseases, or combinations thereof affecting the central nervous system.

[0422] Clause 27. The method of clause 26, wherein the infectious, metabolic, or systemic diseases affecting the central nervous system include syphilis, present hypothyroidism, or present vitamin B 12 or folate deficiency.

[0423] Clause 28. The method of any one of clauses 1 to 27, wherein the subject has not been diagnosed with a current DSM-V diagnosis of active major depression, schizophrenia, or bipolar disorder.

[0424] Clause 29. The method of clause 28, wherein subjects with depressive symptoms successfully managed by a stable dose of an antidepressant are not excluded.

[0425] Clause 30. The method of any one of clauses 1 to 29, wherein the subject has not been diagnosed with a clinically significant, advanced, or unstable disease that may interfere with outcome evaluations.

[0426] Clause 31. The method of any one of clauses 1 to 30, wherein the compound is administered orally.

[0427] Clause 32. The method of any one of clauses 1 to 31 , wherein the compound is administered for about 6 months.

[0428] Clause 33. The method of any one of clauses 1 to 32, wherein the compound is administered for at least about 6 months.

[0429] Clause 34. The method of any one of clauses 1 to 33, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

[0430] Clause 35. The method of any one of clauses 1 to 34, wherein the therapeutically effective amount is about 100 mg.

[0431] Clause 36. The method of any one of clauses 1 to 35, wherein the therapeutically effective amount is about 200 mg.

[0432] Clause 37. The method of any one of clauses 1 to 36, wherein the therapeutically effective amount is about 300 mg.

[0433] Clause 38. The method of any one of clauses 1 to 37, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

[0434] Clause 39. The method of any one of clauses 1 to 38, wherein the therapeutically effective amount is a total daily dose of about 100 mg.

[0435] Clause 40. The method of any one of clauses 1 to 39, wherein the therapeutically effective amount is a total daily dose of about 200 mg.

[0436] Clause 41. The method of any one of clauses 1 to 40, wherein the therapeutically effective amount is a total daily dose about 300 mg.

[0437] Clause 42. The method of any of clauses 34 to 41, wherein the total daily dose is administered for about 6 months.

[0438] Clause 43. The method of any of clauses 34 to 41, wherein the total daily dose is administered for at least about 6 months.

[0439] Clause 44. The method of any one of clauses 1 to 43, wherein administering the compound results in a reduction in the rate of cognitive decline compared to placebo.

[0440] Clause 45. The method of any one of clauses 1 to 44, wherein administering the compound results in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to placebo.

[0441] Clause 46. The method of any one of clauses 1 to 44, wherein administering the compound results in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment.

[0442] Clause 47. The method of any one of clauses 1 to 44, wherein administering the compound results in maintenance of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment.

[0443] Clause 48. The method of any one of clauses 1 to 47, wherein administering the compound results in an improvement in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score compared to placebo.

[0444] Clause 49. The method of any one of clauses 1 to 48, wherein administering the compound results in an improvement in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score compared to the start of treatment.

[0445] Clause 50. The method of any one of clauses 1 to 48, wherein administering the compound results in maintenance of the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score compared to the start of treatment.

[0446] Clause 51. The method of any one of clauses 1 to 50, wherein administering the compound results in an improvement in the Clinical Global Impression of Change (CGIC) score compared to placebo.

[0447] Clause 52. The method of any one of clauses 1 to 51, wherein administering the compound results in an improvement in the Clinical Global Impression of Change (CGIC) score compared to the start of treatment.

[0448] Clause 53. The method of any one of clauses 1 to 51, wherein administering the compound results in maintenance of the Clinical Global Impression of Change (CGIC) score compared to the start of treatment.

[0449] Clause 54. The method of any one of clauses 1 to 53, wherein administering the compound results in an improvement in the Neuropsychological Test Battery (NTB) score compared to placebo.

[0450] Clause 55. The method of any one of clauses 1 to 54, wherein administering the compound results in an improvement in the Neuropsychological Test Battery (NTB) score compared to the start of treatment.

[0451] Clause 56. The method of any one of clauses 1 to 54, wherein the administering the compound results in maintenance of the Neuropsychological Test Battery (NTB) score compared to the start of treatment.

[0452] Clause 57. The method of any one of clauses 1 to 56, wherein administering the compound results in an improvement in the Mini-Mental State Examination (MMSE) score compared to placebo.

[0453] Clause 58. The method of any one of clauses 1 to 57, wherein administering the compound results in an improvement in the Mini-Mental State Examination (MMSE) score compared to the start of treatment.

[0454] Clause 59. The method of any one of clauses 1 to 57, wherein administering the compound results in maintenance of the Mini-Mental State Examination (MMSE) score compared to the start of treatment.

[0455] Clause 60. The method of any one of clauses 1 to 59, wherein administering the compound results in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease.

[0456] Clause 61. The method of any one of clauses 1 to 60, wherein administering the compound results in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease compared to the start of treatment.

[0457] Clause 62. The method of clause 60 or claim 61, wherein the one or more CSF biomarkers are neurofilament light chain (NfL), amyloid beta (Abeta), tau, and phosphorylated tau.

[0458] Clause 63. The method of clause 62, wherein administration results in a reduction in the concentration of NfL compared to a placebo.

[0459] Clause 64. The method of clause 62, wherein the administration results in a reduction in the concentration of NfL compared to the start of treatment.

[0460] Clause 65. The method of clause 63, wherein the Abeta is Abeta 40 or Abeta 42.

[0461] Clause 66. The method of clause 65, wherein administration results in a reduction in the concentration of Abeta 42 compared to a placebo.

[0462] Clause 67. The method of clause 65, wherein administration results in a reduction in the concentration of Abeta 42 compared to the start of treatment.

[0463] Clause 68. The method of any one of clauses 1 to 67, wherein administering a therapeutically effective amount of the compound results in a reduction in the Alzheimer's Disease Assessment Score (ADAS-COG) score of a subject as compared to the ADAS-COG score of the subject compared to the start of treatment.

[0464] Clause 69. The method of clause 68, wherein administering a therapeutically effective amount of the compound results in at a least 3 -point reduction in the Alzheimer's Disease Assessment Score (ADAS-COG) score of a subject compared to the start of treatment.

[0465] Clause 70. The method of any one of clauses 1 to 69, wherein an incidence of treatment-emergent adverse events (TEAEs) is comparable to placebo.

[0466] Clause 71. The method of any one of clauses 1 to 70, wherein the method further comprises monitoring liver function tests (LFTs) during treatment.

[0467] Clause 72. The method of clause 71, wherein less than about 20% of patients treated with 300 mg CT1812 experience LFT elevations >3x upper limit of normal (ULN) for AST or ALT.

[0468] Clause 73. The method of clause 72, wherein the liver function tests return to normal after cessation of treatment with the compound.WORKING EXAMPLES

[0469] Example 1 : Clinical Trial Testing Safety and. Efficacy of CT1812 Treatment in patients with mild-to-moderate Alzheimer’s disease

[0470] Summary: The SHINE study (ClinicalTrials.gov ID No. NCT03507790, which is incorporated herein in its entirety) is a double-blind, placebo-controlled Phase 2 clinical trial that enrolled patients with mild-to-moderate Alzheimer’s disease. Participants are evenly randomized to receive either placebo or one of two doses of CT1812 (100 mg or 300 mg), which is taken orally daily for six months. Endpoints include safety, cognitive function as measured by the ADAS-Cog 11 , a globally recognized cognitive scale, and biomarker evidence of disease modification.

[0471] Patients treated with CT 1812 for six months showed a benefit compared to placebo across all cognitive and functional measures: ADAS-Cog 11, MMSE, ADCS-ADL and ADCS- CGIC. CT 1812 further demonstrated a favorable safety and tolerability profile, consistent with previous clinical experience. Results support amyloid oligomer antagonism as an important mechanism to treat Alzheimer’s disease.

[0472] SHINE enrolled 153 people with mild-to-moderate (MMSE 18-26) Alzheimer's disease who were randomized evenly (1:1:1) to one of two oral daily doses of CT 1812 (lOOmg or 300mg) or placebo. CT1812 treatment was associated with an average 1.66-point decline in ADAS-Cog 11, while participants in the placebo arm declined on average by 2.70 points. In participants who had moderate Alzheimer’s (MMSEs 18-21) at baseline, the average decline in ADAS-Cog 11 of treated participants (n=48) was 1.94 points compared to 3.52 points for those participants on placebo (Table 2).Table 2. Exploratory Outcomes Summary

[0473] The primary obj ective of the SHINE study was safety and tolerability. CT 1812 met the study’s safety and tolerability objective, consistent with previous clinical experience. Overall, the percentage of participants experiencing any adverse event (AE) was similar between the pooled CT1812 treatment group (76.5%) and the placebo group (78%). The most commonly reported treatment emergent adverse events (TEAEs) were gastrointestinal (abdominal pain, nausea, vomiting and constipation) and were balanced between treated and placebo arms. As observed in earlier studies, laboratory test abnormalities, namely transient elevations in liver enzymes, which subsided after cessation of drug, were observed in five participants in the 300mg dose group without evidence of serious liver injury. Symptomatic ARIA was not observed in this study, which is consistent with our understanding of the candidate’s mechanism of action.

[0474] The study evaluated several outcome measures to assess the efficacy of CT 1812 in treating Alzheimer's disease. The primary cognitive endpoint was the change from baseline in ADAS-Cog 11 scores, comparing CT1812-treated groups (combined 300mg and lOOmg) versus placebo. Additional cognitive assessments were performed using ADAS-Cog 13, MMSE, and a cognitive composite score. Functional outcomes were measured using the ADCS-ADL scale, while global clinical changes were assessed with the ADCS-CGIC. These cognitive and functional assessments were conducted at baseline and on study days 42, 98, and 182. The study also included biomarker assessments, with cerebrospinal fluid (CSF) samples collected at screening and day 182 for analysis. Notably, CSF neurofilament light chain (NfL), a marker of neurodegeneration, was measured, along with the A [3 40 / 42 ratio. Statistical analysis of the cognitive data employed a mixed-model repeated measures (MMRM) approach, accounting for treatment effects, visit, baseline scores, and APOE c4 status. Overall, this comprehensive set of outcome measures aimed to evaluate the impact of CT1812 on cognitive function, daily living activities, and relevant biomarkers in patients with mild-to-moderate Alzheimer's disease.

[0475] Patients: In this study, 372 subjects were initially screened, and out of those, 153 were randomized into different treatment groups. The completion rates varied across these groups: 83.7% of participants completed the study overall. Specifically, completion rates were 92.2% for CT1812 lOOmg, 68.6% for CT1812 300mg, and 90.2% for the placebo group. However, 25 participants (16.3%) discontinued the study prematurely. Discontinuation rates differed bytreatment group: 7.8% for CT1912 lOOmg, 31.4% for CT1812 300mg, and 9.8% for placebo. The most common reason for discontinuation was adverse events (AE), accounting for 9.2% of cases across all treatment groups.

[0476] Inclusion Criteria: The inclusion criteria for the clinical trial were as follows: Participants must have been between 55 and 85 years old, have had a clinical diagnosis of mild to moderate Alzheimer’s disease, exhibited a Mini-Mental State Examination (MMSE) score between 16 and 26 (inclusive), maintained stable doses of acetylcholinesterase inhibitors (donepezil, rivastigmine, or galantamine) for at least 3 months prior to screening, used stable doses of memantine for at least 3 months prior to screening, were willing to undergo lumbar puncture for cerebrospinal fluid (CSF) collection, and expressed willingness to comply with study procedures and assessments.

[0477] Exclusion Criteria: Exclusion criteria for the study included significant abnormalities detected on screening MRI (or historical MRI, if applicable) of the brain. These abnormalities can include, but are not limited to, prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, or space-occupying lesions such as abscesses or brain tumors like meningiomas. Additionally, subjects were excluded based on clinical or laboratory findings consistent with other primary degenerative dementias (e.g., dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob Disease, Down syndrome) or other neurodegenerative conditions such as Parkinson's disease or amyotrophic lateral sclerosis. Seizure disorders, as well as infectious, metabolic, or systemic diseases affecting the central nervous system (e.g., syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, or other relevant laboratory values) also lead to exclusion. Furthermore, subjects with a current DSM-V diagnosis of active major depression, schizophrenia, or bipolar disorder were excluded, although those with depressive symptoms successfully managed by a stable dose of an antidepressant were allowed entry. Lastly, any clinically significant, advanced, or unstable disease that may interfere with outcome evaluations served as grounds for exclusion from the study.

[0478] Demographics: The SHINE study enrolled patients with mild-to-moderate Alzheimer's disease. The baseline characteristics (Table 3) were generally well-balanced across the CT 1812 lOOmg, CT 1812 300mg, and placebo groups. The mean age of participants ranged from 71.6 to 74.1 years, with a majority being female (56-66.7%) and predominantly white (93.9- 98%). Mean baseline MMSE scores were between 20.80 and 21.80, indicating mild-to-moderate cognitive impairment. A substantial proportion of patients were using acetylcholinesteraseinhibitors (31-35%). Notably, the majority of patients were APOe4 positive (58.8-63.3%), with the E3 / E4 genotype being the most common (37.3-49%), followed by E3 / E3 (36-41.2%). The E4 / E4 genotype was present in 10-14.3% of patients. This APOe genotype distribution aligns with the increased risk of Alzheimer's disease associated with the E4 allele. Overall, the study population characteristics were consistent with typical Alzheimer's disease clinical trial populations.Table 3. Demographics and Baseline Characteristics

[0479] Cognitive Endpoint- ADAS-Cog 11 : The ADAS-Cog 11 results from the SHINE study suggest a potential cognitive benefit of CT 1812 treatment in patients with mild-to-moderate Alzheimer's disease. Over a 6-month period, the pooled CT 1812 treatment group demonstrated a 39% slowing of ADAS-Cog 11 decline compared to placebo (Table 4; FIG. 1; FIG. 2, FIG. 3, FIG. 4, FIG. 5). The mean change in ADAS-Cog 11 scores was smaller for both CT1812 doses (1.56 points for lOOmg and 1.48 points for 300mg) compared to placebo (2.33 points), indicating less cognitive decline in the treatment groups. The pooled CT1812 group showed an average increase of 1.52 points, compared to 2.33 points in the placebo group. Overall, low and high MMSE reflects typical differences in progression rate of ADAS-Cogl l scores (FIG. 6, FIG. 7, FIG. 8). While these differences did not reach statistical significance (p>0.05), the magnitude of the effect was noted to be similar to that observed with other investigational Alzheimer's treatments such as lecanemab and donanemab. These results, although not statistically significant, suggest a trend towards cognitive benefit with CT 1812 treatment and warrant further investigation in larger studies.Table 4. ADAS-Cog 11

[0480] Cognitive Endpoint- MMSE: The MMSE results from the SHINE study indicate a potential cognitive benefit of CT 1812 treatment in patients with mild-to-moderate Alzheimer's disease. Over the 6-month study period, the pooled CT 1812 treatment group demonstrated a 70% slowing of MMSE decline compared to placebo (Table 5; FIG. 9, FIG. 10, FIG. 11, FIG. 12). The mean change in MMSE scores was smaller for both CT 1812 doses (1.56 points for lOOmg and 2.30 points for 300mg) compared to placebo (3.52 points), suggesting less cognitive decline in the treatment groups. The pooled CT1812 group showed an average increase of 1.94 points, compared to 3.52 points in the placebo group. Interestingly, the lOOmg dose of CT1812 appeared to perform slightly better than the 300mg dose. While these differences did not reach statistical significance (p>0.05), the substantial slowing of MMSE decline in the CT1812 groups suggests a potentially meaningful cognitive benefit. These results, although not statistically significant, indicate a trend towards cognitive preservation with CT 1812 treatment and support further investigation in larger clinical trials.Table 5. MMSE

[0481] ADAS-COG 13:

[0482] The ADAS-Cog 13 results from the SHINE study suggest a potential cognitive benefit of CT 1812 treatment in patients with mild-to-moderate Alzheimer's disease (FIG. 13 and FIG. 14).

[0483] Cognitive Composite:

[0484] The Cognitive Composite results from the SHINE study suggest a potential cognitive benefit of CT 1812 treatment in patients with mild-to-moderate Alzheimer's disease (FIG. 15, FIG. 16, and FIG. 17).

[0485] Functional Endpoints: ADCS-ADL: The ADCS-ADL (Activities of Daily Living) results from the SHINE study suggest a potential benefit of CT 1812 in slowing functional decline in patients with mild-to-moderate Alzheimer's disease. Over the 26-week study period, the pooled CT 1812 treatment group demonstrated a 26% slowing of ADL decline compared to placebo (FIG. 18, FIG. 19, FIG. 20, and FIG. 21). While all groups experienced a decline in functional abilities over time, the CT 1812 treatment groups, particularly the pooled and lOOmg doses, showed a less steep decline compared to the placebo group. By week 26, the placebo group exhibited the most significant functional decline, while the CT 1812 groups maintained higher scores. This pattern suggests that CT 1812 treatment may help preserve daily living functions in Alzheimer's patients.Although specific statistical values were not provided, the observed trend indicates a potentially meaningful impact of CT 1812 on maintaining functional abilities in this patient population.

[0486] Functional Endpoints: ADCS-CGIC: The ADCS-CGIC (Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change) results from the SHINE study suggest a potential benefit of CT 1812 in maintaining overall function in patients with mild-to-moderate Alzheimer's disease (Table 6; FIG. 22, FIG. 23, FIG. 24, and FIG. 25). At the 6-month timepoint, both CT 1812 dosage groups (lOOmg and 300mg) showed a mean score of 4.5, while the placebo group had a higher mean score of 4.8, indicating less decline in the CT1812 groups. Over the 26- week period, all groups showed a decline in function, with the steepest decline occurring between baseline and Week 6. However, the CT1812 treatment groups consistently demonstrated slightly lower (better) scores compared to the placebo group, particularly at Weeks 6 and 14. While the differences were not statistically significant (p>0.05), the consistently lower scores in the CT1812 groups compared to placebo suggest a trend towards better maintenance of overall function with CT 1812 treatment. These results, based on clinician interviews with participants and caregivers, provide a global assessment of change in the patient's condition and support further investigation of CT1812's potential benefits.Table 6. ADCS-CGIC

[0487] Key CSF Biomarkers: The study results showed a significant reduction (p<0.05) in Abeta 1 -42 levels relative to placebo for the 300 mg dose, consistent with previous observations. However, this reduction was not observed at the 100 mg dose. For NfL, a nominally significant (p<0.05) reduction relative to placebo was observed for the 300 mg dose, while a reduction trend (p<0.10) was noted for the 100 mg dose (FIG. 26). These findings support the potential for slowing neurodegeneration. Other CSF biomarkers, including p-Tau, Total tau, Synaptotagmin,Neurogranin, SNAP -25, and GFAP, did not approach statistical significance. It is worth noting that CSF samples were optional and were available in approximately 50% of the full modified intention-to-treat (mITT) population.

[0488] CT 1812 treatment resulted in reductions in CSF NfL, a marker of neurodegeneration measured with little change in the A [1 40 / 42 ratio (FIG. 27).

[0489] Tolerability Profile: CT1812 demonstrated a favorable safety and tolerability profile in the study. The majority of adverse events (AEs) reported were mild or moderate in severity. The overall incidence of AEs was comparable between the pooled CT1812 treatment group (76.5%) and the placebo group (78%). Serious AEs occurred at a lower rate in CT1812- treated subjects (4.9%) compared to placebo subjects (10%). No AEs led to discontinuation in the lOOmg CT1812 group, while 21.6% of subjects in the 300mg group discontinued due to an AE, primarily elective discontinuations resulting from elevated liver enzymes. In the placebo group, 6% of subjects discontinued due to an AE. Notably, all cases of elevated liver enzymes greater than or equal to 3 times the upper limit of normal (ULN) were observed exclusively in the 300mg dose group (Table 7).Table 7. Adverse Events

[0490] Gastrointestinal disorders were more frequent in CT 1812 groups, particularly the lOOmg dose (21.6%), compared to placebo (8.0%) Table 8 and Table 9. Laboratory investigations were notably higher in the CT1812 300mg group (33.3%) compared to the lOOmg group (9.8%) and placebo (14.0%), with some cases of increased liver enzymes observed only in the 300mg group. Serious adverse events (SAEs) were less prevalent in the CT1812 groups (4.9%) compared to placebo (10%). No individual SAE preferred term was reported in more than one participant. The 300mg group had a higher discontinuation rate due to AEs (21.6%), primarily due to elevated liver enzymes, while no discontinuations occurred in the lOOmg group. Overall, the safety profile of CT 1812 appeared acceptable, with the lOOmg dose showing a more favorable tolerability profile than the 300mg dose.Table 8. Most common AE by System Organ Class and Preferred TermTable 9. Treatment Emergent Adverse Events

[0491] Safety Conclusions: The safety conclusions from the COG0201 (SHINE) study indicate that CT 1812 was generally safe and we 11 -tolerated in patients with mild-to-moderate Alzheimer's disease. Most adverse events (AEs) were mild or moderate in severity. The overall percentage of subjects experiencing any AE was similar between the pooled CT 1812 treatment group (76.5%) and the placebo group (78%). Notably, serious AE rates were lower among CT 1812 subjects (4.9%) compared to placebo subjects (10%). The lOOmg dose group showed a more favorable safety profile, with no AEs leading to discontinuation, while 21.6% of subjects in the 300mg group discontinued due to an AE, primarily due to elective discontinuations related to elevated liver enzymes. In comparison, 6% of subjects in the placebo group discontinued due to an AE. All cases of elevated liver enzymes greater than or equal to 3X ULN occurred exclusively in the 300mg dose group. These findings suggest that the lOOmg dose of CT1812 may offer a better balance of efficacy and tolerability compared to the 300mg dose. The overall safety profile supports further investigation of CT 1812, particularly at the lower dose, in larger clinical trials for Alzheimer's disease treatment.

[0492] Methods: For each clinical outcome assessment, the mean change from baseline was analyzed using a MMRM (mixed-model for repeated measures) model. The MMRM model included treatment as the main effect; visit, baseline assessment score, and APOE c4 (+ or -) status as covariates; and treatment by visit as an interaction term.

[0493] All post-baseline analysis visits were included in the model (Day 42, Day 98, and Day 182). No imputation for missing data was performed; only observed data were included in allanalyses. An unstructured covariance matrix was used to model the within-participant errors. The Kenward-Roger approximation was used to estimate degrees of freedom.

[0494] CSF biomarkers were analyzed using an ANCOVA model as only one postbaseline assessment was available (Day 182). The model included treatment as the main effect, and baseline CSF concentration and APOE c4 (+ or -) status as covariates.

[0495] Example 2. Cognition Therapeutics ’ Proof-of-Concept Phase 2 SHINE Trial Demonstrates Consistent Improvement in Cognitive Outcomes with Once-Daily Oral CT1812 in Mild-to-Moderate Alzheimer’s Patients

[0496] A proof-of-concept Phase 2 clinical trial called SHINE (NCT03507790) was conducted to evaluate the efficacy and safety of CT 1812 in patients with mild-to-moderate Alzheimer's disease. The study enrolled 153 adults with mild-to-moderate Alzheimer's disease (MMSE 18-26) who were randomized in a 1:1:1 ratio to receive either CT 1812 100 mg oral daily dose, CT1812 300 mg oral daily dose, or placebo for a treatment duration of 6 months (182 days).

[0497] The primary endpoint of the study was safety and tolerability, while the key secondary endpoint was ADAS-Cog 11. Other cognitive and functional measures included ADAS-Cog 13, cognitive composite, MMSE, ADCS-ADL, and ADCS-CGIC.

[0498] The results showed a consistent trend in cognitive improvement across all measures for CT1812-treated groups compared to placebo, with approximately 40% mean improvement in cognitive measures versus placebo. For ADAS-Cog 11 specifically, the placebo group worsened by approximately 2.70 points at Day 182, while the CT1812-treated groups declined by an average of 1.66 points at Day 182, representing a 39% slowing of decline favoring CT1812. P-values less than 0.05 were observed on ADAS-Cog 11 and MMSE at Day 98, which was the study midpoint.

[0499] Regarding functional outcomes, signals of improvement in ADCS-ADL and ADCS-CGIC were observed at 6 months, favoring CT 1812. Biomarker analysis revealed significant changes in neurofilament light chain (NfL), a marker of neurodegeneration, especially at the 300 mg dose. No significant changes were observed in neurogranin, synaptotagmin, SNAP25, pTau, total Tau, and GFAP.

[0500] The study demonstrated a favorable safety profile consistent with previous clinical experience. The incidence of adverse events (AEs) was similar between CT 1812 (76.5%) and placebo (78%) groups, with the majority of AEs being mild or moderate in severity. The mostcommon treatment-emergent AEs included infections and infestations (urinary tract infection), injury, poisoning, and procedural complications (falls and skin lacerations), gastrointestinal disorders, and nervous system disorders (headache).

[0501] Serious adverse events (SAEs) occurred in 10% of participants in the placebo group compared to 6% in the combined CT 1812 groups. Treatment-emergent SAEs in the 100 mg group included stomatitis, chronic constipation, and hip fracture, which were deemed not related to treatment. In the 300 mg group, treatment-emergent SAEs included hematuria, abdominal pain, and infection (not related to treatment), as well as recurrent presyncope (related to treatment). Regarding liver function test (LFT) elevations, 9 patients in the 300 mg dose group experienced LFT increases (greater than 3xULN), which resolved after drug cessation, while no LFT elevations were observed in the 100 mg dose group.

[0502] Based on the study results, several conclusions may be drawn. CT1812 demonstrated consistent improvement in cognitive outcomes compared to placebo, and the 100 mg dose showed a favorable efficacy and safety profile. The results support the potential of CT 1812 as a synaptoprotective agent and suggest that amyloid oligomer antagonism may have a role in Alzheimer's disease treatment. The data supports advancing the 100 mg dose of CT 1812 in future clinical trials for mild-to-moderate Alzheimer's disease patients.

[0503] CT 1812 is an oral small molecule oligomer antagonist that binds to the sigma-2 (o-2) receptor complex. The SHINE study was supported by approximately $30 million in grants from the National Institute on Aging of the National Institutes of Health (NIH). Future studies include the SHIMMER trial in mild-to-moderate Lewy body dementia and the START trial in early-stage Alzheimer's disease. Additionally, a Phase 2 proof-of-concept trial in dry AMD is currently enrolling patients.

[0504] Example 3: Clinical Trial Testing Safety and. Efficacy of CT1812 Treatment in patients with mild-to-moderate Alzheimer ’s disease with low plasma phosphorylated Tau (pTau- 217)

[0505] Patients enrolled in the clinical trial described in Example 1 where tested for plasma concentrations of phosphorylated Tau, particularly Tau phosphorylated at amino acid 217. Patients with low plasma levels of pTau-217 prior to administration of CT 1812 (n= 57; low p-Tau 217 defined in a prespecified analysis as below the median of 1.0 pg / mL) exhibited robust protection from cognitive decline after treatment with CT1812 as measured by ADAS-Cogl lscores (FIG. 28), MMSE scores (FIG. 29), ADCS-ADL scores (FIG. 30), and ADCS-CGIC scores (FIG. 31). ADCS-ADL and -CGIC show greater than 60% benefit.

[0506] Example 4 : Zervimesine (CT1812) Treatment Benefits Patients with Lower Baseline Plasma p-tau217 Across the Mild-to-Moderate AD Spectrum

[0507] Methods: The experiment employed a comprehensive methodology to evaluate the effects of CT 1812 (Zervimesine) treatment in Alzheimer's Disease patients. The study design included a randomized, double-blind, placebo-controlled trial with participants stratified by baseline plasma p-tau217 levels. Participants were divided into two cohorts based on the median plasma p-tau217 value (1.0 pg / mL): a lower p-tau217 group (<1.0 pg / mL) and a higher p-tau217 group (>1.0 pg / mL). The demographics and baseline characteristics of the patients enrolled in the study are presented in Table 10.

[0508] Table 10. Demographics and Baseline Characteristics (by plasma p-tau217)

[0509] Cognitive and functional assessments were conducted at baseline and at days 42, 98, and 182 following treatment initiation. The assessments included standardized measures such as MMSE, ADAS-Cog, and other cognitive function tests. Plasma biomarkers, particularly p- tau217, were measured using the Quanterix assay with Alzpath p-tau217 antibody at baseline to establish treatment groups.

[0510] Statistical analysis utilized a mixed-model for repeated measures (MMRM) approach to analyze mean changes from baseline. The model incorporated treatment as the main effect, with visit, baseline score, and APOE c4 carrier status as covariates. The treatment-by- visit interaction was also included in the analysis. The modified intention-to-treat (mITT) population was used for primary analyses, which excluded participants who did not receive the intended treatment or lacked baseline measurements.

[0511] Safety monitoring was conducted throughout the study period, with adverse events (AEs) and serious adverse events systematically recorded and compared between the placebo and CT 1812 treatment groups. The results indicated that CT1812 may provide cognitive benefits particularly in patients with lower baseline p-tau217 levels, suggesting that brain disease burden may be a more relevant indicator of treatment response than baseline MMSE score.

[0512] Statistical Analysis: Mean change from baseline was analyzed using a mixed- model for repeated measures (MMRM). Treatment was included as the main effect. Visit, baseline score, and APOE c4 (+ or -) status were included as covariates. Treatment by visit was included as an interaction term.

[0513] Results:

[0514] Adverse Events (Safety Population): CT 1812 demonstrated a generally favorable safety and tolerability profile. Adverse events (AEs) between placebo and CT 1812 didn't differ significantly, nor did serious AEs. See Vijverberg EGB, et al (AAIC) 2024 for full safety findings.

[0515] Clinical Outcomes: The data presented in Table 11 demonstrate consistently better outcomes for participants with below median baseline p-tau217 levels compared to those with above median levels. For the ADAS-Cogl 1 measure, the treatment group with below median p- tau217 showed a greater improvement (-2.66 points) compared to placebo, while the above median group showed a slight worsening (0.42 points). Similar trends were observed for MMSE, ADCS-CGIC, and ADCS-ADL measures, with the below median p-tau217 group consistently showing more favorable outcomes, suggesting a stronger treatment effect in the below median p- tau217 group. These findings indicate that CT 1812 may be more effective in patients with lower baseline p-tau217 levels, potentially identifying a subgroup more likely to benefit from this treatment approach in Alzheimer's disease.

[0516] Table 11.

[0517] This study provides evidence that CT1812 may slow cognitive decline in people with mild-to-moderate Alzheimer's Disease (AD), as illustrated in FIG. 32. The data suggests that plasma p-tau217 levels may define a treatment-responsive population for future studies (FIG. 33). A treatment effect in participants with "low" p-tau217 was observed across the entire MMSE spectrum, as demonstrated in FIG. 34, FIG. 35, FIG. 36, FIG. 37, and FIG. 38. Patients with below-median baseline p-tau217 levels consistently showed better outcomes compared to those with higher levels.

[0518] The treatment effect appears particularly robust in participants with plasma p- tau217 less than 1 pg / mL. This cut-point of approximately 1.0 pg / mL aligns with the literature for median values in the mild-to-moderate AD population, as reported by Rousset et al. (2024). Lower brain disease burden, as indicated by p-tau217 levels, may be a better indicator than MMSE score of potential cognitive impact of CT1812.

Claims

1. CLAIMSWhat is claimed is:

1. A method of inducing cognitive preservation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula:pharmaceutically acceptable salt thereof.

2. A method of improving cognition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula:pharmaceutically acceptable salt thereof.

3. A method of treating Alzheimer’s disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula:pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is a fumarate salt.

5. The method of any one of claims 1 to 4, wherein the subject has reduced plasma levels of Tau protein phosphorylated at amino acid 217 (pTau-217).

6. The method of claim 5, wherein the reduced plasma levels of pTau-217 are detected prior to administration of the compound or pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 6, wherein the subject is diagnosed with Alzheimer’s disease.

8. The method of any one of claims 1 to 6, wherein the subject is diagnosed with mild to moderate cognitive impairment.

9. The method of any one of claims 1 to 8, wherein the compound is administered orally.

10. The method of any one of claims 1 to 9, wherein the compound is administered for about 6 months.

11. The method of any one of claims 1 to 10, wherein the compound is administered for at least about 6 months.

12. The method of any one of claims 1 to 11, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount is about 100 mg.

14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount is about 200 mg.

15. The method of any one of claims 1 to 14, wherein the therapeutically effective amount is about 300 mg.

16. The method of any of claims 12 to 15, wherein the total daily dose is administered for about 6 months.

17. The method of any of claims 12 to 15, wherein the total daily dose is administered for at least about 6 months.

18. The method of any one of claims 1 to 17, wherein administering the compound results in a reduction in the rate of cognitive decline compared to placebo.

19. The method of any one of claims 1 to 18, wherein administering the compound results in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to placebo.

20. The method of any one of claims 1 to 18, wherein administering the compound results in a reduction in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment.

21. The method of any one of claims 1 to 18, wherein administering the compound results in maintenance of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) score compared to the start of treatment.

22. The method of any one of claims 1 to 21, wherein administering the compound results in an improvement in the Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS- ADL) score compared to placebo.

23. The method of any one of claims 1 to 22, wherein administering the compound results in an improvement in the Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS- ADL) score compared to the start of treatment.

24. The method of any one of claims 1 to 22, wherein administering the compound results in maintenance of the Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS- ADL) score compared to the start of treatment.

25. The method of any one of claims 1 to 24, wherein administering the compound results in an improvement in the Clinical Global Impression of Change (CGIC) score compared to placebo.

26. The method of any one of claims 1 to 25, wherein administering the compound results in an improvement in the Clinical Global Impression of Change (CGIC) score compared to the start of treatment.

27. The method of any one of claims 1 to 25, wherein administering the compound results in maintenance of the Clinical Global Impression of Change (CGIC) score compared to the start of treatment.

28. The method of any one of claims 1 to 27, wherein administering the compound results in an improvement in the Neuropsychological Test Battery (NTB) score compared to placebo.

29. The method of any one of claims 1 to 28, wherein administering the compound results in an improvement in the Neuropsychological Test Battery (NTB) score compared to the start of treatment.

30. The method of any one of claims 1 to 28, wherein the administering the compound results in maintenance of the Neuropsychological Test Battery (NTB) score compared to the start of treatment.

31. The method of any one of claims 1 to 30, wherein administering the compound results in an improvement in the Mini-Mental State Examination (MMSE) score compared to placebo.

32. The method of any one of claims 1 to 31, wherein administering the compound results in an improvement in the Mini-Mental State Examination (MMSE) score compared to the start of treatment.

33. The method of any one of claims 1 to 31, wherein administering the compound results in maintenance of the Mini-Mental State Examination (MMSE) score compared to the start of treatment.

34. The method of any one of claims 1 to 33, wherein administering the compound results in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease.

35. The method of any one of claims 1 to 34, wherein administering the compound results in a change in one or more cerebrospinal fluid (CSF) biomarkers associated with Alzheimer's disease compared to the start of treatment.

36. The method of claim 34 or claim 35, wherein the one or more cerebrospinal fluid (CSF) biomarkers are neurofilament light chain (NfL), amyloid beta (Abeta), tau, and phosphorylated tau.

37. The method of claim 36, wherein administration results in a reduction in the concentration of NfL compared to a placebo.

38. The method of claim 36, wherein the administration results in a reduction in the concentration of NfL compared to the start of treatment.

39. The method of claim 37, wherein the Abeta is Abeta 40 or Abeta 42.

40. The method of claim 39, wherein administration results in a reduction in the concentration of Abeta 42 compared to a placebo.

41. The method of claim 39, wherein administration results in a reduction in the concentration of Abeta 42 compared to the start of treatment.

42. The method of any one of claims 1 to 41, wherein administering a therapeutically effective amount of the compound results in a reduction in the Alzheimer’s Disease Assessment Score (ADAS-COG) score of a subject as compared to the ADAS-COG score of the subject compared to the start of treatment.

43. The method of claim 42, wherein administering a therapeutically effective amount of the compound results in at a least 3-point reduction in the Alzheimer’s Disease Assessment Score (ADAS-COG) score of a subject compared to the start of treatment.

44. The method of any one of claims 1 to 43, wherein an incidence of treatment-emergent adverse events (TEAEs) is comparable to placebo.

45. The method of any one of claims 1 to 44, wherein the method further comprises monitoring liver function tests (LFTs) during treatment.

46. The method of claim 45, wherein less than about 20% of patients treated with 300 mg CT 1812 experience LFT elevations >3x upper limit of normal (ULN) for AST or ALT.

47. The method of claim 46, wherein the liver function tests return to normal after cessation of treatment with the compound.

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