Compositions and methods for the treatment of dementia with LEWY bodies

Abstract

The present disclosure provides a method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof. The method improves cognition, activities of daily living, neuropsychiatric symptoms, and motor symptoms in the subject. The compound may be administered orally for about 6 months or longer, with a total daily dose of about 100 mg to about 300 mg. The method results in improvements in various assessment scales including Montreal Cognitive Assessment Scale (MOCA), Cognitive Drug Research Battery (CDR), Clinician Assessment of Fluctuation (CAF), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Unified Parkinson's Disease Rating Scale (UPDRS).

Description

Attorney Docket No. 134851-003002COMPOSITIONS AND METHODS FOR THE TREATMENT OF DEMENTIA WITH LEWY BODIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims priority to U.S. Provisional Application No. 63 / 735,835 filed on December 18, 2024 and U.S. Provisional Application No. 63 / 736,854 filed on December 20, 2024, each of which are incorporated herein by reference in their entireties.FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] The invention described herein was made with government support under Grant No. AG071643 awarded by the National Institutes of Health. The government has certain rights in the invention.SUMMARY OF THE INVENTION

[0003] In aspects of the present disclosure, the techniques described herein relate to a method of treating Dementia with Lewy Bodies (DLB) in a subject, including administering to the subject a therapeutically effective amount of a compound of structure(Compound I) or a pharmaceutically acceptable salt thereof, wherein administration results in treatment of the DLB.

[0004] In aspects of the present disclosure, the techniques described herein relate to a method of inducing cognitive preservation in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt, wherein administration results in cognitive preservation in the subject with DLB.

[0005] In aspects of the present disclosure, the techniques described herein relate to a method of treating Dementia with Lewy Bodies (DLB) in a subject, including administering to the subject a therapeutically effective amount of a compound of formula Compound I, wherein the administration results in an improvement or maintenance of a Global Treatment Endpoint (GTE) score in the subject.Attorney Docket No. 134851-003002

[0006] In aspects of the present disclosure, the techniques described herein relate to a method of improving or maintaining a Global Treatment Endpoint (GTE) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I, wherein the administration results in an improvement or maintenance of a GTE score in the subject with DLB.

[0007] In aspects of the present disclosure, the techniques described herein relate to a method of improving cognition in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0008] In aspects of the present disclosure, the techniques described herein relate to a method of improving activities of daily living in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0009] In aspects of the present disclosure, the techniques described herein relate to a method of reducing neuropsychiatric symptoms in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0010] In aspects of the present disclosure, the techniques described herein relate to a method of reducing motor symptoms in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0011] In aspects of the present disclosure, the techniques described herein relate to a method of reducing caregiver distress associated with a subject having Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0012] In aspects of the present disclosure, the techniques described herein relate to a method of improving Montreal Cognitive Assessment (MOCA) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0013] In aspects of the present disclosure, the techniques described herein relate to a method of improving Cognitive Drug Research Battery (CDR) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.Attorney Docket No. 134851-003002

[0014] In aspects of the present disclosure, the techniques described herein relate to a method of improving Clinician Assessment of Fluctuation (CAF) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0015] In aspects of the present disclosure, the techniques described herein relate to a method of improving Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS- ADL) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0016] In aspects of the present disclosure, the techniques described herein relate to a method of improving Neuropsychiatric Inventory (NPI) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0017] In aspects of the present disclosure, the techniques described herein relate to a method of reducing anxiety in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0018] In aspects of the present disclosure, the techniques described herein relate to a method of reducing hallucinations in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0019] In aspects of the present disclosure, the techniques described herein relate to a method of reducing delusions in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0020] In aspects of the present disclosure, the techniques described herein relate to a method of improving Unified Parkinson's Disease Rating Scale (UPDRS) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF DRAWINGS

[0021] FIG. 1A depicts effect of CT1812 treatment on episodic memory.

[0022] FIG. IB depicts effect of CT1812 treatment on fluctuating confusion Clinician Assessment of Fluctuation (CAF).Attorney Docket No. 134851-003002

[0023] FIG. 1C depicts effect of CT1812 treatment on Neuropsychiatric Inventory (NPI) Total A-J scale.

[0024] FIG. ID depicts effect of CT1812 treatment on Neuropsychiatric Inventory (NPI) Total A-J Distress scale.

[0025] FIG. IE depicts effect of CT1812 treatment on the Montreal Cognitive Assessment Test (MOCA).

[0026] FIG. IF depicts effect of CT 1812 treatment on Alzheimer’s Disease Cooperative Study- Activities of Daily Living scale (ADCS-ADL).

[0027] FIG. 1G depicts effect of CT 1812 treatment on Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor).

[0028] FIG. 1H depicts effect of CT1812 treatment on Alzheimer’s Disease CooperativeStudy- Clinical Global Impression of Change (ADCS-CGIC).

[0029] FIG. 2 depicts the effect of CT1812 treatment on Clinical Dementia Ratings (CDR) episodic memory.

[0030] FIG. 3 depicts the effect of CT1812 treatment on Clinical Dementia Ratings (CDR) quality of memory.

[0031] FIG. 4 depicts effect of CT1812 treatment on the Montreal Cognitive Assessment Test (MOCA).

[0032] FIG. 5 depicts effect of CT 1812 treatment on fluctuating confusion Clinician Assessment of Fluctuation (CAF).

[0033] FIG. 6 depicts effect of CT 1812 treatment on Alzheimer’s Disease Cooperative Study- Activities of Daily Living scale (ADCS-ADL).

[0034] FIG. 7 depicts effect of CT1812 treatment on Neuropsychiatric Inventory (NPI) Total A-J scale.

[0035] FIG. 8 depicts effect of CT1812 treatment on Neuropsychiatric Inventory (NPI) Total A-J Distress scale.

[0036] FIG. 9 depicts effect of CT1812 treatment on Neuropsychiatric Inventory (NPI) Total A-J scale.

[0037] FIG. 10 depicts effect of CT1812 treatment on Neuropsychiatric Inventory (NPI) Total A-J Distress scale.

[0038] FIG. 11 depicts effect of CT1812 treatment on Unified Parkinson's Disease RatingScale (UPDRS).

[0039] FIG. 12 depicts effect of CT1812 treatment on Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC).Attorney Docket No. 134851-003002

[0040] FIG. 13 depicts rating frequency distribution of CT 1812 treatment on the Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC).

[0041] FIG. 14 depicts the correlation of MOCA and CDR-QM scores at baseline.

[0042] FIG. 15 depicts the strength of the correlation of each GTE component.

[0043] FIG. 16A depicts the correlation of the baseline composite score to baseline ADCS-ADL score.

[0044] FIG. 16B depicts the correlation of the day 182 composite score to the day 182 ADCS-ADL score.

[0045] FIG. 17 depicts the composite GTE scores in each study group over time.DETAILED DESCRIPTION OF THE INVENTION

[0046] 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, or methodologies 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.

[0047] 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

[0048] 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.

[0049] 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 %.Attorney Docket No. 134851-003002

[0050] “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.

[0051] 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.

[0052] 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.

[0053] 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 describe a 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.

[0054] 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.

[0055] 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 non-sigma 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 PrusoffAttorney Docket No. 134851-003002(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.

[0056] 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 150 nM, 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.

[0057] 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 Aft-induced membrane trafficking deficits; (ii) it blocks or reduces Af3- 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.

[0058] 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.

[0059] 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.

[0060] “Abeta species” or “AP” or “Abeta” or “Amyloid beta” shall include compositions comprising soluble amyloid peptide-containing components such as Abeta monomers, AbetaAttorney Docket No. 134851-003002 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 Apoligomers are known to be neurotoxic. Even A [3 1- 42 dimers are known to impair synaptic plasticity in mouse hippocampal slices. In one theory known in the art, native Ap 1-42 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., P-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 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, each of which is incorporated herein by reference.

[0061] “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.

[0062] 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.

[0063] 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.

[0064] As used herein, the term "Global Treatment Endpoint (GTE) score" refers to a composite measure derived using global statistical test (GST) methodology to assess overall treatment response in subjects with Dementia with Lewy Bodies (DLB). The GTE score incorporates multiple domains of DLB symptomatology, including neuropsychiatric symptoms, cognition, cognitive fluctuations, and motor function. In some embodiments, the GTE score is derived from the following component assessments: Neuropsychiatric Inventory 4-item version (NPI-4), which assesses anxiety, agitation / aggression, delusions, and hallucinations; Cognitive Drug Research Battery-Quality of Memory subscore (CDR-QM); Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS3); and Clinician Assessment of Fluctuation (CAF). In certain aspects, the GTE score may further incorporate the Alzheimer's Disease Cooperative Study -Attorney Docket No. 134851-003002Activities of Daily Living (ADCS-ADL) as an additional component. The GTE score is calculated by converting the change from baseline for each component assessment into a z-score using pooled standard deviations, and then averaging the z-scores across the different components. In some embodiments, the components are equally weighted. The GTE score provides a comprehensive evaluation of a subject's overall clinical status and response to treatment across the diverse and variable symptomatology characteristic of DLB. Changes in the GTE score over time may be used to assess treatment efficacy, with improvements or maintenance of the score indicating a positive treatment response.

[0065] As used herein, "Neuropsychiatric Inventory - Clinician version (NPI-C)" refers to a clinician-administered version of the Neuropsychiatric Inventory that assesses neuropsychiatric symptoms in patients with dementia, where the 4-item version (NPI-C-4) may specifically evaluate anxiety, agitation / aggression, delusions, and hallucinations.

[0066] As used herein, "Scale for the Assessment of Positive Symptoms in Parkinson's Disease (SAPS-PD)" refers to an assessment tool designed to evaluate positive psychotic symptoms, including hallucinations and delusions, in patients with Parkinson's disease and related disorders including DLB.

[0067] As used herein, the term "Integrated Alzheimer's Disease Rating Scale (iADRS)" refers to a composite outcome measure that combines cognitive assessment scores with functional assessment scores to provide an integrated measure of disease progression.

[0068] As used herein, the term "Clinical Dementia Rating - Sum of Boxes (CDR-SB)" refers to a quantitative measure derived from the Clinical Dementia Rating scale that sums scores across six domains (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care) to provide a continuous measure of dementia severity.

[0069] As used herein, the term "Timed Up and Go (TUG) test" refers to a clinical assessment of functional mobility that measures the time required for a subject to rise from a seated position, walk a predetermined distance, turn around, return to the chair, and sit down.

[0070] As used herein, the term "Agitation" refers to a state of excessive motor activity, verbal aggression, or physical aggression that may occur in patients with dementia and may be associated with distress or functional impairment.

[0071] As used herein, the term "Aggression" refers to hostile or violent behavior that may be verbal or physical in nature and may occur in patients with dementia as a neuropsychiatric symptom.

[0072] 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) suchAttorney Docket No. 134851-003002 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.

[0073] 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 that when a disease state is "improved" the symptoms or physical characteristics associated with the disease state are diminished, reduced, eliminated, delayed or averted. In the context of progressive neurodegenerative disorders such as Dementia with Lewy Bodies (DLB), where continual decline in cognitive, motor, neuropsychiatric, and functional abilities is expected, the term "improves" may also encompass the slowing, stabilization, or maintenance of symptom severity relative to placebo or expected disease progression. Accordingly, in such disorders, maintenance of a similar level of symptoms over time, a reduced rate of decline compared to untreated subjects, or preservation of function that would otherwise be lost may constitute an improvement in the disease state.

[0074] 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.

[0075] 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% maximumAttorney Docket No. 134851-003002 inhibition of the Abeta oligomer effects of soluble Abeta oligomer-induced membrane trafficking deficits, for example, as described in Example 6.

[0076] 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 / [solute]un-ionized, water).

[0077] 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 “Cl -6 alkyl” is specifically intended to individually disclose e.g. methyl (Cl alkyl), ethyl (C2 alkyl), C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl as well as, e.g. C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C2-C3 alkyl, C2-C4 alkyl, C3-C6 alkyl, C4-C5 alkyl, and C5-C6 alkyl.

[0078] 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.

[0079] 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.

[0080] As used herein, the term “CT1812” is synonymous with “Compound I” with a structure

[0081] 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,Attorney Docket No. 134851-003002 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).

[0082] 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.

[0083] As used herein, “alkynyl” refers to an alkyl group having one or more triple carbon-carbon 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.

[0084] 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, CC13, CHC12, C2C15, CH2CF3, and the like.

[0085] 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.

[0086] 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 ringforming 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, norbomyl, 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 lH-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

[0087] 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 moreAttorney Docket No. 134851-003002 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 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0088] 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 ring-forming S atom can be substituted by 1 or 2 oxo [i.e., form a S(O) or S(O)2], For another example, a ringforming 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., having a 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-1- 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.Attorney Docket No. 134851-003002

[0089] As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

[0090] 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.

[0091] 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, - OCC1F2, -OCC13, and the like.

[0092] As used herein, “arylalkyl” refers to a Cl -6 alkyl substituted by aryl and “cycloalkylalkyl” refers to Cl -6 alkyl substituted by cycloalkyl.

[0093] As used herein, “hetero arylalkyl” refers to a Cl -6 alkyl group substituted by a heteroaryl group, and “heterocycloalkylalkyl” refers to a Cl -6 alkyl substituted by heterocycloalkyl.

[0094] As used herein, “amino” refers to NH2.

[0095] As used herein, “alkylamino” refers to an amino group substituted by an alkyl group.

[0096] As used herein, “dialkylamino” refers to an amino group substituted by two alkyl groups.

[0097] As used here, C(O) refers to C(=O).

[0098] 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.

[0099] 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 traffickingAttorney Docket No. 134851-003002 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.

[0100] 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 (seeAttorney Docket No. 134851-003002 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.

[0101] As used herein, the term “a neuronal cell” referd 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, which are 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.

[0102] 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,Attorney Docket No. 134851-003002 methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1’- 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.

[0103] 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.

[0104] 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 pathological process. 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.

[0105] 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 typicallyAttorney Docket No. 134851-003002 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 a compound according to Formula I, and / or Formula II, or a pharmaceutically acceptable salt thereof, per day in single or multiple doses.

[0106] 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 (i.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.

[0107] Generally speaking, the term “tissue” refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.

[0108] As used herein, “cognitive decline” is any negative change in an animal’s cognitive function. 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;Attorney Docket No. 134851-003002 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 mild Alzheimer’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 (PCAD); and Cognitive Impairment No Dementia (CIND).

[0109] 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.

[0110] "Dementia with Lewy Bodies (DLB)" is defined as a progressive neurodegenerative disorder characterized by cognitive decline, visual hallucinations, fluctuating cognition, and parkinsonism.

[0111] 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.

[0112] 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.Attorney Docket No. 134851-003002

[0113] 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.

[0114] 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.

[0115] As used herein, a "fumarate salt" may refer to a salt formed between the active compound and fumaric acid, which may possess desirable pharmacological or physicochemical properties.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.Attorney Docket No. 134851-003002

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] "Activities of daily living" are routine self-care activities that individuals tend to do every day without needing assistance, including tasks related to personal care, basic communication, and basic mobility.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] "Neuropsychiatric symptoms" include a range of non-cognitive symptoms associated with brain disorders, such as hallucinations, delusions, anxiety, and changes in mood or behavior.

[0134] "Motor symptoms" refer to physical manifestations related to movement disorders, including tremor, rigidity, bradykinesia, and postural instability.Attorney Docket No. 134851-003002

[0135] "Caregiver distress" is defined as the physical, emotional, and mental strain or stress that results from caring for an individual with a chronic illness or disability.

[0136] "Montreal Cognitive Assessment (MOCA)" is a rapid screening instrument for mild cognitive dysfunction, assessing various cognitive domains including attention, concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation.

[0137] "Cognitive Drug Research Battery (CDR)" is a computerized cognitive assessment system designed to evaluate various aspects of cognitive function.

[0138] Clinician Assessment of Fluctuation (CAF)" is a scale used to measure the severity and frequency of cognitive fluctuations in dementia patients.

[0139] "Neuropsychiatric Inventory (NPI)" is a comprehensive assessment of psychopathology in patients with brain disorders, evaluating various neuropsychiatric symptoms.

[0140] "Unified Parkinson's Disease Rating Scale (UPDRS)" is a rating tool used to gauge the course of Parkinson's disease, including assessments of mental functioning, behavior, mood, activities of daily living, and motor function.

[0141] "Hoehn and Y ahr stage" refers to a widely used clinical rating scale for Parkinson's disease, describing the progression of motor symptoms.

[0142] "Apolipoprotein E4 genotype" refers to a specific genetic variant associated with increased risk for Alzheimer's disease and potentially other forms of dementia.

[0143] "Amyloid probability score 2 (APS2)" is a measure used to assess the likelihood of amyloid pathology in the brain.

[0144] "Plasma pTau217 / Tau217 ratio" is a biomarker measurement used to assess tau pathology, which is associated with various neuro degenerative disorders.

[0145] "Epworth Sleepiness Scale (ESS)" is a self-administered questionnaire used to measure daytime sleepiness.

[0146] "Quality of Memory composite score" is a measure derived from cognitive tests to assess overall memory function.

[0147] "Quality of Working Memory composite score" is a measure derived from cognitive tests to assess working memory function.

[0148] "Quality of Episodic Secondary Memory composite score" is a measure derived from cognitive tests to assess episodic and secondary memory functions.

[0149] 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.Attorney Docket No. 134851-003002

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] Human amyloid beta

[0155] 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.

[0156] 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 beta oligomers, J. Neurosci. 2004, 24(45): 10191- 10200.

[0157] 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 present in 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 0 oligomers have been demonstrated to induce changes in neuronal synapses that block learning and memory.

[0158] Smaller, soluble A[3 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.Attorney Docket No. 134851-003002

[0159] The presence of soluble A[3 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.

[0160] Sigma-2 Receptors

[0161] 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).

[0162] 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.

[0163] 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 in August 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 SI protein; family members include PGRMC2 and neudesin. PGRMC1 contains a cytochrome b5 heme-binding domain. Endogenous PGRMC1 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). PGRMC1 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 homologAttorney Docket No. 134851-003002VEM1 associates with UNC-40 / DCC to mediate axon guidance. PGRMC1 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. PGRMC1 contains several ITAM sequences involved in membrane trafficking (vesicle transport, clathrin-dependent endocytosis of calveolin-containing pits).

[0164] 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.

[0165] Sigma-2 Antagonists

[0166] 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 for soluble 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.

[0167] 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 neuronalAttorney Docket No. 134851-003002 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.

[0168] 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 Ap 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.

[0169] 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.

[0170] 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 therapeutic phenotype. It is now disclosed that a selective sigma-2 antagonist having a therapeutic phenotype, can block Abeta oligomer-induced synaptic dysfunction.

[0171] 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 antagonistsAttorney Docket No. 134851-003002 compete with Abeta oligomers, and / or stop pathological sigma receptor signaling, that leads to Alzheimer’s disease.

[0172] 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).

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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 otherAttorney Docket No. 134851-003002 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.

[0177] 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.

[0178] 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 11 / 2 > 5 min, > 10 min, > 15 minutes, > 20 minutes, and preferably > 30 min upon exposure of a 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.

[0179] 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.

[0180] Table 1. Disclaimed Compounds.Attorney Docket No. 134851-003002Attorney Docket No. 134851-003002

[0181] 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.

[0182] 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 (against 3H-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.

[0183] 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.

[0184] In some embodiments, the sigma-2 antagonists, are designed to enhance the ability to cross the blood-brain barrier.

[0185] In some embodiments, the specific sigma-2 receptor antagonist compound blocks binding between soluble Abeta oligomers and a sigma-2 receptor.

[0186] In some embodiments, the sigma-2 antagonist compound exhibits high affinity for the sigma-2 receptor.

[0187] Sigma-2 Receptor Ligands for Selection as Sigma-2 Receptor Antagonists

[0188] 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 AB oligomer inducedAttorney Docket No. 134851-003002 synapse loss, and inhibiting soluble AB 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.

[0189] 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. PCI7US2010 / 044136), WO 2010 / 118055 (Application No. PCI7US2010 / 030130), Application No. PCI7US2011 / 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.

[0190] COMPOUNDS

[0191] In some embodiments, the sigma-2 ligand comprises a compound of Formula I:

[0192] or a pharmaceutically acceptable salt thereof, wherein:

[0193] each of R1 and R2 is independently selected from H, C1-C6 alkyl, or CH2OR'; wherein each R' if present in Rl, and R2 is independently H or C1-C6 alkyl;

[0194] each of R3, R4, R5, and R6 is independently selected from the group consisting of H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, Cl -6 alkoxy Cl-6alkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, CO2R’, C(O)R’, NH(Cl-4 alkyl), N(Cl-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(Cl-4 alkyl), CONR’2, NC(O)R’, NS(O)nR’, S(O)nNR’2, S(O)nR’, C(O)O(Cl-4 alkyl), OC(O)N(R’)2, C(O) (Cl-4 alkyl), and C(O)NH(Cl-4 alkyl); wherein each R' if present in R3, R4, R5, and R6 is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl,Attorney Docket No. 134851-003002C1-C6 haloalkyl; optionally substituted aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, Cl -6 alkoxy, NH(Cl-4 alkyl), and N(Cl-4 alkyl)2, wherein the optionally substituted group is selected from C1-C6 alkyl or C2-C7 acyl;

[0195] 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, Cl -6 alkyl, Cl -6 haloalkyl, Cl -6 alkoxy, Cl -6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R3 and R4 are linked together to form a -O-Cl- 2 methylene-O- group;

[0196] 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, Cl -6 alkyl, Cl -6 haloalkyl, Cl -6 alkoxy, Cl -6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R4 and R5 are linked together to form a -O-Cl-2 methylene-O- group;

[0197] each of R7, R8, R9, RIO, and Rl l is independently selected from the group consisting of H, C1-C6 alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6 alkyl), OCF3, OCH2CH2OH, O(C1-C6 alkyl)OH, O(C1-C6 haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, Cl -6 alkoxy Cl-6alkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(Cl-4 alkyl), N(Cl-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(Cl-4 alkyl), CONR’2, NC(O)R’, NS(O)nR’, S(O)nNR’2, S(O)nR', C(O)O(Cl-4 alkyl), OC(O)N(R’)2, C(O) (Cl -4 alkyl), and C(O)NH(Cl-4 alkyl); wherein each R' if present in R7, R8, R9, RIO, and R11 is independently selected from the group consisting of H, CH3, CH2CH3, C3-C6 alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, Cl -6 alkoxy, NH(Cl-4 alkyl), or N(Cl-4 alkyl)2;

[0198] or R7 and R8, 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, Cl -6 alkyl, Cl -6 haloalkyl, Cl -6 alkoxy, Cl -6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R7 and R8 are linked together to form a -O-Cl- 2 methylene-O- group;

[0199] or R8 and R9, 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,Attorney Docket No. 134851-003002 amino, halo, Cl -6 alkyl, Cl -6 haloalkyl, Cl -6 alkoxy, Cl -6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R8 and R9 are linked together to form a -O-Cl- 2 methylene-O- group;

[0200] each n is independently 0, 1, or 2;

[0201] with the proviso that R7, R8, R9, R10, and R11 are not all H; and

[0202] with the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:

[0203] In some embodiments, the sigma-2 ligand comprises a racemic mixture or an enantiomer of compound of Formula I, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are as described above.

[0204] In some embodiments, an isolated compound is provided according to Formula I:

[0206] or a pharmaceutically acceptable salt thereof, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, and Rl 1 are as defined herein, with the proviso that when Rl, R3, R6, R7, R10 and Rl 1 are each H; R2 is CH3; R8 is OCH3 or Cl; and R9 is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3.

[0207] In other embodiments, an isolated compound, or composition thereof, or method comprising administration of, is provided according to Formula I:Attorney Docket No. 134851-003002

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, and Rl l are as defined herein, with the proviso that a compound according to Formula I wherein Rl, R3, R6, R7, R10 and Rl 1 are each H; R2 is CH3; R8 is OCH3 or Cl; and R9 is OH or Cl; R4 is Cl or CF3, and R5 is Cl or CF3, is not a preferred compound.

[0210] 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:

[0211]

[0212] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, and R11 are as defined herein, with the proviso that when Rl, R3, R6, R7, RIO and Rl 1 are each H; R2 is CH3; R8 is OCH3 or Cl; and R9 is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3.

[0213] 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:

[0214]

[0215] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, and Rl 1 are as defined herein, with the proviso that when Rl, R3, R6, R7, R10 and Rl 1 are each H; R2 is CH3; R8 is OCH3 or Cl; and R9 is 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.Attorney Docket No. 134851-003002

[0216] In some embodiments, the sigma-2 ligand comprises a racemic mixture or an enantiomer of compound of Formula II:

[0217]

[0218] wherein R3, R4, R5, R6, R8, and R9 are as described herein.

[0219] In another embodiment, a compound, or pharmaceutically acceptable salt thereof, is provided according to Formula III, wherein R3, R4, R5, R6, R7, R8, R9, RIO and Rl l are as provided herein and wherein each - is independently selected from a single, double or triple bond.

[0220]

[0221] In some aspects, a compound according to Formula III is selected from:or a pharmaceutically acceptable salt thereof.

[0222] In any embodiment of the present disclosure, a compound according to the structure(Compound I or CT 1812) may be used.

[0223] In some embodiments, the sigma-2 ligand comprises a racemic mixture or an enantiomer of a compound of Formula I, wherein R3, R4, R5, R6, R8, and R9 are as described herein.

[0224] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R8 and R9 is independently selected from the group consisting of OH, Cl -6 alkoxy, and hydroxy Cl -6 alkoxy.Attorney Docket No. 134851-003002

[0225] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R8 and R9 is independently selected from OH or NH(C1- 4 alkyl).

[0226] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R8 and R9 is independently selected from the group consisting of H, halo, Cl -6 haloalkyl, and Cl -6 haloalkoxy.

[0227] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R8 and R9 is independently selected from the group consisting of OH, halo, Cl -6 alkoxy and Cl -6 haloalkoxy and each R1 and R2 is independently Cl- 6 alkyl.

[0228] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein R1 and R2 are each methyl.

[0229] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein one of R1 and R2 is methyl and the other is H.

[0230] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each of R8 and R9 is independently selected from the group consisting of OH and Cl -6 alkoxy and R1 and R2 are each independently methyl.

[0231] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each of R8 and R9 is independently selected from H, halo, and Cl -6 haloalkyl, and R1 and R2 are each methyl.

[0232] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each of R8 and R9 is independently selected from H, halo and Cl - 6 haloalkyl.

[0233] 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.

[0234] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4, R5, and R6 is independently selected from the group consisting of H, halo, Cl - 6 alkyl, Cl - 6 haloalkyl and Cl -6 alkoxy.

[0235] 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, Cl - 6 alkyl, Cl - 6 haloalkyl and Cl -6 alkoxy.

[0236] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R3, R4, R5, and R6 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 presentAttorney Docket No. 134851-003002 in R3, R4, R5, and R6 is independently selected from the group consistingof H, CH3, CH2CH3, C3- C6 alkyl, C1-C6 haloalkyl, or optionally C1-C6 alkyl or C2-C7 acyl substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocycloalkyl, and heteroaryl; and n is 2.

[0237] 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, R5, and R6 is independently selected from the group consisting of CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin- 1-yl, piperidin-1- yl, and morpholinyl-4-yl; and where n is 2.

[0238] 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, R5, and R6 is independently selected from the group consisting of CH3, CH2CH3, C3-C6 alkyl, aryl, piperazin- 1-yl, piperidin-1- yl, and morpholinyl-4-yl; each R8 and R9 is independently selected from the group consisting of OH, halo, Cl -6 alkoxy and Cl -6 haloalkoxy; R1 and R2 are each methyl; and n is 2.

[0239] 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 R5 together with the C atom to which they are attached form a 6-membered cycloalkyl, or a heterocycloalkyl, aryl or heteroaryl ring.

[0240] 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 R5 are O, and are linked together to form a -O-Cl-2 methylene-O- group.

[0241] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R2 and R3 is independently selected from the group consisiting of H, OH, halo, Cl -6 alkoxy and Cl -6 haloalkyl.

[0242] 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 group consisting of H, Cl, F, -OMe, -CF3, S(O)nR', and C(O)R’; wherein each R' if present in R7, R8, R9, R10, 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 R8 and R9 is independently selected from OH or Cl -6 alkoxy; and n is 2.

[0243] In some embodiments, the sigma-2 ligand is a compound or a pharmaceutically acceptable salt of Formula I, wherein each R2 and R3 is independently selected from the group consisting of H, OH, Cl, F, -OMe, and -CF3, each R7 and R8 is independently selected from H or Cl -6 alkyl, R9 is H, and each R5 and R6 is independently selected from H or Cl -6 haloalkyl.Attorney Docket No. 134851-003002

[0244] Preferred salts for use in the disclosure include the hydrochloride salts of the above compounds.

[0245] 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.

[0246] In some embodiments, each of the general formulae above may contain a proviso to remove one or more of the following compounds:

[0247] 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.

[0248] 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 acceptorAttorney Docket No. 134851-003002 group can also be present in or near a hydrophobic aliphatic group. For example, a tetrahydro furan group comprises both a hydrogen bond acceptor group and a hydrophobic aliphatic group. The oxygen present in the tetrahydrofuran ring acts as a hydrogen bond acceptor and the carbons in the tetrahydro furan ring act as the hydrophobic aliphatic group.

[0249] 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.

[0250] 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 cycloheteroalkyl 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

[0251] 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.

[0252] 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.

[0253] Salts, solvates, stereoisomers, derivatives, prodrugs and active metabolites of the novel compounds.

[0254] The disclosure further encompasses salts, solvates, stereoisomers, prodrugs and active metabolites of the compounds of any of the formulae above.

[0255] 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 derivedAttorney Docket No. 134851-003002 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).

[0256] 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 solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the disclosure.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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 conventionalAttorney Docket No. 134851-003002 manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.

[0261] 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.

[0262] 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.

[0263] 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 are precipitated 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.).

[0264] The disclosure also encompasses N-oxides of the compounds of formulas I. The term "N-oxide" means that for heterocycles containing an otherwise unsubstituted sp2 N atom, the N atom may bear a covalently bound O atom, i.e., -NDO. Examples of such N-oxide substituted heterocycles include pyridyl N-oxides, pyrimidyl N-oxides, pyrazinyl N-oxides and pyrazolyl N- oxides.

[0265] 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 theAttorney Docket No. 134851-003002 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:

[0266] % ee = (R) - (S) / (R) + (S)

[0267] 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:

[0268] Optical purity = enant. major / (enant. major + enant. minor)

[0269] 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.

[0270] 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.

[0271] 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.Attorney Docket No. 134851-003002

[0272] 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.

[0273] 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. The two resulting diastereomeric products can then be separated. The separated diastereomers are then reconverted to the pure enantiomers by reversing the initial chemical transformation.

[0274] 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.

[0275] 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.

[0276] D-phenylglycine and L-leucine are examples of Type I CSPs and use combinations of n- n 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: n -acid or 71 -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.Attorney Docket No. 134851-003002

[0277] 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.

[0278] 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; and diastereomer 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.

[0279] 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).

[0280] 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).

[0281] 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).Attorney Docket No. 134851-003002

[0282] 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.

[0283] 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 pharmacologically active 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).

[0284] 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.

[0285] 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.

[0286] 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 themAttorney Docket No. 134851-003002 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.

[0287] Routes of Administration and Unit Dosage Forms

[0288] 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.

[0289] 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, see for example FIG. 12B. 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 delivery In 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.

[0290] 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,Attorney Docket No. 134851-003002Mack 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).

[0291] 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 mini-pump 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.

[0292] 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, Gokam 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 mM 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..

[0293] 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. TheAttorney Docket No. 134851-003002 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 acid copolymers, 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.

[0294] 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 may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

[0295] 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.

[0296] 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.

[0297] 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 intermediateAttorney Docket No. 134851-003002 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 suitable mixtures 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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 alsoAttorney Docket No. 134851-003002 contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

[0303] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably com, 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.

[0304] Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] Examples of pharmaceutically acceptable lubricants useful in the compositions of the disclosure include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymersAttorney Docket No. 134851-003002 of ethylene oxide, sodium lauryl sulphate, magnesium lauryl sulphate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.

[0310] 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.

[0311] 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.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulphate and polysorbates.

[0316] 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.

[0317] 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, trichlorofluoromethane, 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 pressurizedAttorney Docket No. 134851-003002 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.

[0318] 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.

[0319] For topical administration by inhalation the compounds according to the disclosure may be delivered for use in human or veterinary medicine via a nebulizer.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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 units or 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.Attorney Docket No. 134851-003002

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] Synthesis of the Compounds

[0330] 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.

[0331] 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.Attorney Docket No. 134851-003002

[0332] 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.

[0333] Patients with Dementia with Lewy Bodies

[0334] The patient population for which Compound I is administered includes subjects diagnosed with Dementia with Lewy Bodies (DLB). In some embodiments, subjects have a mean time since DLB diagnosis of about 1 to about 2 year. In some embodiments, subjects have a mean time since DLB diagnosis ranging from about 6 months to about 10 years. In some aspects, the mean time since diagnosis may be about 1 to 5 years. In other aspects, it may be about 2 to 3 years. The time since diagnosis can vary widely among individual patients.

[0335] Subjects present with various cognitive and functional characteristics before administration of Compound I. In some cases, subjects have a mean Mini-Mental State Examination (MMSE) score of about 24. 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. 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. (mild cognitive decline) In some embodiments, the subject has an MMSE score greater than, or equal to 24.

[0336] In some embodiments, subjects have a Montreal Cognitive Assessment Scale (MOCA) mean score of about 18.4. In some embodiments, subjects have a Montreal Cognitive Assessment Scale (MOCA) mean score ranging from about 10 to about 26. In some aspects, the MOCA mean score is between about 14 and about 22. In other aspects, subjects have a MOCA mean score of about 16 to about 20. The MOCA score varies among individual patients. In some cases, subjects with a MOCA score as low as 8 or as high as 28 are included in the patient population. The MOCA score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. In some embodiments, subjects are categorized based on their MOCA scores. For instance, subjects with MOCA scores between 18 and 26 are classified as having mild cognitive impairment, while those with scores between 10 and 17 are classified as having moderate cognitive impairment. The MOCA score is used in combination with other cognitive assessments to provide a comprehensive evaluation of a subject's cognitive status. In some aspects, changes in MOCA scores over time are used to assess the efficacy of Compound I treatment.Attorney Docket No. 134851-003002

[0337] Cognitive function is further characterized by additional measures. In some cases, subjects have a Quality of Memory composite score of about 177.6 before administration of Compound I. In some embodiments, subjects have a Quality of Memory composite score ranging from about 150 to about 200 before administration of Compound I. In some aspects, the Quality of Memory composite score is between about 160 and about 190. In other embodiments, subjects have a Quality of Memory composite score of about 170 to about 185. The Quality of Memory composite score can vary among individual patients. In some cases, subjects with a Quality of Memory composite score as low as 140 or as high as 210 are included in the patient population. In certain embodiments, the Quality of Memory composite score ranges from about 165 to about 195 before administration of Compound I.

[0338] In some embodiments, subjects have a Quality of Working Memory composite score of about 1.1 before administration of Compound I. In some embodiments, subjects have a Quality of Working Memory composite score ranging from about 0.8 to about 1.4 before administration of Compound I. In certain aspects, the Quality of Working Memory composite score is between about 0.9 and about 1.3. In other embodiments, subjects have a Quality of Working Memory composite score of about 1.0 to about 1.2. The Quality of Working Memory composite score varies among individual patients. In some cases, subjects with a Quality of Working Memory composite score as low as 0.6 or as high as 1.6 are included in the patient population. In particular embodiments, the Quality of Working Memory composite score ranges from about 0.7 to about 1.5 before administration of Compound I. In some aspects, subjects are categorized based on their Quality of Working Memory composite scores. For instance, subjects with scores between 0.8 and 1.0 are classified as having mild working memory impairment, while those with scores between 0.6 and 0.7 are classified as having moderate working memory impairment. The Quality of Working Memory composite score is used in combination with other cognitive assessments to provide a comprehensive evaluation of a subject's cognitive status. Changes in Quality of Working Memory composite scores over time are used to assess the efficacy of Compound I treatment.

[0339] In some embodiments, subjects have a Quality of Episodic Secondary Memory composite score of about 67.1 before administration of Compound I. In some embodiments, subjects have a Quality of Episodic Secondary Memory composite score ranging from about 50 to about 85 before administration of Compound I. In certain aspects, the Quality of Episodic Secondary Memory composite score is between about 60 and about 75. In other embodiments, subjects have a Quality of Episodic Secondary Memory composite score of about 65 to about 70. The Quality of Episodic Secondary Memory composite score varies among individual patients. In some cases, subjects with a Quality of Episodic Secondary Memory composite score as low as 40 or as high as 90 are includedAttorney Docket No. 134851-003002 in the patient population. In particular embodiments, the Quality of Episodic Secondary Memory composite score ranges from about 55 to about 80 before administration of Compound I. In some aspects, subjects are categorized based on their Quality of Episodic Secondary Memory composite scores. For instance, subjects with scores between 65 and 75 are classified as having mild episodic memory impairment, while those with scores between 50 and 64 are classified as having moderate episodic memory impairment. The Quality of Episodic Secondary Memory composite score is used in combination with other cognitive assessments to provide a comprehensive evaluation of a subject's cognitive status. Changes in Quality of Episodic Secondary Memory composite scores over time are used to assess the efficacy of Compound I treatment.

[0340] Functional abilities are assessed using various scales. The Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score is about 62.2 in some subjects before administration. In some embodiments, subjects have an Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score ranging from about 50 to about 75 before administration of Compound I. In certain aspects, the ADCS-ADL score is between about 55 and about 70. In other embodiments, subjects have an ADCS-ADL score of about 58 to about 66. The ADCS-ADL score varies among individual patients. In some cases, subjects with an ADCS-ADL score as low as 45 or as high as 80 are included in the patient population. In particular embodiments, the ADCS-ADL score ranges from about 60 to about 65 before administration of Compound I. In some aspects, subjects are categorized based on their ADCS-ADL scores. For instance, subjects with scores between 60 and 70 are classified as having mild functional impairment, while those with scores between 50 and 59 are classified as having moderate functional impairment. The ADCS-ADL score is used in combination with other functional assessments to provide a comprehensive evaluation of a subject's ability to perform activities of daily living. Changes in ADCS-ADL scores over time are used to assess the efficacy of Compound I treatment in improving or preserving functional abilities in subjects with Dementia with Lewy Bodies.

[0341] The Clinical Assessment of Fluctuation (CAF) severity score is about 5.0 in some cases. In some embodiments, subjects have a Clinical Assessment of Fluctuation (CAF) severity score ranging from about 2.0 to about 8.0 before administration of Compound I. In certain aspects, the CAF severity score is between about 3.0 and about 7.0. In other embodiments, subjects have a CAF severity score of about 4.0 to about 6.0. The CAF severity score varies among individual patients. In some cases, subjects with a CAF severity score as low as 1.0 or as high as 9.0 are included in the patient population. In particular embodiments, the CAF severity score ranges from about 4.5 to about 5.5 before administration of Compound I. In some aspects, subjects are categorized based on their CAF severity scores. For instance, subjects with scores between 3.0 and 5.0 are classified asAttorney Docket No. 134851-003002 having mild cognitive fluctuations, while those with scores between 5.1 and 7.0 are classified as having moderate cognitive fluctuations. The CAF severity score is used in combination with other assessments to provide a comprehensive evaluation of a subject's cognitive fluctuations. Changes in CAF severity scores over time are used to assess the efficacy of Compound I treatment in reducing cognitive fluctuations in subjects with Dementia with Lewy Bodies.

[0342] In some embodiments, motor symptoms are evaluated using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS3). In some cases, subjects have a Total Score of about 27.6 before administration of Compound I. In some embodiments, subjects have a Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS3) Total Score ranging from about 20 to about 35 before administration of Compound I. In certain aspects, the MDS-UPDRS3 Total Score is between about 24 and about 31. In other embodiments, subjects have an MDS-UPDRS3 Total Score of about 25 to about 30. The MDS-UPDRS3 Total Score varies among individual patients. In some cases, subjects with an MDS- UPDRS3 Total Score as low as 15 or as high as 40 are included in the patient population. In particular embodiments, the MDS-UPDRS3 Total Score ranges from about 26 to about 29 before administration of Compound I. In some aspects, subjects are categorized based on their MDS- UPDRS3 Total Scores. For instance, subjects with scores between 20 and 25 are classified as having mild motor symptoms, while those with scores between 26 and 35 are classified as having moderate motor symptoms. The MDS-UPDRS3 Total Score is used in combination with other motor assessments to provide a comprehensive evaluation of a subject's motor function. Changes in MDS- UPDRS3 Total Scores over time are used to assess the efficacy of Compound I treatment in improving or preserving motor function in subjects with Dementia with Lewy Bodies. In some embodiments, the MDS-UPDRS3 Total Score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of MDS- UPDRS3 assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the MDS-UPDRS3 Total Score is assessed monthly, while in other cases, it is assessed every three months or at longer intervals.

[0343] In some embodiments, the subject has a mean Hoehn and Yahr stage of about 2. In some embodiments, the subject has a mean Hoehn and Yahr stage ranging from about 1 to about 4. In certain aspects, subjects have a Hoehn and Yahr stage between 1.5 and 3. In other embodiments, subjects have a Hoehn and Yahr stage of about 2.5 to about 3.5. The Hoehn and Yahr stage varies among individual patients. In some cases, subjects with a Hoehn and Yahr stage as low as 1 or as high as 5 are included in the patient population. In particular embodiments, the Hoehn and Yahr stage ranges from about 1.5 to about 2.5 before administration of Compound I. In some aspects, subjectsAttorney Docket No. 134851-003002 are categorized based on their Hoehn and Yahr stages. For instance, subjects with stages between 1 and 2 are classified as having mild motor impairment, while those with stages between 2.5 and 3 are classified as having moderate motor impairment. The Hoehn and Yahr stage is used in combination with other motor assessments to provide a comprehensive evaluation of a subject's motor function. Changes in Hoehn and Yahr stages over time are used to assess the efficacy of Compound I treatment in slowing the progression of motor symptoms in subjects with Dementia with Lewy Bodies.

[0344] Neuropsychiatric symptoms are assessed using the Neuropsychiatric Inventory (NPI). In some cases, subjects have an NPI total score A-J of about 8.6 and an NPI total distress score A-J of about 5.0 before administration. In some embodiments, subjects have a Neuropsychiatric Inventory (NPI) total score A-J ranging from about 5 to about 15 before administration of Compound I. In certain aspects, the NPI total score A-J is between about 7 and about 12. In other embodiments, subjects have an NPI total score A-J of about 8 to about 10. The NPI total score A-J varies among individual patients. In some cases, subjects with an NPI total score A-J as low as 3 or as high as 20 are included in the patient population. In particular embodiments, the NPI total score A-J ranges from about 6 to about 11 before administration of Compound I. In some embodiments, subjects have a Neuropsychiatric Inventory (NPI) total distress score A-J ranging from about 2 to about 10 before administration of Compound I. In certain aspects, the NPI total distress score A-J is between about 3 and about 8. In other embodiments, subjects have an NPI total distress score A-J of about 4 to about 6. The NPI total distress score A-J varies among individual patients. In some cases, subjects with an NPI total distress score A-J as low as 1 or as high as 15 are included in the patient population. In particular embodiments, the NPI total distress score A-J ranges from about 4 to about 7 before administration of Compound I. Subjects are categorized based on their NPI scores in some aspects. For instance, subjects with NPI total scores A-J between 5 and 10 are classified as having mild neuropsychiatric symptoms, while those with scores between 11 and 15 are classified as having moderate neuropsychiatric symptoms. The NPI scores are used in combination with other assessments to provide a comprehensive evaluation of a subject's neuropsychiatric status. Changes in NPI scores over time are used to assess the efficacy of Compound I treatment in reducing neuropsychiatric symptoms and associated distress in subjects with Dementia with Lewy Bodies.

[0345] In some embodiments, subjects have an Epworth Sleepiness Scale (ESS) score ranging from about 5 to about 15 before administration of Compound I. In certain aspects, the ESS score is between about 7 and about 10. In other embodiments, subjects have an ESS score of about 8 to about 9. The ESS score varies among individual patients. In some cases, subjects with an ESS score as low as 3 or as high as 18 are included in the patient population. In particular embodiments, the ESS score ranges from about 7.5 to about 9.5 before administration of Compound I. The EpworthAttorney Docket No. 134851-003002Sleepiness Scale (ESS) score is about 8.4 in some subjects before administration. In some aspects, subjects are categorized based on their ESS scores. For instance, subjects with scores between 0 and 10 may be classified as having normal daytime sleepiness, while those with scores between 11 and 15 may be classified as having mild to moderate excessive daytime sleepiness. Subjects with scores of 16 and above may be considered to have severe excessive daytime sleepiness. The ESS is used in combination with other assessments to provide a comprehensive evaluation of a subject's sleep patterns and daytime alertness. Changes in ESS scores over time may be used to assess the efficacy of Compound I treatment in improving daytime alertness and reducing excessive sleepiness in subjects with Dementia with Lewy Bodies. In some embodiments, the ESS is administered at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of ESS assessments may be determined based on the study protocol and the individual patient's needs. In certain cases, the ESS may be assessed monthly, while in other cases, it may be assessed every three months or at longer intervals.

[0346] Biomarkers are used to further characterize the patient population. Biomarkers can include amyloid probability score 2 (APS2) or plasma pTau217 / Tau217 ratio. In some cases, subjects have an amyloid probability score 2 (APS2) mean of about 40.3. In some embodiments, subjects have an amyloid probability score 2 (APS2) ranging from about 20 to about 60 before administration of Compound I. In certain aspects, the APS2 score is between about 30 and about 50. In other embodiments, subjects have an APS2 score of about 35 to about 45. The APS2 score varies among individual patients. In some cases, subjects with an APS2 score as low as 10 or as high as 70 are included in the patient population. In particular embodiments, the APS2 score ranges from about 38 to about 42 before administration of Compound I. Subjects are categorized based on their APS2 scores in some aspects. For instance, subjects with APS2 scores between 20 and 40 are classified as having low amyloid probability, while those with scores between 41 and 60 are classified as having high amyloid probability. The APS2 score is used in combination with other biomarkers to provide a comprehensive evaluation of a subject's amyloid pathology. Changes in APS2 scores over time are used to assess the efficacy of Compound I treatment in modulating amyloid pathology in subjects with Dementia with Lewy Bodies.

[0347] The plasma pTau217 / Tau217 ratio mean is about 3.7 in some subjects. In some embodiments, subjects have a plasma pTau217 / Tau217 ratio ranging from about 2.0 to about 5.5 before administration of Compound I. In certain aspects, the plasma pTau217 / Tau217 ratio is between about 3.0 and about 4.5. In other embodiments, subjects have a plasma pTau217 / Tau217 ratio of about 3.5 to about 4.0. The plasma pTau217 / Tau217 ratio varies among individual patients. In some cases, subjects with a plasma pTau217 / Tau217 ratio as low as 1.5 or as high as 6.0 areAttorney Docket No. 134851-003002 included in the patient population. In particular embodiments, the plasma pTau217 / Tau217 ratio ranges from about 3.2 to about 4.2 before administration of Compound I. Subjects are categorized based on their plasma pTau217 / Tau217 ratios in some aspects. For instance, subjects with ratios between 2.0 and 3.5 are classified as having low tau pathology, while those with ratios between 3.6 and 5.5 are classified as having high tau pathology. The plasma pTau217 / Tau217 ratio is used in combination with other biomarkers to provide a comprehensive evaluation of a subject's tau pathology. Changes in plasma pTau217 / Tau217 ratios over time are used to assess the efficacy of Compound I treatment in modulating tau pathology in subjects with Dementia with Lewy Bodies. In some embodiments, the plasma pTau217 / Tau217 ratio is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of plasma pTau217 / Tau217 ratio assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the plasma pTau217 / Tau217 ratio is assessed monthly, while in other cases, it is assessed every three months or at longer intervals. The plasma pTau217 / Tau217 ratio is considered in conjunction with other clinical and biomarker data to provide a more comprehensive understanding of the subject's disease state and potential response to treatment with COMPOUND I. In some aspects, changes in the plasma pTau217 / Tau217 ratio correlate with changes in cognitive function, neuropsychiatric symptoms, or other clinical measures in subjects with Dementia with Lewy Bodies.

[0348] In some aspects, the skin biopsy composite score is used as a biomarker for assessing alpha-synuclein pathology in subjects with Dementia with Lewy Bodies (DLB). The score may be derived from the analysis of skin biopsy samples, which can be obtained through minimally invasive procedures. In certain embodiments, the skin biopsy composite score incorporates multiple parameters, such as the presence, distribution, and density of alpha-synuclein aggregates in cutaneous nerve fibers and other skin structures. The skin biopsy composite score may range from 0 to 15, with higher scores potentially indicating a greater degree of alpha-synuclein pathology. In some cases, the score is calculated based on the assessment of different skin layers, including the epidermis, dermis, and subcutaneous tissue. The evaluation may involve immunohistochemical staining techniques to visualize alpha-synuclein deposits and quantitative analysis of their characteristics. In certain aspects, the skin biopsy composite score may correlate with the severity of DLB symptoms or the progression of the disease. Changes in the skin biopsy composite score over time may be used to monitor the efficacy of Compound I treatment in modulating alpha-synuclein pathology in subjects with DLB. The score may be assessed at various time points, including before treatment initiation, during treatment, and after a specified treatment period. In some embodiments, subjects with a skin biopsy composite score above a certain threshold may be considered to have significant alpha-synucleinAttorney Docket No. 134851-003002 pathology, while those below the threshold may be classified as having minimal pathology. The skin biopsy composite score may be used in combination with other biomarkers and clinical assessments to provide a comprehensive evaluation of a subject's DLB status and to guide treatment decisions. A skin biopsy composite score mean of about 7.3 is observed in some cases. In some embodiments, subjects have a skin biopsy composite score ranging from about 0 to about 15 before administration of Compound I. In certain aspects, the skin biopsy composite score is between about 5 and about 10. In other embodiments, subjects have a skin biopsy composite score of about 6 to about 8. The skin biopsy composite score varies among individual patients. In some cases, subjects with a skin biopsy composite score as low as 1 or as high as 14 are included in the patient population. In particular embodiments, the skin biopsy composite score ranges from about 6.5 to about 8.5 before administration of Compound I. Subjects are categorized based on their skin biopsy composite scores in some aspects. For instance, subjects with scores between 0 and 5 are classified as having minimal alpha-synuclein pathology, those with scores between 6 and 10 are classified as having moderate alpha-synuclein pathology, and those with scores between 11 and 15 are classified as having significant alpha-synuclein pathology. The skin biopsy composite score is used in combination with other biomarkers and clinical assessments to provide a comprehensive evaluation of a subject's alpha- synuclein pathology. Changes in skin biopsy composite scores over time are used to assess the efficacy of Compound I treatment in modulating alpha-synuclein pathology in subjects with Dementia with Lewy Bodies.

[0349] Genetic factors play a role in the development and progression of Dementia with Lewy Bodies (DLB). In some cases, genetic variations may influence an individual's susceptibility to DLB or affect the course of the disease. The apolipoprotein E4 (APOE4) genotype is one genetic factor that may be associated with DLB risk. Subjects with DLB may have either a positive or negative APOE4 genotype, which can be determined through genetic testing. In addition to APOE4, other genetic factors may contribute to DLB pathology. Variations in genes related to alpha-synuclein production and metabolism, such as SNCA, may influence the risk of developing DLB. Mutations in genes associated with other neurodegenerative disorders, including LRRK2, GBA, and MAPT, may also play a role in some cases of DLB. Genetic factors can affect various aspects of DLB, including age of onset, rate of cognitive decline, and severity of symptoms. In some instances, genetic variations may influence the response to treatment with compounds such as Compound I. The assessment of genetic factors, in combination with clinical evaluations and biomarker analyses, may provide a more comprehensive understanding of an individual's DLB profile and potentially guide personalized treatment approaches. It is important to note that while genetic factors may contribute to DLB risk and progression, the disease is typically considered to have a complex etiology involvingAttorney Docket No. 134851-003002 both genetic and environmental factors. Ongoing research aims to further elucidate the role of genetics in DLB and identify potential targets for therapeutic interventions. In some embodiments, subjects have an apolipoprotein E4 genotype that is either positive or negative.

[0350] In some cases, subjects are on a stable regimen of acetylcholinesterase inhibitors or memantine before administration of Compound I.

[0351] In some embodiments, subjects with Dementia with Lewy Bodies (DLB) are aged 50 years or older at the time of diagnosis. The age range of subjects varies, with some individuals diagnosed in their early 50s while others are diagnosed in their 80s or beyond. In certain aspects, the mean age of subjects at the time of DLB diagnosis is between 65 and 75 years. Some studies include subjects with an age range of 60 to 85 years old. In other embodiments, the subject population includes individuals aged 55 to 90 years old at the time of enrollment in clinical trials or treatment initiation with Compound I. The age of onset for DLB symptoms often occurs earlier than the age of diagnosis. In some cases, subjects report experiencing initial symptoms 1 to 3 years before receiving a formal DLB diagnosis. The age of symptom onset varies among individuals, with some subjects noticing initial signs in their late 40s or early 50s, while others develop symptoms later in life. In certain aspects, the subject population is stratified by age groups to assess potential differences in treatment response or disease progression. For instance, subjects are categorized into groups such as 50-64 years, 65-74 years, and 75 years and older. This stratification allows for analysis of age-related factors that influence the efficacy of Compound I or the course of DLB. The age of subjects is considered in conjunction with other factors such as disease duration, severity of symptoms, and presence of comorbidities. In some embodiments, older subjects (e.g., those over 75 years) have a higher likelihood of presenting with multiple comorbidities, which is taken into account when assessing treatment outcomes and potential adverse effects. The relationship between age and specific DLB symptoms is also examined in some studies. For example, younger subjects (e.g., those under 65 years) are observed to have a higher prevalence of certain symptoms, such as visual hallucinations or REM sleep behavior disorder, compared to older subjects. These age-related differences in symptom presentation are considered when evaluating the efficacy of Compound I across different age groups. In some cases, the age of subjects influences the dosing regimen or administration schedule of Compound I. Factors such as age-related changes in metabolism, potential drug interactions with medications for age-related conditions, and differences in drug tolerability across age groups are taken into account when determining the optimal therapeutic approach for individual subjects.Attorney Docket No. 134851-003002

[0352] These characteristics help define the patient population for which Compound I is administered. However, it should be noted that not all subjects exhibit all of these characteristics, and individual variations occur.

[0353] METHODS OF USE

[0354] Compound I or a pharmaceutically acceptable salt thereof is used to treat Dementia with Lewy Bodies (DLB) in subjects. The methods of treatment involve administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a subject with DLB. In some cases, the treatment results in improvements in various aspects of DLB symptomatology, including cognition, activities of daily living, neuropsychiatric symptoms, and motor symptoms.

[0355] Improving Dementia with Lewy Bodies

[0356] Administration of Compound I or a pharmaceutically acceptable salt thereof improves cognition in subjects with DLB. Cognitive improvements are assessed using various scales and assessments.

[0357] Administration of Compound I or a pharmaceutically acceptable salt thereof may improve or maintain the Global Treatment Endpoint (GTE) score in subjects with DLB. In some embodiments, the administration of Compound I or a pharmaceutically acceptable salt thereof results in an improvement in the GTE score in the subject compared to placebo. In some cases, the improvement in the GTE score is about 5% to about 50% better than placebo. In certain aspects, the improvement in the GTE score is about 10% to about 30% better than placebo. In other embodiments, the improvement in the GTE score is about 15% to about 25% better than placebo.

[0358] In some embodiments, the Global Treatment Endpoint (GTE) score is used to assess overall treatment response in subjects with Dementia with Lewy Bodies (DLB). The GTE score may be a composite measure that incorporates multiple domains of DLB symptomatology. In some aspects, the GTE score comprises assessments of one or more of cognition, activities of daily living, neuropsychiatric symptoms, and motor symptoms. In certain embodiments, the GTE score comprises assessments of at least two of cognition, activities of daily living, neuropsychiatric symptoms, and motor symptoms. In other embodiments, the GTE score comprises assessments of cognition, activities of daily living, neuropsychiatric symptoms, and motor symptoms.

[0359] In some embodiments, the Global Treatment Endpoint (GTE) score is a composite score derived from one or more of Montreal Cognitive Assessment Scale (MOCA), Cognitive Drug Research Battery (CDR), Clinician Assessment of Fluctuation (CAF), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Unified Parkinson's Disease Rating Scale (UPDRS). In certain aspects, the GTE score is derivedAttorney Docket No. 134851-003002 from at least three of these assessments. In some cases, the GTE score is derived from all of these assessments. The GTE score may be calculated using weighted or unweighted contributions from each component assessment. In some embodiments, the GTE score provides a comprehensive evaluation of a subject's overall response to treatment with Compound I.

[0360] In some embodiments, the administration of Compound I or a pharmaceutically acceptable salt thereof results in maintenance of the GTE score in the subject compared to placebo. The maintenance of the GTE score may be quantified as a percent slowing of decline compared to placebo. In some cases, the percent slowing of decline compared to placebo is about 20% to about 80% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing of decline compared to placebo is about 40% to about 60% after 6 months of treatment. In other aspects, the percent slowing of decline compared to placebo is about 50% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the improvement or maintenance of the GTE score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of GTE assessments may be determined based on the study protocol and the individual patient's needs. In certain cases, the GTE score is assessed monthly, while in other cases, it is assessed every three months or at longer intervals. Changes in GTE scores over time may be used to assess the efficacy of Compound I treatment in improving or preserving overall function in subjects with Dementia with Lewy Bodies.

[0362] In some aspects, subjects are categorized based on their GTE scores. For instance, subjects with GTE scores above a certain threshold may be classified as treatment responders, while those below the threshold may be classified as non-responders. The GTE score may be used in combination with other clinical assessments and biomarker analyses to provide a comprehensive evaluation of a subject's response to treatment with Compound I.

[0363] In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof improves SAPS-PD score in subjects with DLB. In some cases, the SAPS-PD score improves by about 50% to about 95% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in a SAPS-PD score reduction of about 75% to about 90%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to a SAPS-PD score reduction of about 70% to about 85%. In some cases, the SAPS-PD score reduction is about 80% after daily administration of Compound I or a pharmaceutically acceptable salt thereof. The reduction in SAPS-PD score is also expressed as a percent slowing compared to placebo. In some cases, theAttorney Docket No. 134851-003002 percent slowing in SAPS-PD score is about 60% to about 90% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 75% to about 85%, or about 80% after 6 months of treatment. Treatment with Compound I or a pharmaceutically acceptable salt thereof results in improvement in positive psychotic symptoms including hallucinations and delusions as assessed by the SAPS-PD. In some cases, the improvement in hallucinations is about 70% to about 90% compared to placebo, and the improvement in delusions is about 65% to about 85% compared to placebo.

[0364] In some embodiments, subjects have a Scale for the Assessment of Positive Symptoms in Parkinson's Disease (SAPS-PD) score, including a modified version thereof, ranging from about 0 to about 45 before administration of Compound I. In certain aspects, the SAPS-PD score is between about 5 and about 25. In other embodiments, subjects have a SAPS-PD score of about 10 to about 20. The SAPS-PD score varies among individual patients. In some cases, subjects with a SAPS-PD score as low as 0 or as high as 40 are included in the patient population. In particular embodiments, the SAPS-PD score ranges from about 8 to about 18 before administration of Compound I. In some aspects, subjects are categorized based on their SAPS-PD scores. For instance, subjects with scores between 0 and 12 are classified as having mild positive symptoms, while those with scores between 13 and 25 are classified as having moderate positive symptoms, and those with scores above 25 are classified as having severe positive symptoms. The SAPS-PD (modified) may assess positive psychotic symptoms including hallucinations and delusions that are commonly observed in DLB patients. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in a reduction in positive symptoms as measured by the SAPS-PD compared to placebo. In some cases, the SAPS-PD may provide a disease-specific assessment of psychotic symptoms that may be particularly relevant to the parkinsonian features of DLB. The SAPS-PD score is used in combination with other neuropsychiatric assessments to provide a comprehensive evaluation of a subject's psychotic symptom status. Changes in SAPS-PD scores over time are used to assess the efficacy of Compound I treatment in reducing positive psychotic symptoms in subjects with Dementia with Lewy Bodies. In some embodiments, the SAPS-PD score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of SAPS-PD assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the SAPS-PD is assessed monthly, while in other cases, it is assessed every three months or at longer intervals.

[0365] Improving Cognition

[0366] In some cases, the Montreal Cognitive Assessment (MOCA) score improves in subjects with DLB following treatment with Compound I. The improvement in MOCA score rangesAttorney Docket No. 134851-003002 from about 15% to about 110% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in a MOCA score improvement of about 95% to about 110%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to a MOCA score improvement of about 15% to about 25%. In some cases, the MOCA score improvement is about 60% after daily administration of Compound I or a pharmaceutically acceptable salt thereof.

[0367] The Cognitive Drug Research Battery (CDR) is used to assess cognitive improvements. In some embodiments, the CDR episodic memory score improves by about 78% to about 92%, with an improvement of about 85% in some cases. CDR episodic memory is measured by one or more of Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall. Improvements in CDR memory quality are also observed. CDR memory quality is measured by one or more of Spatial Working Memory, Numeric Working Memory, Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall.

[0368] The Clinician Assessment of Fluctuation (CAF) score improves in subjects with DLB following treatment with Compound I. In some cases, the CAF score improvement ranges from about 90% to about 100%, with an improvement of about 95% in some embodiments.

[0369] The Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) score improves by about 21% to about 33%, with an improvement of about 27% in some cases.

[0370] In some embodiments, the improvement in cognition is measured as a reduction of about 2 to about 10 points compared to placebo on various cognitive assessment scales. This reduction is observed in MOCA scores, CDR episodic memory scale scores, CAF scores, or ADCS- GCIC scores.

[0371] In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof improves iADRS score in subjects with DLB. In some cases, the iADRS score improves by about 40% to about 80% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in an iADRS score improvement of about 55% to about 70%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to an iADRS score improvement of about 50% to about 65%. In some cases, the iADRS score improvement is about 60% after daily administration of Compound I or a pharmaceutically acceptable salt thereof. The improvement in iADRS score is also expressed as a percent slowing compared to placebo. In some cases, the percent slowing in iADRS score decline is about 50% to about 75% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments,Attorney Docket No. 134851-003002 the percent slowing is about 55% to about 65%, or about 60% after 6 months of treatment. Treatment with Compound I or a pharmaceutically acceptable salt thereof results in preservation of iADRS score compared to placebo. In some cases, the improvement in the cognitive component of the iADRS is about 55% to about 70% compared to placebo, and the improvement in the functional component is about 45% to about 60% compared to placebo.

[0372] In some embodiments, subjects have an Integrated Alzheimer's Disease Rating Scale (iADRS) score ranging from about 50 to about 130 before administration of Compound I. In certain aspects, the iADRS score is between about 70 and about 110. In other embodiments, subjects have an iADRS score of about 80 to about 100. The iADRS score varies among individual patients. In some cases, subjects with an iADRS score as low as 40 or as high as 140 are included in the patient population. In particular embodiments, the iADRS score ranges from about 75 to about 105 before administration of Compound I. In some aspects, subjects are categorized based on their iADRS scores. For instance, subjects with scores between 100 and 130 are classified as having mild impairment, while those with scores between 70 and 99 are classified as having moderate impairment, and those with scores below 70 are classified as having severe impairment. The iADRS is a composite measure that integrates cognitive and functional assessments to provide a comprehensive evaluation of disease progression. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in an improvement or preservation of the iADRS score compared to placebo. In some cases, the iADRS may serve as an alternative cognitive assessment measure that captures both cognitive function and instrumental activities of daily living in a single integrated score. The iADRS score is used in combination with other cognitive and functional assessments to provide a comprehensive evaluation of a subject's disease status. Changes in iADRS scores over time are used to assess the efficacy of Compound I treatment in improving or preserving cognitive and functional abilities in subjects with Dementia with Lewy Bodies. In some embodiments, the iADRS score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of iADRS assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the iADRS is assessed monthly, while in other cases, it is assessed every three months or at longer intervals.

[0373] In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof improves CDR-SB score in subjects with DLB. In some cases, the CDR-SB score improves by about 50% to about 90% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in a CDR-SB score improvement of about 70% to about 85%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to a CDR-SB scoreAttorney Docket No. 134851-003002 improvement of about 65% to about 80%. In some cases, the CDR-SB score improvement is about 75% after daily administration of Compound I or a pharmaceutically acceptable salt thereof. The improvement in CDR-SB score is also expressed as a percent slowing of worsening compared to placebo. In some cases, the percent slowing in CDR-SB score increase is about 60% to about 85% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 70% to about 80%, or about 75% after 6 months of treatment. Treatment with Compound I or a pharmaceutically acceptable salt thereof results in preservation of CDR-SB score compared to placebo. In some cases, the improvement in the memory domain of the CDR-SB is about 75% to about 90% compared to placebo, and the improvement in the functional domains is about 50% to about 70% compared to placebo.

[0374] In some embodiments, subjects have a Clinical Dementia Rating - Sum of Boxes (CDR-SB) score ranging from about 0 to about 18 before administration of Compound I. In certain aspects, the CDR-SB score is between about 4 and about 12. In other embodiments, subjects have a CDR-SB score of about 6 to about 10. The CDR-SB score varies among individual patients. In some cases, subjects with a CDR-SB score as low as 0.5 or as high as 16 are included in the patient population. In particular embodiments, the CDR-SB score ranges from about 5 to about 9 before administration of Compound I. In some aspects, subjects are categorized based on their CDR-SB scores. For instance, subjects with scores between 0.5 and 4.0 are classified as having questionable or mild dementia, while those with scores between 4.5 and 9.0 are classified as having mild to moderate dementia, and those with scores between 9.5 and 18.0 are classified as having moderate to severe dementia. The CDR-SB assesses dementia severity across multiple domains including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in a reduction or slowing of increase in the CDR-SB score compared to placebo. In some cases, the CDR-SB may provide a more granular assessment of dementia severity than global CDR staging and may be sensitive to treatment effects across the spectrum of DLB severity. The CDR-SB score is used in combination with other cognitive and functional assessments to provide a comprehensive evaluation of a subject's dementia status. Changes in CDR-SB scores over time are used to assess the efficacy of Compound I treatment in slowing disease progression in subjects with Dementia with Lewy Bodies. In some embodiments, the CDR-SB score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of CDR-SB assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the CDR-SB is assessed monthly, while in other cases, it is assessed every three months or at longer intervals.Attorney Docket No. 134851-003002

[0375] Treatment with Compound I or a pharmaceutically acceptable salt thereof also results in preservation of cognition as measured by at least one of MOCA, CDR memory scale, CDR- SB, CAF, iADRS, or ADCS-GCIC compared to placebo. This preservation is quantified as a percent slowing of cognitive decline compared to placebo after 6 months of treatment.

[0376] Improving Activities of Daily Living

[0377] Administration of Compound I or a pharmaceutically acceptable salt thereof improves activities of daily living in subjects with DLB. These improvements are assessed using the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale.

[0378] In some cases, the ADCS-ADL score improves by about 2 to about 8 points compared to placebo. In some embodiments, the improvement is about 4 points better than placebo. The improvement in ADCS-ADL score is also expressed as a percent slowing compared to placebo. In some cases, the percent slowing in ADCS-ADL score is about 40% to about 60% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 48% to about 55%, or about 50% after 6 months of treatment.

[0379] Treatment with Compound I or a pharmaceutically acceptable salt thereof also results in preservation of ADCS-ADL score compared to placebo. This preservation is quantified as a percent slowing compared to placebo.

[0380] Reducing Neuropsychiatric Symptoms

[0381] Compound I or a pharmaceutically acceptable salt thereof reduces neuropsychiatric symptoms in subjects with DLB. These improvements are assessed using the Neuropsychiatric Inventory (NPI).

[0382] In some cases, the NPI total score improves by about 2 to about 10 points compared to placebo, with an improvement of about 5 points in some embodiments. The improvement in NPI total score includes improvements in assessments of anxiety, hallucinations, and delusions. In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof improves NPI-C-4 score in subjects with DLB. In some cases, the NPI-C-4 score improves by about 40% to about 90% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in an NPI-C-4 score improvement of about 80% to about 90%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to an NPI-C-4 score improvement of about 75% to about 85%. In some cases, the NPI-C-4 score improvement is about 82% after daily administration of Compound I or a pharmaceutically acceptable salt thereof. The reduction in NPI-C-4 score is also expressed as a percent slowing compared to placebo. In someAttorney Docket No. 134851-003002 cases, the percent slowing in NPI-C-4 score is about 70% to about 95% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 80% to about 85%, or about 82% after 6 months of treatment. Treatment with Compound I or a pharmaceutically acceptable salt thereof results in improvement in at least one of anxiety, agitation / aggression, delusions, or hallucinations as assessed by the NPI-C-4. In some cases, improvements are observed in at least two of these symptoms, or in all four symptoms.

[0383] In aspects of the present disclosure, the techniques described herein relate to a method of improving Neuropsychiatric Inventory - Clinician version 4-item (NPI-C-4) score in a subject with Dementia with Lewy Bodies (DLB), including administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof. The NPI-C-4 may assess clinician-rated neuropsychiatric symptoms including anxiety, agitation / aggression, delusions, and hallucinations. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in an improvement in the NPI-C-4 score compared to placebo. In some cases, the improvement may be quantified as a percent slowing of symptom progression compared to placebo. The NPI-C-4 may provide a clinician-administered assessment that complements caregiver-reported NPI measures and may offer enhanced reliability in clinical trial settings. In some embodiments, subjects have a Neuropsychiatric Inventory - Clinician version 4-item (NPI-C-4) score ranging from about 0 to about 48 before administration of Compound I. In certain aspects, the NPI-C-4 score is between about 5 and about 20. In other embodiments, subjects have an NPI-C-4 score of about 8 to about 15. The NPI-C-4 score varies among individual patients. In some cases, subjects with an NPI-C-4 score as low as 0 or as high as 40 are included in the patient population. In particular embodiments, the NPI- C-4 score ranges from about 6 to about 12 before administration of Compound I. In some aspects, subjects are categorized based on their NPI-C-4 scores. For instance, subjects with scores between 0 and 10 are classified as having mild neuropsychiatric symptoms, while those with scores between 11 and 25 are classified as having moderate neuropsychiatric symptoms, and those with scores above 25 are classified as having severe neuropsychiatric symptoms. The NPI-C-4 score is used in combination with other neuropsychiatric assessments to provide a comprehensive evaluation of a subject's neuropsychiatric status. Changes in NPI-C-4 scores over time are used to assess the efficacy of Compound I treatment in reducing neuropsychiatric symptoms in subjects with Dementia with Lewy Bodies. In some embodiments, the NPI-C-4 score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of NPI-C-4 assessments is determined based on the study protocol and the individual patient's needs. InAttorney Docket No. 134851-003002 certain cases, the NPI-C-4 is assessed monthly, while in other cases, it is assessed every three months or at longer intervals.

[0384] In some embodiments, subjects have an agitation score as measured by the Neuropsychiatric Inventory (NPI) agitation / aggression domain ranging from about 0 to about 12 before administration of Compound I. In certain aspects, the agitation score is between about 2 and about 8. In other embodiments, subjects have an agitation score of about 3 to about 6. The agitation score varies among individual patients. In some cases, subjects with an agitation score as low as 0 or as high as 12 are included in the patient population. In particular embodiments, the agitation score ranges from about 4 to about 7 before administration of Compound I. In some aspects, subjects are categorized based on their agitation scores. For instance, subjects with scores between 0 and 4 are classified as having mild agitation, while those with scores between 5 and 8 are classified as having moderate agitation, and those with scores above 8 are classified as having severe agitation. Agitation may be a neuropsychiatric symptom characterized by excessive motor activity, verbal outbursts, or restlessness that may significantly impact quality of life for both DLB patients and their caregivers. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in a reduction in agitation symptoms compared to placebo. The agitation score is used in combination with other neuropsychiatric assessments to provide a comprehensive evaluation of a subject's neuropsychiatric status. Changes in agitation scores over time are used to assess the efficacy of Compound I treatment in reducing agitation symptoms in subjects with Dementia with Lewy Bodies. In some embodiments, the agitation score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of agitation assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the agitation score is assessed monthly, while in other cases, it is assessed every three months or at longer intervals. The improvement in agitation may contribute to reduced caregiver distress and may help maintain patients in lower levels of care.

[0385] The reduction in neuropsychiatric symptoms is also expressed as a percent slowing compared to placebo. In some cases, the percent slowing in NPI total score is about 40% to about 60% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 48% to about 55%, or about 50% after 6 months of treatment.

[0386] Treatment with Compound I or a pharmaceutically acceptable salt thereof results in improvement in at least one of anxiety, hallucinations, or delusions. In some cases, improvements are observed in at least two of these symptoms, or in all three symptoms. The improvement in anxiety, hallucinations, or delusions is assessed by theAttorney Docket No. 134851-003002

[0387] Compound I or a pharmaceutically acceptable salt thereof be used to treat Dementia with Lewy Bodies (DLB) in subjects. The methods of treatment involve administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a subject with DLB. In some cases, the treatment result in improvements in various aspects of DLB symptomatology, including cognition, activities of daily living, neuropsychiatric symptoms, and motor symptoms.

[0388] In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof reduces agitation and aggression in subjects with DLB. In some cases, the agitation / aggression score as measured by the NPI improves by about 60% to about 95% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in an agitation / aggression score reduction of about 75% to about 90%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to an agitation / aggression score reduction of about 70% to about 85%. In some cases, the agitation / aggression score reduction is about 80% after daily administration of Compound I or a pharmaceutically acceptable salt thereof. The reduction in agitation / aggression score is also expressed as a percent slowing compared to placebo. In some cases, the percent slowing in agitation / aggression score is about 70% to about 90% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 78% to about 85%, or about 80% after 6 months of treatment. Treatment with Compound I or a pharmaceutically acceptable salt thereof results in improvement in agitation symptoms of about 2 to about 6 points better than placebo as measured by the NPI agitation / aggression domain. In some cases, the improvement in aggression symptoms is about 1 to about 4 points better than placebo. The reduction in agitation and aggression contributes to reduced caregiver distress, with caregiver distress scores for the agitation / aggression domain improving by about 70% to about 90% compared to placebo.

[0389] In some embodiments, subjects have an aggression score as measured by the Neuropsychiatric Inventory (NPI) agitation / aggression domain ranging from about 0 to about 12 before administration of Compound I. In certain aspects, the aggression score is between about 1 and about 6. In other embodiments, subjects have an aggression score of about 2 to about 5. The aggression score varies among individual patients. In some cases, subjects with an aggression score as low as 0 or as high as 12 are included in the patient population. In particular embodiments, the aggression score ranges from about 3 to about 6 before administration of Compound I. In some aspects, subjects are categorized based on their aggression scores. For instance, subjects with scores between 0 and 3 are classified as having mild aggression, while those with scores between 4 and 7Attorney Docket No. 134851-003002 are classified as having moderate aggression, and those with scores above 7 are classified as having severe aggression. Aggression may be a neuropsychiatric symptom characterized by hostile or violent behavior that may be verbal or physical in nature and may occur in patients with dementia. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in a reduction in aggression symptoms compared to placebo. The aggression score is used in combination with other neuropsychiatric assessments to provide a comprehensive evaluation of a subject's neuropsychiatric status. Changes in aggression scores over time are used to assess the efficacy of Compound I treatment in reducing aggression symptoms in subjects with Dementia with Lewy Bodies. In some embodiments, the aggression score is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of aggression assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the aggression score is assessed monthly, while in other cases, it is assessed every three months or at longer intervals. The improvement in aggression may contribute to reduced caregiver distress and may help maintain patients in lower levels of care.

[0390] Improving Cognition

[0391] Administration of Compound I or a pharmaceutically acceptable salt thereof improve cognition in subjects with DLB. Cognitive improvements be assessed using various scales and assessments.

[0392] In some cases, the Montreal Cognitive Assessment (MOCA) score improve in subjects with DLB following treatment with Compound I. The improvement in MOCA score range from about 15% to about 110% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof result in a MOCA score improvement of about 95% to about 110%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof lead to a MOCA score improvement of about 15% to about 25%. In some cases, the MOCA score improvement be about 60% after daily administration of Compound I or a pharmaceutically acceptable salt thereof.

[0393] The Cognitive Drug Research Battery (CDR) be used to assess cognitive improvements. In some embodiments, the CDR episodic memory score improve by about 78% to about 92%, with an improvement of about 85% in some cases. CDR episodic memory be measured by one or more of Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall. Improvements in CDR memory quality also be observed. CDR memory quality be measured by one or more of Spatial Working Memory, Numeric Working Memory, Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall.Attorney Docket No. 134851-003002

[0394] The Clinician Assessment of Fluctuation (CAF) score improve in subjects with DLB following treatment with Compound I. In some cases, the CAF score improvement range from about 90% to about 100%, with an improvement of about 95% in some embodiments.

[0395] The Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) score improve by about 21% to about 33%, with an improvement of about 27% in some cases.

[0396] In some embodiments, the improvement in cognition be measured as a reduction of about 2 to about 10 points compared to placebo on various cognitive assessment scales. This reduction be observed in MOCA scores, CDR episodic memory scale scores, CAF scores, or ADCS- GCIC scores.

[0397] Treatment with Compound I or a pharmaceutically acceptable salt thereof also result in preservation of cognition as measured by at least one of MOCA, CDR memory scale, CAF, or ADCS-GCIC compared to placebo. This preservation be quantified as a percent slowing of cognitive decline compared to placebo after 6 months of treatment.

[0398] Improving Activities of Daily Living

[0399] Administration of Compound I or a pharmaceutically acceptable salt thereof improve activities of daily living in subjects with DLB. These improvements be assessed using the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale.

[0400] In some cases, the ADCS-ADL score improve by about 2 to about 8 points compared to placebo. In some embodiments, the improvement be about 4 points better than placebo. The improvement in ADCS-ADL score also be expressed as a percent slowing compared to placebo. In some cases, the percent slowing in ADCS-ADL score be about 40% to about 60% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing be about 48% to about 55%, or about 50% after 6 months of treatment.

[0401] Treatment with Compound I or a pharmaceutically acceptable salt thereof also result in preservation of ADCS-ADL score compared to placebo. This preservation be quantified as a percent slowing compared to placebo.

[0402] Reducing Neuropsychiatric Symptoms

[0403] Compound I or a pharmaceutically acceptable salt thereof reduce neuropsychiatric symptoms in subjects with DLB. These improvements be assessed using the Neuropsychiatric Inventory (NPI).Attorney Docket No. 134851-003002

[0404] In some cases, the NPI total score improve by about 2 to about 10 points compared to placebo, with an improvement of about 5 points in some embodiments. The improvement in NPI total score include improvements in assessments of anxiety, hallucinations, and delusions.

[0405] The reduction in neuropsychiatric symptoms also be expressed as a percent slowing compared to placebo. In some cases, the percent slowing in NPI total score be about 40% to about 60% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing be about 48% to about 55%, or about 50% after 6 months of treatment.

[0406] Treatment with Compound I or a pharmaceutically acceptable salt thereof result in improvement in at least one of anxiety, hallucinations, or delusions. In some cases, improvements be observed in at least two of these symptoms, or in all three symptoms. The improvement in anxiety, hallucinations, or delusions be assessed by the NPI compared to placebo.

[0407] Administration of Compound I or a pharmaceutically acceptable salt thereof also lead to preservation of at least one of anxiety, hallucinations, or delusions in subjects with DLB compared to placebo. This preservation be quantified as a percent slowing compared to placebo. In some cases, the percent slowing be about 50% to about 90% after 6 months of treatment. In certain embodiments, the percent slowing be about 80% to about 82%, or about 80% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof.

[0408] Reducing Motor Symptoms

[0409] Compound I or a pharmaceutically acceptable salt thereof reduce motor symptoms in subjects with DLB. These improvements be assessed using the Unified Parkinson's Disease Rating Scale (UPDRS).

[0410] In some cases, treatment with Compound I or a pharmaceutically acceptable salt thereof result in an improvement in motor symptoms as measured by the UPDRS compared to placebo. This improvement be quantified as a reduction in the UPDRS score of about 2 to about 10 points compared to placebo.

[0411] The reduction in motor symptoms also be expressed as a percent slowing in the increase of the UPDRS score compared to placebo. In some cases, the percent slowing be about 50% to about 70% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing be about 55% to about 66%, or about 62% after 6 months of treatment.

[0412] Administration of Compound I or a pharmaceutically acceptable salt thereof result in an improvement in at least one of rigidity, tremor, or bradykinesia as measured by the UPDRS. InAttorney Docket No. 134851-003002 some cases, treatment lead to preservation of at least one of these motor symptoms as measured by the UPDRS.

[0413] In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof improves TUG test performance in subjects with DLB. In some cases, the TUG test time improves by about 40% to about 70% compared to placebo. In some embodiments, daily administration of 100 mg of Compound I or a pharmaceutically acceptable salt thereof results in a TUG test time improvement of about 55% to about 70%. In other embodiments, daily administration of 300 mg of Compound I or a pharmaceutically acceptable salt thereof leads to a TUG test time improvement of about 50% to about 65%. In some cases, the TUG test time improvement is about 62% after daily administration of Compound I or a pharmaceutically acceptable salt thereof. The improvement in TUG test performance is also expressed as a percent slowing of worsening compared to placebo. In some cases, the percent slowing in TUG test time increase is about 50% to about 70% after 6 months of administration of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, the percent slowing is about 55% to about 66%, or about 62% after 6 months of treatment. Treatment with Compound I or a pharmaceutically acceptable salt thereof results in preservation of TUG test performance compared to placebo. In some cases, the improvement in TUG test time is a reduction of about 1 to about 5 seconds compared to placebo, indicating improved functional mobility and potentially reduced fall risk.

[0414] In some embodiments, subjects have a Timed Up and Go (TUG) test time ranging from about 8 seconds to about 30 seconds before administration of Compound I. In certain aspects, the TUG test time is between about 10 seconds and about 20 seconds. In other embodiments, subjects have a TUG test time of about 12 seconds to about 18 seconds. The TUG test time varies among individual patients. In some cases, subjects with a TUG test time as low as 7 seconds or as high as 40 seconds are included in the patient population. In particular embodiments, the TUG test time ranges from about 11 seconds to about 16 seconds before administration of Compound I. In some aspects, subjects are categorized based on their TUG test times. For instance, subjects with times between 8 and 12 seconds are classified as having normal mobility, while those with times between 12 and 20 seconds are classified as having mild mobility impairment, and those with times above 20 seconds are classified as having moderate to severe mobility impairment. The TUG test assesses functional mobility by measuring the time required for a subject to rise from a chair, walk a specified distance (typically 3 meters), turn, walk back, and sit down. In some aspects, administration of Compound I or a pharmaceutically acceptable salt thereof may result in an improvement or preservation of TUG test performance compared to placebo. In some cases, the TUG test may provideAttorney Docket No. 134851-003002 an objective, quantitative measure of motor function and mobility that may be relevant to fall risk assessment and functional independence in DLB patients. The TUG test time is used in combination with other motor assessments to provide a comprehensive evaluation of a subject's functional mobility status. Changes in TUG test times over time are used to assess the efficacy of Compound I treatment in improving or preserving functional mobility in subjects with Dementia with Lewy Bodies. In some embodiments, the TUG test is assessed at different time points, including before treatment initiation, during treatment, and after a specified treatment period. The frequency of TUG test assessments is determined based on the study protocol and the individual patient's needs. In certain cases, the TUG test is assessed monthly, while in other cases, it is assessed every three months or at longer intervals.

[0415] Reducing Caregiver Distress

[0416] Treatment of subjects with DLB using Compound I or a pharmaceutically acceptable salt thereof result in reduced caregiver distress. This reduction in caregiver distress be associated with improvements in the subject's cognitive function, activities of daily living, neuropsychiatric symptoms, and motor symptoms.

[0417] In some cases, the reduction in caregiver distress be assessed using the caregiver distress component of the Neuropsychiatric Inventory (NPI). Improvements in the subject's condition and associated reductions in caregiver distress contribute to an overall improvement in quality of life for both the subject with DLB and their caregiver.

[0418] A number of implementations have been described. Nevertheless, it will be understood that various modifications be made without departing from the spirit and scope of the disclosure. Accordingly, other implementations are within the scope of the following claims.

[0419] In some embodiments, administration of Compound I or a pharmaceutically acceptable salt thereof to subjects with Dementia with Lewy Bodies (DLB) results in improvements in certain symptoms without exacerbating other symptoms associated with the condition. In some embodiments, treatment with Compound I leads to a reduction in neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI), including improvements in anxiety, hallucinations, and delusions. These improvements are observed without concurrent worsening of cognitive function, motor symptoms, or activities of daily living. The reduction in anxiety, hallucinations, and delusions is quantifiable and clinically significant, contributing to an overall enhancement in the subject's quality of life. Importantly, these improvements in neuropsychiatric symptoms occur while maintaining or potentially improving other aspects of DLB symptomatology, demonstrating the balanced therapeutic effect of Compound I in managing the complex presentation of DLB.Attorney Docket No. 134851-003002

[0420] ADDITIONAL EMBODIMENTS

[0421] Clause 1. A method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of structure (Compound I) or a pharmaceutically acceptable salt thereof, wherein the administration results treatment of the DLB in the subject.

[0422] Clause 2. A method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I, wherein the administration results in an improvement or maintenance of a Global Treatment Endpoint (GTE) score in the subject.

[0423] Clause 3. A method of improving or maintaining a Global Treatment Endpoint (GTE) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I, wherein the administration results in an improvement or maintenance of a GTE score in the subject with DLB.

[0424] Clause 4. A method of inducing cognitive preservation in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt, wherein the administration results in cognitive preservation in the subject with DLB.

[0425] Clause 5. A method of improving cognition in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves cognition in the subject with DLB.

[0426] Clause 6. A method of improving activities of daily living in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves activities of daily living in the subject with DLB.

[0427] Clause 7. A method of reducing neuropsychiatric symptoms in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces neuropsychiatric symptoms in the subject with DLB.

[0428] Clause 8. A method of reducing motor symptoms in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces motor symptoms in the subject with DLB.Attorney Docket No. 134851-003002

[0429] Clause 9. A method of improving a Timed Up and Go (TUG) test performance in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the TUG test performance in the subject with DLB.

[0430] Clause 10. A method of reducing caregiver distress associated with a subject having Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces caregiver distress associated with the subject having DLB.

[0431] Clause I L A method of improving a Montreal Cognitive Assessment (MOCA) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the MOCA score in the subject with DLB.

[0432] Clause 12. A method of improving a Scale for the Assessment of Positive Symptoms in Parkinson's Disease (SAPS-PD) score in a patient with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the SAPS-PD score in the subject with DLB.

[0433] Clause 13. A method of improving an Integrated Alzheimer's Disease Rating (iADRS) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the iADRS score in the subject with DLB.

[0434] Clause 14. A method of improving a Clinical Dementia Rating- Sum of Boxes (CDR-SB) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the CDR-SB score in the subject with DLB.

[0435] Clause 15. A method of improving a Cognitive Drug Research Battery (CDR) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the CDR score in the subject with DLB.Attorney Docket No. 134851-003002

[0436] Clause 16. A method of improving a Clinician Assessment of Fluctuation (CAF) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the CAF score in the subject with DLB.

[0437] Clause 17. A method of improving a Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the ADCS-ADL score in the subject with DLB.

[0438] Clause 18. A method of improving a Neuropsychiatric Inventory (NPI) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the NPI score in the subject with DLB.

[0439] Clause 19. A method of improving a Neuropsychiatric Inventory Clinical version 4-item (NPI-C-4) score in a subject with Dementia with Lewy Bodies), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration improves the NPI-C-4 score in the subject with DLB.

[0440] Clause 20. A method of reducing anxiety in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces the anxiety in the subject with DLB.

[0441] Clause 21. A method of reducing hallucinations in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces hallucinations in the subject with DLB.

[0442] Clause 22. A method of reducing delusions in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces the delusions in the subject with DLB.

[0443] Clause 23. A method of reducing aggression in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduced the aggression in the subject with DLB.Attorney Docket No. 134851-003002

[0444] Clause 24. A method of reducing aggression in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, wherein the administration reduces the aggression in the subject with DLB.

[0445] Clause 25. A method of improving a Unified Parkinson's Disease Rating Scale (UPDRS) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I or a pharmaceutically acceptable salt thereof, where in the administration impoves the UPDRS score in the subject with DLB.

[0446] Clause 26. The method of any one of clauses 1-6 or 17, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS- ADL) score in the subject compared to placebo.

[0447] Clause 27. The method of clause 26, wherein the improvement in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in the subject is about 2 to about 8 points better than placebo.

[0448] Clause 28. The method of clause 26, wherein the improvement in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in the subject is about 4 points better than placebo.

[0449] Clause 29. The method of any one of clauses 1-6 or 17, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in the subject compared to placebo.

[0450] Clause 30. The method of clause 29, wherein the preservation in the ADCS-ADL score is a percent slowing compared to placebo.

[0451] Clause 31. The method of clause 30, wherein the percent slowing compared to placebo is about 40% to about 60% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0452] Clause 32. The method of clause 30, wherein the percent slowing compared to placebo is about 48 to about 55% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0453] Clause 33. The method of clause 30, wherein the percent slowing compared to placebo is about 50% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.Attorney Docket No. 134851-003002

[0454] Clause 34. The method of any one of clauses 1-5 or 7 or 12-15, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in Neuropsychiatric Inventory (NPI) total score in the subject compared to placebo.

[0455] Clause 35. The method of clause 34, wherein the improvement in Neuropsychiatric Inventory (NPI) total score includes improvements in assessments of anxiety, hallucinations, and delusions.

[0456] Clause 36. The method of clause 34, wherein the improvement inNeuropsychiatric Inventory (NPI) total score is about 2 to about 10 points better than placebo.

[0457] Clause 37. The method of clause 34, wherein the improvement inNeuropsychiatric Inventory (NPI) total score is about 5 points better than placebo.

[0458] Clause 38. The method of any one of clauses 1-5 or 7 or 12-15, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of a Neuropsychiatric Inventory (NPI) total score in the subject compared to placebo.

[0459] Clause 39. The method of clause 38, wherein the preservation in the Neuropsychiatric Inventory (NPI) total score is a percent slowing compared to placebo.

[0460] Clause 40. The method of clause 39, wherein the percent slowing compared to placebo is about 40% to about 60% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0461] Clause 41. The method of clause 39, wherein the percent slowing compared to placebo is about 48 to about 55% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0462] Clause 42. The method of clause 39, wherein the percent slowing compared to placebo is about 50% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0463] Clause 43. The method of any one of clauses 1-5 or 7 or 12-15, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in at least one of anxiety, hallucinations, or delusions.

[0464] Clause 44. The method of clause 43, wherein the improvement in at least one of anxiety, hallucinations, or delusions is assessed by a Neuropsychiatric Inventory (NPI) compared to placebo.

[0465] Clause 45. The method of clause 43, wherein the improvement is observed in at least two of anxiety, hallucinations, or delusions.Attorney Docket No. 134851-003002

[0466] Clause 46. The method of clause 43, wherein the improvement is observed in anxiety, hallucinations, and delusions.

[0467] Clause 47. The method of any one of clauses 1-5 or 7 or 12-15, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of at least one of anxiety, hallucinations, or delusions in the subject compared to placebo.

[0468] Clause 48. The method of clause 47, wherein the preservation of at least one of anxiety, hallucinations, or delusions is a percent slowing compared to placebo.

[0469] Clause 49. The method of clause 48, wherein the percent slowing compared to placebo is about 50% to about 90% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0470] Clause 50. The method of clause 48, wherein the percent slowing compared to placebo is about 80% to about 82% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0471] Clause 51. The method of clause 48, wherein the percent slowing compared to placebo is about 80% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0472] Clause 52. The method of any one of clauses 1-5 or 8 or 16, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in motor symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) in the subject compared to placebo.

[0473] Clause 53. The method of any one of clauses 1-5 or 8 or 16, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of motor symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) in the subject compared to placebo.

[0474] Clause 54. The method of clause 52, wherein the improvement in motor symptoms is a reduction in the UPDRS score of about 2 to about 10 points compared to placebo.

[0475] Clause 55. The method of clause 53, wherein the preservation of motor symptoms is a percent slowing in an increase of the UPDRS score compared to placebo.

[0476] Clause 56. The method of clause 55, wherein the percent slowing is about 50% to about 70% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.Attorney Docket No. 134851-003002

[0477] Clause 57. The method of clause 55, wherein the percent slowing is about 55% to about 66% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0478] Clause 58. The method of clause 55, wherein the percent slowing is about 62% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0479] Clause 59. The method of any one of clauses 1-5 or 8 or 16, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in at least one of rigidity, tremor, or bradykinesia as measured by the UPDRS.

[0480] Clause 60. The method of any one of clauses 1-5 or 8 or 16, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of at least one of rigidity, tremor, or bradykinesia as measured by the UPDRS.

[0481] Clause 61. The method of any one of clauses 1-5 or 11-16, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in cognition as measured by at least one of Montreal Cognitive Assessment Scale (MOCA), Cognitive Drug Research Battery (CDR) memory scale, Clinician Assessment of Fluctuation (CAF), or Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) in the subject compared to placebo.

[0482] Clause 62. The method of clause 61, wherein the improvement in Cognitive Drug Research Battery (CDR) is an improvement in CDR episodic memory.

[0483] Clause 63. The method of clause 62, wherein CDR episodic memory is measured by one or more of Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall.

[0484] Clause 64. The method of clause 61, wherein the improvement in Cognitive Drug Research Battery (CDR) is an improvement in CDR memory quality.

[0485] Clause 65. The method of clause 64, wherein CDR memory quality is measured by one or more of Spatial Working Memory, Numeric Working Memory, Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall.

[0486] Clause 66. The method of any one of clauses 61-65, wherein the improvement in cognition is a percent improvement compared to placebo after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0487] Clause 67. The method of any one of clauses 61-65, wherein the MOCA score is improved by about 15% to about 110%.Attorney Docket No. 134851-003002

[0488] Clause 68. The method of any one of clauses 61-65, wherein the MOCA score is improved by about 95% to about 110% after daily administration of 100 mg of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0489] Clause 69. The method of any one of clauses 61-65, wherein the MOCA score is improved by about 15% to about 25% after daily administration of 300 mg of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0490] Clause 70. The method of any one of clauses 61-65, wherein the MOCA score is improved by about 60% after daily administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0491] Clause 71. The method of any one of clauses 61-65, wherein the CDR episodic score is improved by about 78% to about 92%.

[0492] Clause 72. The method of any one of clauses 61-65, wherein the CDR episodic score is improved by about 85%.

[0493] Clause 73. The method of any one of clauses 61-65, wherein the CAF score is improved by about 90% to about 100%.

[0494] Clause 74. The method of any one of clauses 61-65, wherein the CAF episodic score is improved by about 95%.

[0495] Clause 75. The method of any one of clauses 61-65, wherein the ADCS-GCIC score is improved by about 21% to about 33%.

[0496] Clause 76. The method of any one of clauses 61-65, wherein the ADCS-GCIC score is improved by about 27%.

[0497] Clause 77. The method of any one of clauses 61-65, wherein the improvement in cognition is a reduction of about 2 to about 10 points compared to placebo.

[0498] Clause 78. The method of any one of clauses 61-65, wherein the improvement in cognition as measured by the Montreal Cognitive Assessment Scale (MOCA) is a reduction of about 2 to about 10 points compared to placebo.

[0499] Clause 79. The method of any one of clauses 61-65, wherein the improvement in cognition as measured by the Cognitive Drug Research Battery (CDR) episodic memory scale is a reduction of about 2 to about 10 points compared to placebo.

[0500] Clause 80. The method of any one of clauses 61-65, wherein the improvement in cognition as measured by the Clinician Assessment of Fluctuation (CAF) is a reduction of about 2 to about 10 points compared to placebo.Attorney Docket No. 134851-003002

[0501] Clause 81. The method of any one of clauses 61-65, wherein the improvement in cognition as measured by the Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) is a reduction of about 2 to about 10 points compared to placebo.

[0502] Clause 82. The method of any one of clauses 1-5 or 11-16, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of cognition as measured by at least one of Montreal Cognitive Assessment Scale (MOCA), Cognitive Drug Research Battery (CDR) memory scale, Clinician Assessment of Fluctuation (CAF), or Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) in the subject compared to placebo.

[0503] Clause 83. The method of clause 82, wherein the preservation in Cognitive Drug Research Battery (CDR) is a preservation of CDR episodic memory.

[0504] Clause 84. The method of clause 83, wherein CDR episodic memory is measured by one or more of Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall.

[0505] Clause 85. The method of clause 84, wherein the preservation in Cognitive Drug Research Battery (CDR) is a preservation of CDR memory quality.

[0506] Clause 86. The method of clause 85, wherein CDR memory quality is measured by one or more of Spatial Working Memory, Numeric Working Memory, Word Recognition, Picture Recognition, Immediate Word Recall, and Delayed Word Recall.

[0507] Clause 87. The method of clause 82, wherein the preservation of cognition is a percent slowing of cognitive decline compared to placebo after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0508] Clause 88. The method of any one of clauses 83-87, wherein the preservation of cognition is a percent slowing compared to placebo after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0509] Clause 89. The method of any one of clauses 83-87, wherein the MOCA score is preserved compared to placebo.

[0510] Clause 90. The method of any one of clauses 83-87, wherein the CDR episodic score is preserved compared to placebo.

[0511] Clause 91. The method of any one of clauses 83-87, wherein the CAF score is preserved compared to placebo.

[0512] Clause 92. The method of any one of clauses 83-87, wherein the ADCS-GCIC score is preserved compared to placebo.Attorney Docket No. 134851-003002

[0513] Clause 93. The method of any one of clauses 1-92, wherein the pharmaceutically acceptable salt is a fumarate salt.

[0514] Clause 94. The method of any one of clauses 1-93, wherein the subject has a mean Mini-Mental State Examination (MMSE) score of about 24 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0515] Clause 95. The method of any one of clauses 1-94, wherein the subject is on a stable regimen of acetylcholinesterase inhibitors or memantine.

[0516] Clause 96. The method of any one of clauses 1-95, wherein the subject has a mean time since Dementia with Lewy Bodies diagnosis of about 1 to about 2 years.

[0517] Clause 97. The method of any one of clauses 1-96, wherein the subject has a mean Hoehn and Yahr stage of about 2.

[0518] Clause 98. The method of any one of clauses 1-97, wherein the subject has an apolipoprotein E4 genotype that is either positive or negative.

[0519] Clause 99. The method of any one of clauses 1-98, wherein the subject has an amyloid probability score 2 (APS2) mean of about 40.3.

[0520] Clause 100. The method of any one of clauses 1-99, wherein the subject has a plasma pTau217 / Tau217 ratio mean of about 3.7.

[0521] Clause 101. The method of any one of clauses 1-100, wherein the subject has a skin biopsy composite score mean of about 7.3.

[0522] Clause 102. The method of any one of clauses 1-101, wherein the subject has a Montreal Cognitive Assessment Scale (MOCA) mean score of about 18.4 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0523] Clause 103. The method of any one of clauses 1-102, wherein the subject has an Epworth Sleepiness Scale (ESS) score of about 8.4 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0524] Clause 104. The method of any one of clauses 1-103, wherein the subject has a Clinical Assessment of Fluctuation (CAF) severity score of about 5.0 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0525] Clause 105. The method of any one of clauses 1-104, wherein the subject has an Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score of about 62.2 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0526] Clause 106. The method of any one of clauses 1-105, wherein the subject has a Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS3)Attorney Docket No. 134851-003002Total Score of about 27.6 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0527] Clause 107. The method of any one of clauses 1-106, wherein the subject has a Neuropsychiatric Inventory (NPI) total score A- J of about 8.6 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0528] Clause 108. The method of any one of clauses 1-107, wherein the subject has a Neuropsychiatric Inventory (NPI) total distress score A-J of about 5.0 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0529] Clause 109. The method of any one of clauses 1-108, wherein the subject has a Quality of Memory composite score of about 177.6 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0530] Clause 110. The method of any one of clauses 1-109, wherein the subject has a Quality of Working Memory composite score of about 1.1 before administration of a compound of formula COMPOUND I or a pharmaceutically acceptable salt thereof.

[0531] Clause 111. The method of any one of clauses 1-110, wherein the subject has a Quality of Episodic Secondary Memory composite score of about 67.1 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.

[0532] Clause 112. The method of any one of clauses 1-111, wherein the compound is administered orally.

[0533] Clause 113. The method of any one of clauses 1-112, wherein the compound is administered for about 6 months.

[0534] Clause 114. The method of any one of clauses 1-113, wherein the compound is administered for at least about 6 months.

[0535] Clause 115. The method of any one of clauses 1-114, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

[0536] Clause 116. The method of any one of clauses 1-115, wherein the therapeutically effective amount is about 100 mg.

[0537] Clause 117. The method of any one of clauses 1-116, wherein the therapeutically effective amount is about 200 mg.

[0538] Clause 118. The method of any one of clauses 1-117, wherein the therapeutically effective amount is about 300 mg.

[0539] Clause 119. The method of any one of clauses 1-118, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.Attorney Docket No. 134851-003002

[0540] Clause 120. The method of any one of clauses 1-119, wherein the therapeutically effective amount is a total daily dose of about 100 mg.

[0541] Clause 121. The method of any one of clauses 1-120, wherein the therapeutically effective amount is a total daily dose of about 200 mg.

[0542] Clause 122. The method of any one of clauses 1-121, wherein the therapeutically effective amount is a total daily dose about 300 mg.

[0543] Clause 123. The method of any of clauses 115-122, wherein the total daily dose is administered for about 6 months.

[0544] Clause 124. The method of any of clauses 115-122, wherein the total daily dose is administered for at least about 6 months.

[0545] EXAMPLES

[0546] In all examples, CT 1812 is Compound I with a structure of

[0547] Example 1: Clinical Trial Testing Safety and Efficacy of CT1812 in Patients with Dementia with Lewy Bodies

[0548] The SHIMMER study was a double-blind, placebo-controlled, 6-month clinical trial designed to evaluate the safety and efficacy of CT1812 in patients with Dementia with Lewy Bodies (DLB). The trial enrolled 120 participants who were evenly randomized into three groups: CT1812 300 mg (N=40), CT1812 100 mg (N=40), and placebo (N=40). Participants were screened for DLB using diagnostic MRI and lumbar puncture (LP), and their Mini-Mental State Examination (MMSE) scores ranged from 18 to 27. The study's primary and secondary endpoints included assessments of safety, cognitive function, and neuropsychiatric symptoms.

[0549] For each clinical outcome assessment, the difference between treatment groups (combined CT 1812 vs. placebo) was assessed using a mixed model for repeated measures (MMRM) with change from baseline values at Day 28, Day 98, and Day 182 as the response values, treatment group (CT 1812 100 mg, CT 1812 300 mg, placebo), time point, and a treatment group by time point interaction as fixed effects, subject as a random effect, and baseline value as a covariate. ADCS- CGIC was assessed similarly, the only difference was the observed values at Day 28, Day 98, and Day 182 were used as the response values, rather than the change from baseline values, as the observed CGIC score inherently reflects the subject’s change from baseline. Other than the controlledAttorney Docket No. 134851-003002 formal statistical testing of the change from baseline in MoCA score at Day 182, no adjustments for multiplicity were made for the testing of other endpoints evaluated in the study.

[0550] Table SLIDE 10 shows the key characteristics of the study patients, which were generally well balanced between treatment groups.Table SLIDE 10. Demographics and Baseline Characteristics

[0551] Safety assessments were conducted throughout the study, including monitoring for treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Cognitive function was evaluated using the Montreal Cognitive Assessment (MOCA) and the Cognitive Drug Research Battery (CDR). The Clinician Assessment of Fluctuation (CAF) was used to measure cognitive fluctuations, while the Epworth Sleepiness Scale (ESS) assessed daytime sleepiness. Motor symptoms were evaluated using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III). Functional outcomes were measured using the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, and global clinical changes were assessed with the Alzheimer's Disease Cooperative Study - Clinical Global ImpressionAttorney Docket No. 134851-003002 of Change (ADCS-CGIC). Neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI).

[0552] Plasma biomarkers, including phosphorylated tau (pTaul81, pTau217), amyloidbeta (AP), glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and alpha- synuclein (a-Syn), were measured at baseline and at the end of the study (Day 182).

[0553] The study employed a mixed-model for repeated measures (MMRM) to analyze the change from baseline values for each clinical outcome assessment at Days 28, 98, and 182, with treatment group, time point, and treatment group by time point interaction as fixed effects, subject as a random effect, and baseline value as a covariate. ADCS-CGIC was assessed similarly, the only difference was the observed values at Day 28, Day 98, and Day 182 were used as the response values, rather than the change from baseline values, as the observed CGIC score inherently reflects the subject’s change from baseline.

[0554] Example 2: Cognition Therapeutics ’ Proof-of-Concept SHIMMER Trial Demonstrates Consistent Improvement in Cognitive Outcomes with Once-Daily Oral CT1812 in Mild-to-Moderate Dementia with Lewy Bodies Patients

[0555] The SHIMMER study demonstrated that CT 1812 was generally safe and well- tolerated in patients with Dementia with Lewy Bodies. 293 subjects were screened, 130 were randomized, and 109 (83.8%) completed the study. Baseline characteristics included the following, listed in Table 2 A and Table 2B.Table 2A. Baseline Characteristics for Treatment GroupsAttorney Docket No. 134851-003002Table 2B. Baseline Characteristics for Combined Treatment, Placebo, and TotalAttorney Docket No. 134851-003002Table 3 A. Baseline Characteristics for Scores for Treatment GroupsAttorney Docket No. 134851-003002Attorney Docket No. 134851-003002Attorney Docket No. 134851-003002Table 3B. Baseline Characteristics for Scores for Combined Treatment Groups, placebo and total.Attorney Docket No. 134851-003002Attorney Docket No. 134851-003002Attorney Docket No. 134851-003002Attorney Docket No. 134851-003002

[0556] The completion rates were 90.9% for the CT1812 100 mg group, 75.0% for the CT1812300 mg group, and 85.7% for the placebo group. 21 patients (16.2%) discontinued the study. Discontinuation rates per group were 9.1% in CT1812 lOOmg, 25.0% in CT1812 300mg, and 14.3% in placebo. The most common reason for discontinuation was adverse events (AEs), which were 11.5% across all treatment groups. Overall, the percentage of subjects experiencing any AE was similar between the pooled CT 1812 treatment group (94.3%) and the placebo group (88.1 %). Serious AE rates were 10.3% among CT1812 subjects and 19.0% among placebo subjects. Most subjects had adverse events that were mild or moderate, as shown in Table 4 which shows the incidence of treatment-emergent adverse events by maximum severity for an adverse event within each subject. In the lOOmg group, more subjects had mild adverse events and fewer had severe adverse events relative to subjects in the 300mg and placebo groups.Table 4. Safety Summary

[0557] Adverse events led to discontinuation with a rate of 9.1% in the CT1812 100 mg group, 20.5% in the CT1812 300 mg group, and 4.8% in the placebo group. The overall incidence ofAttorney Docket No. 134851-003002TEAEs was similar across groups, with 95.5% in the CT1812 100 mg group, 93.0% in the CT1812 300 mg group, and 88.1% in the placebo group. Serious adverse events (SAEs) were less frequent in the CT1812 groups compared to placebo, with rates of 9.1% in the CT1812 100 mg group, 11.6% in the CT1812 300 mg group, and 19.0% in the placebo group. The SAE that was related to treatment was for subject 125-0003 (CT1812 300mg). The preferred term was “metabolic encephalopathy”. Severity was moderate, drug was interrupted, it was rated as “probably related”, and the outcome was recovered / resolved. It emerged on day 120 and ended on Day 190. During the study, one participant in the placebo group passed away due to sepsis. Additionally, two participants in the 300mg dose group also passed away; one due to aspiration pneumonia and the other peacefully in her sleep. These events were determined to be unrelated to the treatment.Table 5. Safety SummaryAttorney Docket No. 134851-003002Table 6. Somnolence AEs DetailsTable 7. Dates of Somnolence AEsAttorney Docket No. 134851-003002

[0559] Liver function tests (LFTs) such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were monitored. Elevations in these enzymes above the ULN were considered significant and were used to identify potential liver toxicity associated with the treatment. Four subjects (9.3%) in the 300mg group and 1 subject (2.3%) in the lOOmg group had ALT or AST levels exceed 3 times the ULN (>3x ULN), which were closely monitored (Table 8).Table 8. LFT AbnormalitiesAttorney Docket No. 134851-003002

[0560] Subjects with LFT elevations greater than 3x ULN included those listed in Table 9 and Table 10.Table SLIDE 9. Subjects with LFT Elevations > 3X ULNAttorney Docket No. 134851-003002Table 10. Subjects with LFT Elevations > 3X ULN[0561 Efficacy assessments showed favorable treatment differences for CT1812, including nearly significant differences (p<0.1) for ADCS-ADL, NPI, MOCA, CDR (episodic memory), CAF, UPDRS, and ADCS-CGIC. Within the NPI, notable favorable treatment differences were observed for anxiety (p<0.01), hallucinations (p<0.05), and delusions (p<0.10) domains with similarly favorable treatment differences observed on NPI caregiver distress ratings for anxiety (p<0.05), hallucinations (p<0.01), and delusions (p<0.10). The percent slowing of decline for the pooled CT1812 treatment group at 6 months ranged from 27% on the CGIC to 114% on the NPI distress rating (60% for MOCA, 85% for CDR episodic memory, 72% for CDR memory, 91% for CAF, 52% for ADL, 82% for NPI total, 114% for NPI distress, 62% for UPDRS, 27% for ADCS- CGIC).Attorney Docket No. 134851-003002

[0562] Most outcomes showed positive treatment differences, including CDR Episodic Memory, CAF, MOCA, ADCS-ADL, NPI Total Score (A-J), NPI Distress Score (A-J), UPDRS, ADCS-CGIC, NPI Total Score (A-J), NPI Distress Score, Anxiety, Anxiety (Distress), Hallucinations, Hallucinations (Distress), Delusions, and Delusions (Distress). Results are summarized in Table 11, FIG. 1A, FIG. IB, FIG. 1C, FIG. ID, FIG. IE, FIG. IF, FIG. 1G, and FIG. 1H, where deltas reflect the difference in LS means vs. placebo at each timepoint.Table 11. Exploratory Outcomes SummaryAttorney Docket No. 134851-003002

[0563] The percent slowing was based on the deltas of the differences in LS means vs. placebo at Day 182, as shown in Table 12.Table 12. Exploratory Outcomes SummaryAttorney Docket No. 134851-003002

[0564] The measurement of episodic memory (CDR) includes word recognition, picture recognition, immediate word recall and delayed word recall. There was an 85% slowing of worsening of episodic memory when pooled treatment data was compared with placebo (FIG. 2). CDR (Quality of Memory) includes spatial working memory, numeric working memory, word recognition, picture recognition, immediate word recall and delayed word recall. A 72% slowing of the worsening of CDR was observed when pooled treatment data was compared with placebo (FIG. 3). Measurements of MOCA slowed 60% when pooled treatment data was compared with placebo (FIG. 4). For patients with Hoehn and Yahr measurements greater than 2, MOCA measurements slowed 75% in the treated groups compared to placebo (FIG. 5). In addition, patients who were biopsy positive had MOCA measurements that showed 116% slowing compared to placebo (FIG. 6). Clinician assessment of fluctuations (CAF) showed 91% slowing of worsening of the LS mean change from baseline when the pooled treatment data were compared with the placebo (FIG. 7). Measurements of ADCS-ADL showed 52% slowing when pooled treatment data was compared to placebo (FIG. 8). Measurements of NPI Total Score showed 82% slowing when pooled was compared with placebo (FIG. 9). For measurements of NPI Total Distress Score (A- J), the pooled treatment data showed a 114% slowing compared to placebo data (FIG. 10). Pooled data from the unified Parkinson’s disease rating scale (UPDRS) showed a 62% slowing when pooled treatment data were compared to placebo data (FIG. 11). Measurements of clinical global impression of change (ADCS-CGIC) showed a 27% slowing when pooled treatment data were compared with placebo (FIG. 12).

[0565] Treatment with CT 1812 improved measurements of ADCS-CGIC, with fewer treated patients becoming minimally, moderately or markedly worse than patients treated with placebo (FIG. 13). More patients were minimally improved, moderately improved, or even showed no change in the treatment groups compared to the placebo. CT1812 benefits a variety of DLB symptoms relative to placebo treatment over 6 months, including memory impairment and cognitive fluctuations (CDR memory and CAF), behavioral symptoms (NPI total, and particularly the anxiety, hallucinations, and delusions domains), motor deficits (UPDRS) and activities of daily living (ADCS-ADL). In addition, caregiver distress due to patient neuropsychiatric symptoms is lower relative to placebo in patients treated with CT1812.

[0566] Plasma biomarker analyses will reveal that CT 1812 treatment results in reductions in neurofilament light chain (NFL), a marker of neurodegeneration. Other biomarkers, including pTaul81, pTau217, A0, GFAP, and a-Syn, will also show reductions.

[0567] Overall, the SHIMMER study provided evidence that CT 1812 may benefit a variety of DLB symptoms, including memory impairment, cognitive fluctuations, behavioral symptoms, motor deficits, and activities of daily living. The study also suggested that caregiverAttorney Docket No. 134851-003002 distress due to patient neuropsychiatric symptoms was lower in patients treated with CT 1812 compared to placebo.

[0568] Example 3: Global Treatment Endpoint (GTE) as treatment indication of CT1812 in DLB and primary endpoint for a Phase 2b study

[0569] DLB is recognized as a condition with highly heterogeneous and fluctuating symptoms, including variability in presence, severity, and timing of symptom emergence. No single “gold-standard” instrument or specific symptom outcome exists that adequately captures the diverse clinical presentation of DLB.

[0570] The composite global treatment endpoint (GTE), derived by using the global statistical test (GST) methodology, addressed the limitations of single-domain outcome measures by capturing the holistic CT1812 treatment effect in a population with diverse and fluctuating symptoms. A composite score derived from multiple trial measures captures a holistic picture of the participant’s health, analogous to the use of trial instruments such as the Clinician Interview-based impression of change plus caregiver input (CIBIC+), but with the advantage of objective measure of multiple domains. The GTE was developed based on scores / subscores from COG1201 key outcomes, including the Neuropsychiatric Inventory 4 (NPI-4), Cognitive Drug Research System Battery, quality of memory subscore (CDR-QM), CAF, and UPDRS3. NPI-4 was assessed as a post-hoc analysis focusing on anxiety, agitation / aggression, delusions and hallucinations item scores.

[0571] In the Phase 2 COG1201 study in DLB, data exhibited good assay sensitivity, showed consistent benefits of CT1812 over 6 months across symptom domains (behavior, function, cognition, motor, fluctuations) used in GTE, and those effects were observed on top of background symptomatic therapy (e.g., AChE inhibitors, memantine, dopaminergics), underscoring added clinical value in real-world practice. The GTE generated from SHIMMER data demonstrated that CT1812 treatment improved the GTE score compared to that of placebo. The ADCS-ADL had been analyzed separately to determine functional change, with the option to include it within the GTE. Through surveys of individuals with DLB, caregivers, healthcare professionals and review of the literature, hallucinations and delusions, Parkinsonism, fluctuations in cognition, sleep and motor disturbances have been identified as the priority symptoms of DLB reported in more than fifty percent of respondents. The GTE addressed all those priority symptoms with the exception of REM Sleep Behavior Disorder which could be studied in the future with appropriate sleep labs. Secondary analyses included patient-reported quality of life assessments.

[0572] Measures used in GTE were qualified as they had verified psychometric properties, as listed in Table 13. While information on the psychometric properties of CDR-QM were limited, CDR-QM were highly and significantly correlated with both MMSE and MoCA measuresAttorney Docket No. 134851-003002 at baseline for the COG1201 (FIG. 14). Based on the high correlation, it was evident that the CDR- QM tracks with general cognitive measures such as the MMSE and MOCA. Given its greater sensitivity to detect change over time in DLB patients, the CDR-QM was an appropriate measure to track cognitive performance in the context of overall DLB symptomatology particularly within a GTE composite and with functional benchmarking of the GTE composite to the ADCS-ADL.

[0573] Table 13. Psychometric Properties of Components of the proposed GST

[0574] The baseline characteristics of the overall SHIMMER study population reasonably reflected what is known about the mild to moderate DLB population (Table 14). All participants had significant cognitive impairment as assessed by MMSE to qualify for the study. Analysis of the study population from the study across domains of behavior as measured by NPI-4, fluctuations as measured by CAF and movement as measured by UPDRS3 supported the idea that few participants experienced all other symptoms (Table 15). Cut points were applied to identify individuals with mild or no symptoms, counting only those with meaningful domainAttorney Docket No. 134851-003002 symptomatology. At baseline, 44% of participants had experienced only one or two domains beyond cognitive impairment, which further supported using a composite score integrating outcomes across all potential symptom domains. Cognitive impairment itself was excluded from the analysis because it was an inclusion requirement for the study and thus present in all participants. In the SHIMMER study, which recruited according to McKeith criteria, only 16% of participants had more than mild symptoms in all domains, making it difficult to power a study that evaluated each symptom domain separately without requiring an excessively large sample size. While a study could have recruited only individuals with a particular symptom profile — such as troubling hallucinations and delusions — to assess that domain as a primary outcome, this approach would have limited the ability to measure the effects of a drug intended to broadly affect the overall disease state, as CT1812 were believed to do in DLB. The study dataset had mean baseline scores of the GTE composite components and Z scores well balanced across treatment groups and adequately characterized DLB symptomatology within the study population, making it adequate for modeling the composite GTE (Table 16).

[0575] Table 14. Baseline characteristics of the SHIMMER participants

[0576] Table 15. Mean baseline scores of the components of the composite and ADCS- ADL with related z-scores.SHIMMER Baseline Score: Mean (SD)Attorney Docket No. 134851-003002

[0577] *Z-Scores have been harmonized so that positive scores represent higher performance

[0578] The strength of how each GTE component was correlated as well as correlations with the GTE itself and the ADCS-ADL were shown in FIG. 15. The components were weakly correlated, which was ideal. The GTE was calculated using the following steps:

[0579] 1. The standard deviation of the change from baseline for each component of GTE, at each visit, and within each treatment arm was calculated to determine component level variability.

[0580] 2. The standard deviations by visit and endpoint were pooled for each component using the following formula:

[0581] 3. The change from baseline (CHG) of each component for all patients was divided by the corresponding pooled standard deviation to get a z-score for subject i and outcome j.CHGi j z . . = - -2_A, 7 nSpooled j

[0582] 4. The mean of the z-scores across different components by subject and visit were calculated to get the GST change from baseline (Z) for subject I with J outcomes being included in the GST.

[0583] The performance of the GTE within the study dataset was evaluated by assessing certain validation criteria as shown in Table 16.

[0584] Table 16. Endpoint Validation Criteria for Development of the GTEAttorney Docket No. 134851-003002Attorney Docket No. 134851-003002

[0585] While internal consistency was desirable in the context of many composites, the unique information contributed by each of the components was more important than the shared information and having high internal consistency only decreases the contribution of additional outcomes to our understanding of disease progression and treatment effect. To test the internal consistency of the GST, Cronbach’s alpha analysis was performed using the different subscales to be put into the composite scores for placebo subjects. These alpha values ranged from 0.32 for the composite without ADCS-ADL to 0.53 with ADCS-ADL which is below the typical acceptable threshold of 0.7 required for a validated composite score with higher values representing higher internal consistency. However, the subscales were designed to measure different symptomology within DLB patients. As such, it was unexpected for this value to be as high as a composite that was meant to measure the same symptoms.

[0586] To test the construct validity, or whether the measurement tool truly captures the theoretical concept or characteristic it was intended to measure, an exploratory factor analysis (EFA) was run within placebo subjects on the different components or subscales to be combined into the GTE. Only one factor was identified at Day 182 with most factor loadings being higher than 0.3.Attorney Docket No. 134851-003002This indicated that all the outcomes are contributing to one construct (DLB progression). The EFA confirmed a single underlying factor, demonstrating that every component, regardless of its specific domain, was driven by the same fundamental disease process. The composite was fundamentally a single measure of disease progression. The modest Cronbach's Alpha value confirmed that while the components were unified in their purpose, they were not redundant. They each captured distinct facets or manifestations of the disease, providing a holistic, multi-dimensional, and highly sensitive measure of treatment effect.

[0587] To determine if the GTE scale was correlated with other established measures of clinically meaningful difference in DLB patients over time, the composite was correlated with the ADCS-ADL. These correlations were strong for both the baseline and change from baseline scores, indicating that the GTE tracks with the actual severity and progression of DLB (FIG. 16A and FIG 16B).

[0588] In addition to correlation with the ADCS-ADL, to further show meaningfulness and importance in a real-world, clinical context, the GTE composite was correlated with ADCS- CGIC. These correlations (r 0.39, p=0.00002) indicated that the composite is highly associated with detectable differences in the day-to-day lives of DLB patients.

[0589] To confirm the GTA composite scale's statistical ability to detect change over time within the study population, the study dataset was applied to calculate composite scores with the GTE over time (FIG. 17). The resulting changes were large and statistically significant (p=0.004, 0.003 and 0.0008 for 100 mg, 300 mg and pooled CT1812 groups, respectively) indicating that this scale is highly effective for measuring differences between treatment arms in a longitudinal study.

[0590] The heterogeneity of symptomatology also leads to ceiling and floor effects for specific symptom assessments. This was addressed by the GTE as well. The clustering of data at minimal and maximal values or within mild to no symptomatology was evident.

[0591] The heterogeneity of symptoms captured by the composite's subscales suggested that differences in individual subscale scores were expected. Each subscale provided unique and essential information on disease progression, evidenced by the low correlation observed among them.

[0592] The test-retest reliability was evaluated to accurately assess the stability and reproducibility of the scores. Pearson correlation coefficients (a measure of linear consistency) and the Intraclass Correlation Coefficients (ICC) were calculated for each score across sequential time points in the SHIMMER trial (baseline vs. month 1, month 1 vs. month 3, month 3 vs. month 6). Based on the consistently high and statistically significant correlation coefficients observed in the placebo group across multiple time intervals, the GTE composite score demonstrated acceptable test- retest reliability when considering the large intervals of time between visits.Attorney Docket No. 134851-003002

[0593] The performance characteristics of the GTE composite (Table 16) and modeled statistics from the pooled treatment group at Day 182 (Table 17) of each of the components from the study dataset demonstrated the advantage of the composite approach versus the individual components, supporting the basis for the GTE composite approach.

[0594] Table 16. Performance properties of GTE and components modeled fromSHIMMER

[0595] Table 17. Statistics of each component of the GTE modeled from the study dataset

[0596] The intention of using GTE was not to derive clinical meaningfulness. Instead, GTE should be correlated to ADCS-ADL measures and used to demonstrate an overall treatment effect on global DLB symptomatology while the ADCS-ADL demonstrated real-world, functional impact. The ADCS-ADL had been used in a similar fashion as a component of composite outcomes (iADRS) or as one of co-primary outcomes (ADAS-Cog and ADCS-ADL) for AD. Because AD presents primarily as a memory disorder at least until more advanced stages, the ADAS-Cog workedAttorney Docket No. 134851-003002 as an excellent scale to assess nearly the entirety of the clinical symptomatology, and the ADCS- ADL gave real-world functional context to what a change on the ADAS-Cog scale may mean for an individual with AD. In contrast, DLB, being different from AD, presents with diverse symptoms that vary in presence, severity and timing of onset. The GTE assessed the broad disease symptomatology while the ADCS-ADL provided context to real-world, functional meaningfulness.

Claims

1. Attorney Docket No. 134851-003002CLAIMS1. A method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of structure(Compound I) or a pharmaceutically acceptable salt thereof, wherein the administration results treatment of the DLB in the subject.2 A method of treating Dementia with Lewy Bodies (DLB) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I, wherein the administration results in an improvement or maintenance of a Global Treatment Endpoint (GTE) score in the subject.3 A method of improving or maintaining a Global Treatment Endpoint (GTE) score in a subject with Dementia with Lewy Bodies (DLB), comprising administering to the subject a therapeutically effective amount of a compound of formula Compound I, wherein the administration results in an improvement or maintenance of a GTE score in the subject with DLB.4 The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in a Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in the subject compared to placebo.5 The method of claim 4, wherein the improvement in a Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in the subject is about 2 to about 8 points better than placebo.6 The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation in a Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score in the subject compared to placebo.7 The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in a europsychiatric Inventory (NPI) total score in the subject compared to placebo.Attorney Docket No. 134851-0030028. The method of claim 7, wherein the improvement in the Neuropsychiatric Inventory (NPI) total score includes improvements in assessments of anxiety, hallucinations, and delusions.

9. The method of claim 7, wherein the improvement in the Neuropsychiatric Inventory (NPI) total score is about 2 to about 10 points better than placebo.

10. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of a europsychiatric Inventory (NPI) total score in the subject compared to placebo.

11. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in at least one of anxiety, hallucinations, or delusions.

12. The method of claim 11, wherein the improvement in at least one of anxiety, hallucinations, or delusions is assessed by a Neuropsychiatric Inventory (NPI) compared to placebo.

13. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of at least one of anxiety, hallucinations, or delusions in the subject compared to placebo.

14. The method of claim 13, wherein the preservation of at least one of anxiety, hallucinations, or delusions is a percent slowing compared to placebo.

15. The method of claim 14, wherein the percent slowing compared to placebo is about 50% to about 90% after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in motor symptoms as measured by a Unified Parkinson's Disease Rating Scale (UPDRS) in the subject compared to placebo.

17. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of motor symptoms as measured by a Unified Parkinson's Disease Rating Scale (UPDRS) in the subject compared to placebo.

18. The method of claim 16, wherein the improvement in motor symptoms is a reduction in the UPDRS score of about 2 to about 10 points compared to placebo.Attorney Docket No. 134851-00300219. The method of claim 17, wherein the preservation of motor symptoms is a percent slowing in an increase of the UPDRS score compared to placebo.

20. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in at least one of rigidity, tremor, or bradykinesia as measured by a UPDRS.

21. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of at least one of rigidity, tremor, or bradykinesia as measured by a UPDRS.

22. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in an improvement in cognition as measured by at least one of a Montreal Cognitive Assessment Scale (MOCA), a Cognitive Drug Research Battery (CDR) memory scale, a Clinician Assessment of Fluctuation (CAF), or a Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) in the subject compared to placebo.

23. The method of any one of claims 22, wherein the improvement in cognition is a percent improvement compared to placebo after 6 months of administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 22, wherein the MOCA score is improved by about 15% to about 110%.

25. The method of any one of claims 1-3, wherein the administration of the compound of formula Compound I or a pharmaceutically acceptable salt thereof results in preservation of cognition as measured by at least one of a Montreal Cognitive Assessment Scale (MOCA), a Cognitive Drug Research Battery (CDR) memory scale, a Clinician Assessment of Fluctuation (CAF), or a Alzheimer's Disease Cooperative Study - Global Clinical Impression of Change (ADCS-GCIC) in the subject compared to placebo.

26. The method of any one of claims 1-25, wherein the pharmaceutically acceptable salt is a fumarate salt.

27. The method of any one of claims 1-26, wherein the subject has a mean Mini-Mental State Examination (MMSE) score of about 24 before administration of a compound of formula Compound I or a pharmaceutically acceptable salt thereof.Attorney Docket No. 134851-00300228. The method of any one of claims 1-27, wherein the subject is on a stable regimen of acetylcholinesterase inhibitors or memantine.

29. The method of any one of claims 1-28, wherein the subject has a mean time since Dementia with Lewy Bodies diagnosis of about 1 to about 2 years.

30. The method of any one of claims 1-29, wherein the subject has a mean Hoehn and Yahr stage of about 2.

31. The method of any one of claims 1-30, wherein the subject has an apolipoprotein E4 genotype that is either positive or negative.

32. The method of any one of claims 1-31, wherein the compound is administered orally.

33. The method of any one of claims 1-32, wherein the compound is administered for about 6 months.

34. The method of any one of claims 1-33, wherein the compound is administered for at least about 6 months.

35. The method of any one of claims 1-34, wherein the therapeutically effective amount is a total daily dose of about 100 mg to about 300 mg.

36. The method of any of claims 35, wherein the total daily dose is administered for about 6 months.

37. The method of any of claims 35, wherein the total daily dose is administered for at least about 6 months.

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