Sulfopropanoic acid derivatives for treating neurodegenerative disorders

Abstract

Provided herein is the use of a compound of Formula I: or a pharmaceutically acceptable salt thereof, for treating a disease characterized by amyloid and amyloid-like aggregates, e.g., Alzheimer's disease.

Description

(19) *EP004671757A2* (11) EP 4 671 757 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 31.12.2025 Bulletin 2026 / 01 (21) Application number: 25210213.2 (22) Date of filing: 30.07.2019 (51) International Patent Classification (IPC): G01N 33 / 52 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 31 / 222; A61K 31 / 221; A61K 31 / 223; A61K 31 / 225; A61K 31 / 255; A61P 25 / 28; G01N 33 / 50; G01N 33 / 52; G01N 2800 / 2821 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 01.08.2018 US 201862713056 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 23188362.0 / 4 296 670 19752609.8 / 3 829 568 (71) Applicant: Alzheon, Inc. Framingham, MA 01701 (US) (72) Inventors: • Kocis, Petr Framingham, 01701 (US) • Hey, John Framingham, 01701 (US) • Tolar, Martin Framingham, 01701 (US) (74) Representative: Potter Clarkson Chapel Quarter Mount Street Nottingham NG1 6HQ (GB) Remarks: •This application was filed on 21‑10‑2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of filing of the application (Rule 68(4) EPC). (54) SULFOPROPANOIC ACID DERIVATIVES FOR TREATING NEURODEGENERATIVE DISORDERS (57) Provided herein is the use of a compound of Formula I: or a pharmaceutically acceptable salt thereof, for treating a disease characterized by amyloid and amyloid-like aggre- gates, e.g., Alzheimer’s disease. EP 4 67 1 75 7 A 2 Processed by Luminess, 75001 PARIS (FR) Description RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62 / 713,056, filed August 1, 2018, the entire contents of which are incorporate herein by reference. BACKGROUND

[0002] Alzheimer’s disease (AD) is a progressivedegenerative diseaseof the brain primarily associatedwith aging. The growing magnitude of the health care cost to society for AD is underscored by the number of patients afflicted across geographical regions with over 5.7 million in the U.S. (Alzheimer’s Association 2018) and 35 million worldwide (World Alzheimer Report 2016). Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and linguistic abilities are also affected until there is global impairment ofmultiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years.

[0003] Presently, the two classes of approved drugs for AD are cholinesterase inhibitors and memantine. Both classes are symptomatic agents that target secondary neurotransmitter deficiencies seen in AD. Neither class, however, demonstrates efficacy beyond 6 months of treatment in clinical trials and there is no evidence of these classes targeting the underlying disease pathology. Emerging anti-amyloid antibodies (e.g. aducanumab) show promise as potential disease-modifying treatments when used at early stages of the disease. See e.g., Lasser et al. Efficacy and Safety of Gantenerumab in Prodromal AD: Results from Scarlet Road-a Global, Multicenter Trial. Alzheimer’s Association International Conference (AAIC) 2015 Abstract ID: 5963. However, some amyloid immunotherapies have been asso- ciated with a dose-dependent risk of amyloid related imaging abnormalities with edema (ARIA-E), with increased risk reported in APOE4 carriers. See e.g., Salloway et al. Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease. N Engl J Med 2014; 370:322‑33; Sevigny et al., The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 2016; 537:50‑6; and Caselli et al. Longitudinal modeling of age-related memory decline and theAPOEepsilon4effect.NEngl JMed2009; 361:255- 263.This presents adevelopment challenge, sincedoses that showamyloid clearanceandclinical benefit areassociatedwithapproximately 40% incidenceofARIA-Eat the twohighest doses of aducanumab. See Sevigny et al. A dose titration regimen with aducanumab still shows approximately 35% incidence of ARIA-E in APOE carriers. See e.g., Viglietta et al., Aducanumab titration dosing regimen: 12-month interim analysis from prime, a randomized double blind, placebo-controlled phase Ib study in patients with prodromal or mild Alzheimer’s disease. J Prev Alzheimers Dis 2016; 3, suppl 1:378. Although ARIA-E may be asymptomatic or mildly symptomatic inmost patients, some patientsmay develop seizures or other serious adverse events. The risk of ARIA-E in AD patients may require MRI monitoring, which is burdensome in elderly population, and could limit the utility of these drugs in clinical practice.

[0004] Soluble low molecular weight Aβ42 oligomers are now recognized as key drivers of AD pathogenesis and increased concentration of Aβ42 oligomers correlates closely with onset and progression of clinical symptoms. See e.g., Viglietta et al. Soluble Aβ oligomers have been shown to cause synaptic damage, neuronal death, promote tau phosphorylation and drive tau pathology. See e.g., Esparza et al., Amyolid beta oligomerization in Alzheimer’s dementia vs. high pathology controls. AnnNeurol 2013; 73(1):104‑119;Hashimoto et al. ApolipoproteinE, especially apolipoprotein E4, increases t peptide. J Neurosci. 2012; 32:15181‑15192; Ono et al., Low-n oligomers as therapeutic targets of Alzheimer’s disease. J. Neurochem. 2011;117:19‑28; Townsend et al., Effects of secreted oligomers of amyloid beta- protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol.; 2006;572:477‑92; and Lambert et al. Diffusible, nonfibrillar ligands derived from A 1‑42 are potent central nervous system neurotoxins. PNAS. 1998; 95:6448‑53. Importantly, APOE 4 / 4 AD patients have been shown to a have a higher burden of soluble amyloid oligomers (Usui et al., Site-specific modification of Alzheimer’s peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity. PNAS.; 2009;106:18563‑8), which is likely responsible for the earlier disease onset in this population.

[0005] Todate, only agents targetingAβoligomers suchasaducanumabandALZ‑801 / tramiprosatehaveshownclinical benefits in amyloid positive AD patients. Tramiprosate, 3-amino‑1-propanesulfonic acid (3APS) is an oral amyloid anti- aggregation agent which reduces amyloid beta oligomer neurotoxicity. The tramiprosate Phase 3 trials in mild-to- moderate AD showed an excellent drug profile, including the capability to slow the reduction of brain hippocampal volume, and to improve brain cognition and function in subset analyses. See e.g., Gauthier, S. et al. Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: exploratory analyses of theMRI sub-group of the Alphase study. J Nutr Health Aging 13, 550‑557 (2009); Saumier, D., Duong, A., Haine, D., Garceau, D. & Sampalis, J. Domain-specific cognitive effects of tramiprosate in patients with mild to moderate Alzheimer’s disease: ADAS-cog subscale results from the Alphase Study. J Nutr Health Aging 13, 808‑812 (2009); and Aisen, P. S. et al. Tramiprosate in mild-to-moderate 2 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 7, 102‑111 (2011).

[0006] ALZ‑801 is in clinical development asanoral, smallmolecule inhibitor of beta amyloid (Aβ) oligomer formation for the treatment of Alzheimer’s disease (AD). ALZ‑801 is a valine conjugate of tramiprosate with improved pharmacokinetic properties and gastrointestinal tolerability. See e.g., Hey et al., Clinical Pharmacokinetics and Safety of ALZ‑801, a Novel ProdrugofTramiprosate inDevelopment for theTreatmentofAlzheimer’sDisease.ClinPharmacokinetics2018;315‑333. Tramiprosate, theactivemoietyofALZ‑801, inhibits the formationofAβoligomers in vitro.Seee.g.,Kociset al.,Elucidating the Abeta42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods. Pharmacokinetic and Clinical Data. CNSDrugs 2017; 31:495‑509. Oral tramiprosate was previously evaluated in two Phase 3 studies, which included 2,015 patients with mild to moderate AD, treated with 100 mg BID of tramiprosate, 150mgBIDof tramiprosate, or placebo.Safetydata from thesePhase3 trialsand thesafetyextensionstudy, suggest a favorable safetyprofilewith tramiprosateexposuresof up to2.5years.Seee.g.,Abushakraet al.,Clinical effects of tramiprosate inAPOE4 / 4homozygouspatientswithmildAlzheimer’s disease suggest diseasemodification potential. J Prev Alzheimers Dis 2017; 4:149‑56. In a subgroup analysis of subjects with the ε4 allele of apolipoprotein E (APOE4), there was a positive and clinically meaningful benefit on cognition. SUMMARY

[0007] The biotransformation of ALZ‑801 to tramiprosate is shown in FIG. 1. As explained earlier, tramiprosate inhibits the formation of Aβ oligomers and is being evaluated for the treatment of mild to moderate AD.

[0008] Wehavenow foundametaboliteof tramiprosate, 3-sulfopropanoicacid (3-SPA),present inhumancerebrospinal fluid (CSF) andplasmaof drug-naive subjects (Seee.g.,FIG.2andFIG.3), andhave identified that thismetabolite inhibits aggregationofAβ42 into small oligomerswithefficacycomparable to that of tramiprosate itself. Seee.g.,FIG.4andFIG. 5.

[0009] Inaddition,we identifiedan inversecorrelationbetweencognitive impairment severity and theconcentrationof3- SPA in subjects havingmild tomoderate AD, therefore suggesting that the level of 3-SPA diminishes as the severity of the cognitive impairment increasesand thatmaintaininghigher levels of 3-SPAmayplaya role inpreventingor diminishing the cognitive decline associated with AD, for example as measured by a subject’s Mini Mental State Examination ("MMSE") score, a well-documentedmethod for determining the severity of Alzheimer’s Disease in the subject. See e.g., Pangman, et al., AppliedNursingResearch. 13 (4): 209‑213.Whatwe foundwas thatADsubjectswithahigherMMSEscore (i.e., less cognitive impairment) possessed higher levels of 3-SPA in theCSFwhen compared to subjects with lowerMMSE scores. See e.g., FIG. 6. This correlation allowed us to determine the trend, or line of best fit, between MMSE score and 3-SPA concentration in CSF for subjects in the test population who were suffering from mild to moderate AD.

[0010] From these findings,wehypothesize that increasing3-SPACSF levels, e.g., to above those found inADsubjects with the least cognitive impairment (i.e., MMSE = 30) (a "baseline threshold level") and maintaining such elevated levels should protect those subjects from further cognitive decline or reduce the rate of cognitive decline as compared to a placebo treatment. Increasing 3-SPACSF levels to above such baseline threshold level can be achieved by administering ALZ‑801, tramiprosate, or a precursor thereof (all of which ultimately produce 3-SPA), or by administering an exogenous form of 3-SPA directly.

[0011] Providedherein, therefore, arecompoundswhicharedesigned tometabolize to3-SPA,and therefore increase3- SPA CSF levels to those subjects in need of protection, e.g., subjects suffering from Alzheimer’s disease, dementia, or cognitive decline. The compounds described herein include compounds having the Formula I: or a pharmaceutically acceptable salt thereof.

[0012] Also provided herein are methods for using the disclosed compounds to treat Alzheimer’s disease (AD) in subjects having a 3-SPA concentration below a certain baseline threshold level e.g., below the 3-SPACSF concentration (± 10%) value determined for a MMSE of 30 in a best fit of a random population of subjects with AD of varying cognitive impairment

[0013] Also provided herein are methods for treating selected AD subjects defined by various severities of cognitive impairment. For example, in oneaspect, the selected subjects for treatmentmayhave certainMMSEscores indicating, for example, an AD severity of mild or mild tomoderate. In other aspects, subjects may have certain MMSE scores and have one ormore of the ε4 allele of the apolipoprotein E (APOE) gene (e.g., be homozygous for APOE4), an abnormal Free and Cued Selective Reminding (FCSR) memory test indicating mild cognitive impairment, and a certain clinical dementia 3 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 rating (CDR).

[0014] Further provided herein are methods for preventing dementia or preventing further cognitive decline in subjects having a 3-SPA concentration below a certain baseline threshold level e.g., below the 3-SPACSF concentration (± 10%) value determined for a MMSE of 30 in a best fit of a random population of subjects suffering from cognitive decline. BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 illustrates the metabolic transformation of ALZ‑801 to 3-sulfopropanoic acid (3-SPA). FIG.2 is agraphshowing the concentration (ng / ml) of 3-SPApresent inhumancerebrospinal fluid (CSF)of drug-naive subjects who have not been diagnosed with AD. FIG. 3 depicts the ion-mobility spectrometry-mass spectrometry (IMS-MS) drift time as a function of mass / charge (m / z) after 4 hr incubation of Aβ42 with 3-SPA in ratio 1:1000 with the profile of Aβ42 oligomers. Detection of Aβ42 dimers, trimersandpentamersunder theseconditions reveals that 4hoursof in-vitro incubationwasnot sufficient for a complete inhibition of oligomer formation. FIG. 4 depicts the ion-mobility spectrometry-mass spectrometry (IMS-MS) drift time as a function of mass / charge (m / z) after 24 hours of incubation shows the profile of Aβ42 oligomers with 1,000-fold excess of 3-SPA. Only pentamers were detected. FIG. 5 is the representation of a molecular dynamics experiment showing semi-cyclic conformation of Aβ42 in the presence of 1,000:1 excess of 3-SPA. The functional result of 3-SPA is similar to the functional end results, i.e. inhibition of Aβ42 oligomer formation, found with tramiprosate (Kocis et al., Pharmacokinetic and Clinical Data. CNS Drugs 2017; 31:495‑509). FIG. 6 illustrates an inverse correlation between 3-SPA levels in humanCSF from a population of subjects having AD with varying MMSE scores (severity of AD). FIG. 7 represents the LC-MS / MS spectra of the authentic 3-SPA reference standard (derivatized with EDC and TFEA). FIG. 8 Panel A represents the LC-MS / MS chromatograms for 3-SPA standard. FIG. 8 Panel B represents the LC-MS / MS chromatograms for human CSF from a single AD subject with MMSE 20. FIG. 9 shows themeanpharmacokinetic curves for single oral and iv dosesof 3-SPA inmaleSD rats (30mg / kgand10 mg / kg, respectively; n=3). Data shown are mean ± SD. FIG. 10 shows the mean brain, CSF and plasma concentration time course of 3-SPA after a single oral dose of 30 mg / kg in male SD rats (n=3). Data shown are mean ± SD. DETAILED DESCRIPTION 1. Definitions

[0016] As used herein, a hyphen ("‑") at the beginning or end of a recited group designates the point at which a recited group is attached to a defined group. For example, ‑O‑(C1‑C4 alkyl)means that the group is attached via the oxygen atom.

[0017] The term "alkylene" refers to a straight or branched bivalent alkyl group.

[0018] The term "C0 alkylene" as used hereinmeans a bond. Thus, amoiety defined herein as "‑(C0‑C20 alkylene)‑aryl" includes both -aryl (i.e., C0 alkylene-aryl) and ‑(C1‑C20 alkylene)‑aryl.

[0019] The term "alkenylene" refers to a straight or branched bivalent alkenyl group.

[0020] The term "alkynylene" refers to a straight or branched bivalent alkynyl group.

[0021] The term "alkyl", used alone or as a part of a larger moiety such as e.g., "haloalkyl", means a saturated monovalent straight or branchedhydrocarbon grouphaving, unless otherwise specified, 1‑10 carbon atomsand includes, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl and the like.

[0022] The term "alkenyl", used alone or as a part of a larger moiety such as e.g., "haloalkenyl", means a monovalent group derived from a straight‑ or branched-chain aliphatic moiety having at least one carbon-carbon double bond having, unless otherwise specified 1‑10 carbon atoms. Representative alkenyl groups include, but are not limited to, ethenyl ("vinyl"), propenyl ("allyl"), butenyl, 1-methyl‑2-buten‑1-yl, and the like.

[0023] The term "alkynyl", used alone or as a part of a larger moiety such as e.g., "haloalkynyl", means a monovalent group derived from a straight‑ or branched-chain aliphatic moiety having at least one carbon-carbon triple bond having, unless otherwise specified 1‑10 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl ("propargyl"), 1-propynyl, and the like.

[0024] "Alkoxy" is an alkyl group which is attached to another moiety via an oxygen linker (-O(alkyl)). Non-limiting 4 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 examples include methoxy, ethoxy, propoxy, and butoxy.

[0025] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, ‑F), chlorine (chloro, ‑Cl), bromine (bromo, ‑Br), and iodine (iodo, ‑I).

[0026] The term "carbocyclyl" (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), as used herein, meansamonocyclic hydrocarbonorbicyclic hydrocarbon,whereineach ring is completely saturatedorpartially saturated, but not aromatic.

[0027] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers monocyclic andbicyclic carbon ringsystemhavinga total of five to10 ringmembers,wherein at least one ring in thesystem is aromatic. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like. In one embodiment, "aryl" is phenyl. It will be understood that when specified, optional substituents on an aryl group may be present on any substitutable position.

[0028] The term "heteroaryl" used alone or as part of a larger moiety as in "heteroarylalkyl", "heteroarylalkoxy", or "heteroarylaminoalkyl", refers to a 5‑ to 12-membered, fully aromatic ring system containing 1‑4 heteroatoms selected fromN, O, and S. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". A heteroaryl group may be mono‑ or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thia- diazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrro- lopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.

[0029] The term "heterocyclyl" means a 4‑ to 12-membered ring system,which is saturated or partially unsaturated (but not aromatic), containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", and "heterocyclic moiety", are used interchangeably herein. A heterocyclyl ring canbeattached to its pendant groupat any heteroatomor carbonatom that results in a stable structure. A heterocyclyl group may be mono‑ or bicyclic. Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Bi-cyclic heterocyclyl groups include, e.g., a hetero- cyclic ring fused to another unsaturated heterocyclic, cycloalkyl, aromatic or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, 6,7-dihydro-SH-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyr- idinyl, 1,2-dihydroquinolinyl, dihydrobenzofuranyl, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, quinoli- none, dioxaspirodecane. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.

[0030] The term "cyclic moiety" refers to a saturated, unsaturated, or partially saturated monocyclic or polycyclic ring system. Such rings systems included, e.g., a carbocyclyl, aryl, heteroaryl, or heterocyclyl as defined above.

[0031] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%or 99.9%byweight optically pure. Percent optical purity byweight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

[0032] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompassesmore than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or anymixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the totalweight in themixtureof thestereoisomersencompassedby thenameor structureby the totalweight in the mixture of all of the stereoisomers.

[0033] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer.

[0034] When a disclosed compound is named or depicted by structure without indicating the stereochemistry and e.g., the compound has more than one chiral center (e.g., at least two chiral centers), it is to be understood that the name or structure encompasses one stereoisomer free of other stereoisomers, mixtures of stereoisomers, or mixtures of 5 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s). For example, the name or structuremay encompass one stereoisomer free of other diastereomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).

[0035] The term "pharmaceutically acceptable salt" is a salt of a basic group (e.g., an amino group) or of an acidic group (e.g., a sulfonic acid) on the compounds described herein. Illustrative salts of a basic group include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, genti- sinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfo- nate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and pamoate (i.e., 1,1 ’-methylene-bis‑(2-hydroxy‑3- naphthoate)) salts. Illustrative salts of an acidic group include, but are not limited, to lithium, sodium, potassium, calcium, magnesium, aluminum, chromium, iron, copper, zinc, cadmium, ammonium, guanidinium, pyridinium, and organic ammonium salts.

[0036] "Pharmaceutically acceptable" refers to drugs, medicaments, inert ingredients etc., which the term describes, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. In one aspect, pharmaceu- tically acceptable refers to a compound or composition that is approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans.

[0037] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carbox- ymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0038] The terms "subject" and "patient" are used interchangeably. In one aspect, the subject is a human. In some aspects, the subject is human age 85 years old or less. In other aspects, the subject is human age 65‑85 years old. In yet other aspects, the subject is human age 58 years old or older.

[0039] 3-sulfopropanoic acid and 3-SPA are used interchangeably and refer to the compound having the structure as well as the mono‑ ( or di-ionic salt forms, where X+ is a counter ion such as sodium.

[0040] Asusedherein, the term"treat", "treating"or "treatment"means reversing, alleviating, or inhibiting theprogressof a neurodegenerative disease such as AD, or one or more symptoms associated therewith.

[0041] Factors for determining if a subject is suffering fromAD includee.g., oneormoreof thesubject’sMMSEscore, the presence of brain amyloid (e.g., as determined by PET imaging), the subject’s CDR score, FCSR memory test results consistent with mild cognitive impairment, or the identification of brain biomarkers of amyloid in the cerebrospinal fluid (CSF) such as Abeta‑40, Abeta‑42, tau protein, or Abeta oligomers, or combinations thereof. For example, a subject is 6 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 suffering fromAD if 1) thesubject is homozygous forAPOE4andhascognitivesymptoms;2) thesubject ishomozygous for APOE4 and has subjectivememory impairments, MCI, or anMMSE of 30, and the subject has an abnormal FCSR; 3) the subject the subject is homozygous for APOE4 and has early AD symptoms such asMCI or anMMSE of 26‑30 and aCDR global score of 0.5; 4) the subject is heterozygous for APOE4 and has an MMSE of less than 20; 5) the subject is heterozygous for APOE4 and has an MMSE of 20 or greater, and the subject has brain amyloid as determined by one or more of the methods described herein (e.g., PET imaging or CSF biomarkers selected from Abeta‑40, Abeta‑42, and tau protein, or for Abeta oligomers); or 6) the subject is APOE4negative and the subject has anMMSEscore of 20 or higher or anMMSEscore of less than 20 and the subject has brain amyloid as determined by one ormore of themethods described herein (e.g., PET imaging or CSF biomarkers selected fromAbeta‑40, Abeta‑42, and tau protein, or for Abeta oligomers). For classification of abnormal FCSR see e.g., E. Grober, R.B Lipton, C. Hall et al; Neurology 2000; 54: 827‑832.

[0042] "Effective amount" or "effective dose" is the quantity of the compound which is sufficient to treat a neurode- generative disease such asAD. Effective amounts can vary, as recognized by one of ordinary skill in the art, depending on e.g., the severity of the neurodegenerative disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician or other medical provider. Exemplary effective amounts of the compounds useful in the methods described herein are provided below. In some aspects, an effective amount is an amount that increases CSF 3-SPA concentration above the pre-determined baseline threshold. In more specific aspects, an effective amount is an amount that increases CSF 3-SPA concentration to 1.1X, 1.2X, 1.3X, 1.4X, 1.5X, 2X, 2.5X, 3X, 4X, 5X, or more than the pre-determined baseline threshold.

[0043] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend uponavarietyof factors, includingage,bodyweight, general health, sex, diet, timeof administration, rateofexcretion, drug combination, the judgment of the treatingphysician, and the severity of theparticular diseasebeing treated. Theamount of a provided compound in the composition will also depend upon the particular compound in the composition. Exemplary regimens are provided below.

[0044] "Pre-determined baseline threshold", "pre-determined baseline level", or "certain baseline level" in the present methods (e.g., as in the first through tenth, twelfth, and fifteenth embodiment) are used interchangeably and refer to one or more of the following: (1) the 3-SPA CSF concentration (±10%) value determined for a MMSE of 30 in the line of best fit between the concentration of 3-SPA and MMSE scores in a random population of subjects with Alzheimer’s Disease of varyingdegreesof severity (a "RandomADPopulation"; (2) thehighest 3-SPACSFconcentration (±10%)determined ina Random AD Population for MMSE ≤ 29; (3) a subject’s own 3-SPA CSF concentration (± 5%) determined prior to exhibiting any symptoms of AD; (4) the average 3-SPACSF concentration (± 5%) determined in an age-matched normal (non-AD)population; (5) for embodimentswheresubjectsare further selectedbybeingwithina rangeofMMSEscores, the higher of: (a) the 3-SPACSF concentration (± 10%) value determined for a MMSE of 30 in the line of best fit between the concentration of 3-SPA and MMSE scores in a Random AD Population; or (b) the highest 3-SPA CSF concentration (± 10%) determined in aRandomADPopulation forMMSE scores equal to or above the lowestMMSE score in the selection range (e.g., if the selection requires a MMSE score between 22‑28, then (b) is the highest 3-SPA CSF concentration (± 10%) determined in a Random AD Population for MMSE scores equal to or above 22); (6) the 3-SPA CSF concentration (±10%) value for the subject’s MMSE score as determined by the line of best fit between the concentration of 3-SPA and MMSE scores in a random population of subjects. If not otherwise indicated, the value for a pre-determined baseline threshold obtained using any of the parameters above,may be decreased or increased by up to 10% in order to be less or more inclusive of subjects to be treated, and to reduce the number of false positives or false negatives. The random population of subjects with Alzheimer’s Disease is a randomly selected sampling of AD patients by degree of severity of their Alzheimer’s Disease (e.g., by degree of cognitive decline or by their MMSE score), age, weight, general health, sex, diet, and the like, andcancomprisee.g., at least 10, at least 15,at least 20, at least 25, at least 50, at least 75, at least 100, at least 500, at least 1000 subjects. In one aspect, however, the population of subjects has an average age of 85 years old or less. In other aspects, the population of subjects has an average age of 65‑85 years old. In yet other aspects, the populationof subjects hasanaverageageof 58 yearsoldor older. In someaspects,when the selectioncriteria additionally include ApoE4 status, the random population of subjects with Alzheimer’s Disease of varying degrees of severity from which to derive the best fit line or determine the highest level of 3-SPA CSF concentration is limited to those AD subjects having the same ApoE4 status as the ApoE4 status selection criteria. 2. Uses / Methods

[0045] In a first embodiment, providedherein ismethodof treating adisease characterizedbyamyloid aggregates (e.g., Alzheimer’s disease) inasubject in need thereof, comprising thestepof administering to thesubject aneffectiveamount of a compound of Formula I: 7 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from ‑O-R3, ‑O-R4‑CH(NHR6)‑C(O)‑R5, and ‑[N(R6)‑CH(R7)‑C(O)]1‑2‑R5 R2 is selected from hydrogen, R3, and R4‑CH(NHR6)‑C(O)‑O-R5; each R3 is independently selected from C1‑C20 alkyl, ‑C2‑C20 alkenyl, ‑C2‑C20 alkynyl, ‑(C0‑C20 alkylene)‑aryl, ‑(C0‑C20 alkylene)‑carbocyclyl, ‑(C0‑C20 alkylene)‑heterocyclyl, ‑(C0‑C20 alkylene)‑heteroaryl, ‑(C2‑C20 alkenyle- ne)‑aryl, ‑(C2‑C20 alkenylene)‑carbocyclyl, ‑(C2‑C20 alkenylene)‑heterocyclyl, ‑(C2‑C20 alkenylene)‑heteroaryl, ‑(C2‑C20 alkynylene)‑aryl, ‑(C2‑C20 alkynylene)‑carbocyclyl, ‑(C2‑C20 alkynylene)‑heterocyclyl, and ‑(C2‑C20 alky- nylene)‑heteroaryl; each R4 is an independently selected derivatized side chain of a natural or unnatural α-amino acid wherein the side chain has been derivatized through a free - OH group present on the side chain prior to derivatization; each R5 is independently selected from ‑OH, ‑O-C1‑C4 alkyl and ‑NH2; each R6 is independently selected from hydrogen and ‑C(O)R8; R7 is a side chain of an α-amino acid; and each R8 is independently selected from hydrogen, C1‑C4 alkyl, ‑O-C1‑C4 alkyl, ‑(C1‑C4 alkylene)‑aryl, and (C1‑C4 alkoxy)‑aryl; wherein: each alkyl, alkylene, alkenyl, alkenylene, alkynyl or alkynylene portion of R3 is optionally substituted with up to 6 substituents independently selected from halo, - OH, ‑O‑(C1‑C4 alkyl), ‑O‑(C1‑C4 haloalkyl), carbocyclyl, aryl, heterocyclyl, and heteroaryl; eachcarbocyclyl, aryl, heterocyclyl, or heteroaryl portionofR3 is optionally substitutedwithup to four substituents independently selected from halo, ‑OH, ‑O‑(C1‑C4 alkyl), ‑O‑(C1‑C4 haloalkyl), C1‑C18 alkyl, C2‑C18 alkenyl, and C2‑C18 alkynyl, wherein the alkyl, alkenyl, or alkynyl portions of the C1‑C18 alkyl, C2‑C18 alkenyl, or C2‑C18 alkynyl, respectively, are optionally substitutedwith up to six substituents independently selected fromhalo, ‑OH, ‑O‑(C1‑C4 alkyl), and ‑O‑(C1‑C4 haloalkyl); R1 comprises no more than 2 cyclic moieties; and R2 comprises no more than 2 cyclic moieties.

[0046] Diseases characterized by amyloid aggregates include, but are not limited to, Alzheimer’s disease including familial (hereditary) forms thereof, Down’s syndrome dementia, Parkinson’s Disease, Acute macular degeneration (AMD), glaucoma, Inclusion Body Myositis (IBM), traumatic brain injury, Lewy Bodies dementia, Huntington’s disease, Nieman‑PicksTypeC,CerebralAmyloidAngiopathy (CAA),Creutzfeldt-Jakobdisease,AAAmyloidosis,ALAmyloidosis, ATTR amyloidosis, Familial amyloid polyneuropathy (FAP), Familial amyloid cardiomyopathy (FAC), Senile systemic amyloidosis, and prion disease. In one aspect, the disease characterized by amyloid aggregates is Alzheimer’s disease.

[0047] In a second embodiment, provided is a method of selecting and treating a subject suffering from Alzheimer’s disease comprising the steps of: a) selecting the subject if the concentration of 3-SPA present in the subject is less than a pre-determined baseline threshold; and b) administering to selected subject an effective amount of a compound having the Formula I: (I),orapharmaceutically acceptable salt thereof,wherein thevariables forFormula Iareasdescribedabove in thefirst embodiment.

[0048] In a third embodiment, provided herein is a method of treating a subject suffering from Alzheimer’s disease comprising the steps of: 8 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 a) determining if 3-SPA is present in the subject at a concentration less than apre-determined baseline threshold; and b) administering to the selected subject an effective amount of a compound having the Formula I: (I),orapharmaceutically acceptable salt thereof,wherein thevariables forFormula I areasdescribedabove in thefirst embodiment.

[0049] Subjects in the presentmethodsmay be stratified (i.e., further selected) by theirMMSEscores prior to treatment. In an fourth embodiment for example, the subject being treated in the embodiments described herein (e.g., as in the first, second, or third embodiment) has anMMSE score of greater than 19 (e.g., greater than 20, greater than 21, greater than 22, greater than 23, greater than 24, greater than 25, or greater than 26) prior to treatment. In another aspect, the subject being treated in the embodiments described herein (e.g., as in the first, second, or third embodiment) has anMMSE score of 16 to 30 (e.g., anMMSEscore of 22 to 30, anMMSEscore of 22 to 28, anMMSEscore of 16 to 19, anMMSEscore of 18 to 26, an MMSE score of 20 to 26, or an MMSE score of 22 to 26) prior to treatment.

[0050] In addition to theMMSEscore, the subjectmay also have certain genetic factors such as the presence of APOE4 alleles (e.g., homo‑ or heterozygous for APOE4) or have other amyloidmarkers such as the presence of brain amyloid, or both. Subjects described herein may also have at least one ε4 allele of APOE. For example, in a fifth embodiment, the subject being treated in the embodiments described herein (e.g., as in the first, second, third, or fourth embodiment) is APOE4 heterozygous prior to treatment. Alternatively, in a sixth embodiment, the subject being treated in the embodi- mentsdescribedherein (e.g., as in thefirst, second, third, or fourth embodiment) isAPOE4homozygousprior to treatment. The term "heterozygous for APOE4" and "APOE4 heterozygous" are used interchangeably and refer to subjects having one APOE4 allele. The term "homozygous for APOE4", "APOE4 homozygous", "homozygous for APOE4 / 4", and "APOE4 / 4 homozygous" are used interchangeably and refer to subjects having two APOE4 alleles. In a more specific aspect of the sixth embodiment, the subject is selected for treatment if he or she is APOE4 homozygous and has aMMSE score of 22‑28.

[0051] In a seventhembodiment, providedherein is amethodof preventingAlzheimer’sdiseaseor cognitive decline in a subject (e.g., a subject who hasADor dementia due to head trauma) comprising the step of administering to the subject in need thereof a compound having the Formula I: (I), or a pharmaceutically acceptable salt thereof, wherein the variables for Formula I are as described above in the first embodiment.

[0052] In an eighth embodiment, the subject in the seventh embodiment is in need of prevention if one or more of the followingarepresent: a) the level of 3-SPA in thesubject is belowapre-determinedbaseline threshold; b) thesubject hasat least one ApoE4 allele; or c) the subject has a familial history of Alzheimer’s disease. Alternatively, the subject in the seventh embodiment is in need of prevention if one ormore of the following are present: a) the level of 3-SPA in the subject is below a pre-determined baseline threshold; b) the subject has at least two ApoE4 allele; or c) the subject has a familial history of Alzheimer’s disease.

[0053] In a ninth embodiment, provided herein amethod of preventing dementia in a subject (e.g., a subjectwho hasAD or dementia due to head trauma) comprising the step of administering to the subject in need thereof a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein the variables for Formula I are as described above in the first embodiment.

[0054] In a tenthembodiment, thedementia in theninthembodiment is related toahead injury (e.g., head trauma).Head 9 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 injury occurs when an outside force hits the head hard enough to cause the brain to move violently within the skull. This force can causeshaking, twisting, bruising (contusion), or suddenchange in themovement of thebrain (concussion). It will be understood that even relatively mild head injuries can case prolonged or permanent declines in cognition.

[0055] In aneleventhembodiment, thedementia in theninthembodiment is related toahead injuryand thesubject in the thirteenth embodiment is in need of prevention if the level of 3-SPA in the subject is below a pre-determined baseline threshold.

[0056] In one aspect, the concentration of 3-SPA present in the subject of the describedmethods (e.g., as in the second through fifth, eighth, and eleventh embodiment) is determined from a sample of cerebrospinal fluid. Thus, in one aspect, the pre-determined baseline threshold of 3-SPA in the subject is the baseline concentration of 3-SPA in the cerebral spinal fluid (CSF) of the subject obtained prior to exhibiting symptoms of AD and / or at a time when the subject’s MMSE was 30.

[0057] In oneaspect, thepre-determinedbaseline thresholdof 3-SPA in thepresentmethods (e.g., as in the first through tenth, twelfth, and fifteenth embodiment) is defined as an 3-SPA concentration in a subject of less than 25 ng / ml (e.g., less than 20 ng / ml, less than 15 ng / ml, less than 12 ng / ml, less than 10 ng / ml, less than 8 ng / ml, less than 6 ng / ml, less than 5 ng / ml, less than 4ng / ml, less than3ng / ml, less than 2.9 ng / ml, less than2.8 ng / ml, less than2.7 ng / ml, less than2.6 ng / ml, less than2.5 ng / ml, less than2.4 ng / ml, less than2.3 ng / ml, less than2.2ng / ml, less than2.1ng / ml, less than2.0 ng / ml). In other aspects, thepre-determinedbaseline thresholdof 3-SPA is definedasa3-SPAconcentration ina subject of between 2.0 ng / ml and 25 ng / mL (e.g., between 7 ng / ml and 25 ng / mL, between 8 ng / ml and 25 ng / mL, between 9 ng / ml and 25 ng / mL, between 6 ng / ml and 24 ng / mL, or between 6 ng / ml and 23 ng / mL.

[0058] In oneaspect, thepre-determinedbaseline thresholdof 3-SPA in thepresentmethods (e.g., as in the first through tenth, twelfth, and fifteenth embodiment) is defined as a subject having an MMSE score of 22‑28 or an MMSE score of 22‑26; and a 3-SPA concentration (e.g., in CSF) of less than 5 ng / mL, less than 4 ng / ml, less than 3 ng / ml, less than 2.9 ng / ml, less than 2.8 ng / ml, less than 2.7 ng / ml, less than 2.6 ng / ml, less than 2.5 ng / ml, less than 2.4 ng / ml, less than 2.3 ng / ml, less than 2.2 ng / ml, less than 2.1 ng / ml, or less than 2.0 ng / ml. In other aspects, the pre-determined baseline threshold of 3-SPA in the present methods (e.g., as in the first through tenth, twelfth, and fifteenth embodiment) is defined as a subject having anMMSE score of 22‑28 or an MMSE score of 22‑26 and a 3-SPA concentration (e.g., in CSF) of 2‑4 ng / mL.

[0059] In a twelfth embodiment, provided herein is a method for treating a subject suffering from AD, comprising administering to the subject an effective amount of a compound having the Formula I as defined herein, or a pharma- ceutically acceptable salt thereof, wherein the subject has MMSE score of 30, is homozygous for APOE4, and has an abnormal FCSRmemory test indicatingMCI. For classification of abnormal FCSR see e.g., E. Grober, R.B Lipton, C. Hall et al; Neurology 2000; 54: 827‑832.

[0060] In a thirteenth embodiment, provided herein a method for selecting and treating a subject suffering from AD, comprising: a) selecting a subject having aMMSEscore of 22‑28; and b) administering to the selected subject an effective amount of a compound having the Formula I as defined herein, or a pharmaceutically acceptable salt thereof.

[0061] In a fourteenth embodiment, provided herein is a method for selecting and treating a subject suffering from AD, comprising: a) selecting a subject who is APOE4 homozygous or APOE4 heterozygous; and b) administering to the selected subject an effective amount of a compound having the Formula I as defined herein, or a pharmaceutically acceptable salt thereof.

[0062] In a fifteenth embodiment, provided herein is a method for selecting and treating a subject suffering from AD, comprising: a) selecting a subject having a MMSE score of 22‑28 and is APOE4 homozygous or APOE4 heterozygous; andb)administering to theselectedsubject aneffectiveamountof a compoundhaving theFormula I asdefinedherein, or a pharmaceutically acceptable salt thereof.

[0063] In someaspects of the thirteenth through fifteenth embodiment, the subject is selected if the subject hasaMMSE score of 22‑26. In some aspects of the thirteenth through fifteenth embodiment, the subject is selected if the subject is APOE4homozygous. In someaspects of the thirteenth through fifteenth embodiment, the subject is selected if the subject is APOE4 homozygous and has aMMSE score of 22‑28. In some aspects of the thirteenth through fifteenth embodiment, the subject is selected if the subject is APOE4 homozygous and has a MMSE score of 22‑26.

[0064] In a sixteenth embodiment, provided herein is a method for selecting and treating a subject suffering from AD, comprising: a) selecting a subject havinganMMSEscore of greater than 19 (e.g., greater than 20, greater than 21, greater than 22, greater than 23, greater than 24, greater than 25, or greater than 26) prior to treatment; and administering to the selected subject an effective amount of a compound having the Formula I as defined herein, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method for selecting and treating a subject suffering from AD, comprising: a) selectinga subject havinganMMSEscoreof 16 to30 (e.g., anMMSEscoreof 22 to 30, anMMSEscore of 22 to 28, anMMSEscore of 16 to 19, anMMSEscore of 18 to 26, anMMSEscore of 20 to 26, or anMMSEscore of 22 to 26) prior to treatment; andadministering to theselectedsubject aneffectiveamountof acompoundhaving theFormula I as defined herein, or a pharmaceutically acceptable salt thereof.

[0065] In a seventeenth embodiment, provided herein is a method for preventing AD comprising administering to a subject in need thereof an effective amount of a compound having the Formula I as defined herein, or a pharmaceutically 10 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 acceptable salt thereof.

[0066] In aneighteenthembodiment, providedherein is amethod for preventingadecline in cognition in a subjectwho is asymptomatic, but who is at risk for AD or cognitive decline comprising administering to a subject in need thereof an effective amount of a compound having the Formula I as defined herein, or a pharmaceutically acceptable salt thereof. Subjects who are at risk would include e.g., the presence of APOE4 / 4 (or both APOE4 andAPOE4 / 4), advanced age, or a pattern of familial cognitive decline, or with a combination of two or more of the above.

[0067] In terms of preventing AD or preventing a decline in cognition in a subject who is asymptomatic, but who is at risk for AD or cognitive decline, we hypothesize from the data shown below that 3-SPA is always active in the brain preventing or inhibiting the formation of the toxic oligomers. Therefore, the lower the amount of 3-SPA, the greater the susceptibility a subject would have to developing cognitive decline, or to develop it earlier. Administration of compounds such as those described herein should produce more 3-SPA in the brain. This in turn should establish consistent and / or enhanced inhibition of Aβ oligomers and thereby lead to prevention of AD or a decline in cognition. 3. Compounds of the Present Uses / Methods

[0068] The compounds utilized in the present methods include those having the Formula I as defined above, or a pharmaceutically acceptable salt thereof.

[0069] Alternatively, in a sixteenthembodiment, thecompoundsutilized in thepresentmethods include thosehaving the Formula Iasdefinedabove,whereinR2 is selected fromhydrogenandC1‑C6alkyl, andwherein the remainingvariables for the compound are as described above for Formula I. Alternatively, the compounds utilized in the presentmethods include those having the Formula I as defined above, wherein R2 is ‑CH3, and wherein the remaining variables are as described above for Formula I.

[0070] Alternatively, in a seventeenth embodiment, the compoundsutilized in thepresentmethods include thosehaving the Formula I as defined above, wherein R1 is selected from -O-R3, ‑O-R4‑CH(NHR6)‑C(O)‑R5, and ‑O- R4‑CH(NHR6)‑CH(OH)‑R5. R3 is C1‑C4 alkyl; and R4 is selected from ‑CH(CH3)‑, ‑CH2‑, and and wherein the remaining variables for the compound are as described above for Formula I, or the second embodiment.

[0071] Alternatively, in an eighteenth embodiment, the compounds utilized in the presentmethods include those having the Formula I as defined above,whereinR6 is selected fromhydrogen, ‑C(O)H, ‑C(O)CH3, ‑C(O)O-C(CH3)3, and ‑C(O)O- benzyl, andwherein the remaining variables for the compound are as described above for Formula I, or the second or third embodiment.

[0072] Alternatively, in a nineteenth embodiment, the compounds utilized in the present methods include those having the Formula I as defined above, wherein R5 is selected from ‑OH, ‑OCH3, and ‑OCH2CH3, and wherein the remaining variables for the compound are as described above for Formula I, or the second, third, or fourth embodiment.

[0073] Alternatively, in a twentieth embodiment, the compoundof Formula I is selected fromany compound inTable1or a pharmaceutically acceptable salt thereof: Table 1 # Structure # Structure 100 168 11 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 101 169 102 170 103 171 104 172 105 173 106 174 107 175 108 176 109 177 12 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 110 178 111 179 112 180 113 181 114 182 115 183 116 184 117 185 118 186 13 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 119 187 120 188 121 189 122 190 123 191 124 192 125 193 126 194 127 195 14 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 128 196 129 197 130 198 131 199 132 200 133 201 134 202 15 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 135 203 136 204 137 205 138 206 139 207 140 208 16 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 141 209 142 210 143 211 144 212 145 213 146 214 147 215 148 216 149 217 17 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 150 218 151 219 152 220 153 221 154 222 155 223 156 224 157 225 18 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) # Structure # Structure 158 226 159 227 160 228 161 229 162 230 163 231 164 232 165 233 166 234 167 235 19 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 4. Formulation and Administration

[0074] The compounds of the methods described herein can be formulated as pharmaceutical compositions and administered to a subject, such as a human. Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intra- hepatic, intralesional and intracranial injection or infusion techniques. Liquid dosage forms, injectable preparations, solid dispersion forms, and dosage forms for topical or transdermal administration of a compound are included herein. In one aspect, administration is orally.

[0075] Pharmaceutically acceptable carriers thatmay be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid, potassiumsorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0076] Methods of administration can use an amount and a route of administration effective for treating or lessening the severity of a disease described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Provided compounds are preferably formulated in unit dosage form for ease of administration anduniformity of dosage. For example, provided compoundsmaybe formulated such that a dosageof between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder being treated and the severity of the disorder; 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; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0077] Certain embodiments of the invention are set out in the following numbered paragraphs: Paragraph 1. Amethod of treating a subject suffering fromAlzheimer’s disease, comprising the step of administering to the subject an effective amount of a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from ‑O-R3, ‑O-R4‑CH(NHR6)‑C(O)‑R5, and ‑[N(R6)‑CH(R7)‑C(O)]1‑2‑R5; R2 is selected from hydrogen, R3, and R4‑CH(NHR6)‑C(O)‑O-R5; each R3 is independently selected from C1‑C20 alkyl, ‑C2‑C20 alkenyl, ‑C2‑C20 alkynyl, ‑(C0‑C20 alkylene)‑aryl, ‑(C0‑C20 alkylene)‑carbocyclyl, ‑(C0‑C20 alkylene)‑heterocyclyl, ‑(C0‑C20 alkylene)‑heteroaryl, ‑(C2‑C20 alkeny- lene)‑aryl, ‑(C2‑C20 alkenylene)‑carbocyclyl, ‑(C2‑C20 alkenylene)‑heterocyclyl, ‑(C2‑C20 alkenylene)‑heteroar- yl, ‑(C2‑C20 alkynylene)‑aryl, ‑(C2‑C20 alkynylene)‑carbocyclyl, ‑(C2‑C20 alkynylene)‑heterocyclyl, and ‑(C2‑C20 alkynylene)‑heteroaryl; each R4 is an independently selected derivatized side chain of a natural or unnatural α-amino acid wherein the side chain has been derivatized through a free - OH group present on the side chain prior to derivatization; each R5 is independently selected from ‑OH, ‑O-C1‑C4 alkyl and ‑NH2; each R6 is independently selected from hydrogen and ‑C(O)R8; R7 is a side chain of an α-amino acid; and eachR8 is independently selected fromhydrogen,C1‑C4alkyl, ‑O-C1‑C4alkyl, ‑(C1‑C4alkylene)‑aryl, and (C1‑C4 alkoxy)‑aryl; 20 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 wherein: each alkyl, alkylene, alkenyl, alkenylene, alkynyl or alkynylene portion of R3 is optionally substituted with up to 6 substituents independently selected fromhalo, -OH, ‑O‑(C1‑C4alkyl), ‑O‑(C1‑C4haloalkyl), carbocyclyl, aryl, heterocyclyl, and heteroaryl; each carbocyclyl, aryl, heterocyclyl, or heteroaryl portion of R3 is optionally substituted with up to four substituents independently selected from halo, ‑OH, ‑O‑(C1‑C4 alkyl), ‑O‑(C1‑C4 haloalkyl), C1‑C18 alkyl, C2‑C18 alkenyl, and C2‑C18 alkynyl, wherein the alkyl, alkenyl, or alkynyl portions of the C1‑C18 alkyl, C2‑C18 alkenyl, or C2‑C18 alkynyl, respectively, are optionally substituted with up to six substituents independently selected from halo, ‑OH, ‑O‑(C1‑C4 alkyl), and ‑O‑(C1‑C4 haloalkyl); R1 comprises no more than 2 cyclic moieties; and R2 comprises no more than 2 cyclic moieties. Paragraph 2. The method of paragraph 1, wherein R2 is selected from hydrogen and C1‑C6 alkyl. Paragraph 3. The method of paragraph 1 or 2, wherein R2 is selected from hydrogen and ‑CH3. Paragraph 4. The method of any one of paragraphs 1‑3, wherein: R1 is selected from ‑O-R3, ‑O-R4‑CH(NHR6)‑C(O)‑R5, and ‑O-R4‑CH(NHR6)‑CH(OH)‑R5; R3 is C1‑C4 alkyl; and R4 is selected from ‑CH(CH3)‑, ‑CH2‑, and Paragraph 5. Themethod of any one of paragraphs 1 to 4, wherein R6 is selected from hydrogen, ‑C(O)H, ‑C(O)CH3, ‑C(O)O-C(CH3)3, and ‑C(O)O-benzyl. Paragraph 6. Themethod of any one of paragraphs 1 to 5, wherein R5 is selected from ‑OH, ‑OCH3, and ‑OCH2CH3. Paragraph7. Themethodof anyoneof paragraphs1 to6,wherein the subject is treatedonly after beingdetermined to have an endogenous level of a compound of the formula: below a pre-determined baseline threshold prior to the treatment. paragraph 8. Themethod of Paragraph 7, wherein the concentration of 3-SPA in the subject is the concentration of 3- SPA in the cerebrospinal fluid. Paragraph9. Themethodof anyoneofParagraph1 to8,wherein the subject is administeredacompoundofFormula I only if the subject is ApoE4 heterozygous. Paragraph 10. The method of any one of Paragraphs 1 to 8, wherein the subject is administered a compound of Formula I only if the subject is ApoE4 / 4 homozygous. 21 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 Paragraph 11. The method of any one of Paragraphs 1 to 10, wherein the subject is selected or administered a compound of Formula I only if the subject has a MMSE score of 22 to 28 prior to treatment. Paragraph 12. The method of any one of Paragraphs 1 to 11, wherein the subject is selected or administered a compound of Formula I only if the subject has a MMSE score of 22 to 26 prior to treatment. Paragraph13.ThemethodofanyoneofParagraphs1 to12,wherein thepre-determinedbaseline threshold isdefined as a 3-SPA concentration of less than 25 ng / mL. Paragraph14.ThemethodofanyoneofParagraphs1 to13,wherein thepre-determinedbaseline threshold isdefined as a 3-SPA concentration of between 6 ng / ml and 25 ng / ml. Paragraph15.ThemethodofanyoneofParagraphs1 to13,wherein thepre-determinedbaseline threshold isdefined as a 3-SPA concentration of less than 5 ng / mL. Paragraph16. Themethodof anyoneofParagraphs1 to 13and15,wherein thepre-determinedbaseline threshold is defined as a 3-SPA concentration of 2 ng / ml to 4 ng / mL. Paragraph 17. A method of selecting and treating a subject suffering from Alzheimer’s disease comprising: a) selecting the subject if: i. 3-SPA is present in a cerebral spinal fluid sample taken from the subject at a concentration of less than 10 ng / ml; ii. the subject has a baseline MMSE score of 22 to 28; and iii. the subject has at least one ApoE4 allele; and b) administering to the selected subject an effective amount of a compound of any one of Paragraphs 1 to 6, or a pharmaceutically acceptable salt thereof. Paragraph 18. Themethod of Paragraph 17, wherein the concentration of 3-SPApresent in the cerebral spinal fluid of the subject is 2‑4 ng / ml. Paragraph 19. The method of Paragraph 17 or 18, wherein the subject is ApoE4 homozygous. Paragraph 20. A method of treating a subject suffering from Alzheimer’s disease comprising the steps of: a) determining the concentration of 3-SPA present in the cerebral spinal fluid of the subject; and b) administering to the subject an effective amount of a compound of any one of Paragraphs 1 to 6, or a pharmaceutically acceptable salt thereof, only if: i) the concentration of 3-SPA in the cerebral spinal fluid of the subject is less than 10 ng / ml; and ii) the subject has a baseline MMSE score of 22 to 30. Paragraph21.ThemethodofParagraph20,wherein thesubject is administeredaneffectiveamount of thecompound only if: i) the concentration of the endogenous compound in the CSF of the subject is less than 10 ng / ml; ii) the subject has a baseline MMSE score of 22 to 28; and iii) the subject has two ApoE4 alleles. Paragraph 22. Themethod of paragraph 20 or 21, wherein the subject is selected only if the concentration of 3-SPA in the cerebral spinal fluid of the subject is 2‑4 ng / ml. EXEMPLIFICATION 1. Methods 22 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 Human CSF samples collection and processing

[0078] Individual CSF samples were obtained from 64 male and female subjects with cognitive impairment (MMSE range of 15‑30) due to a variety of neurogenerative diseases (the descriptive characteristics are summarized in Table 1). These patients were referred to the Cognitive Center at the Department of Neurology, Charles University, 2nd Medical faculty and Motol University Hospital, Prague Czech Republic. The 64 samples were obtained from patients that were clinically diagnosed with the following conditions: Alzheimer’s dementia (AD dementia; n=14), Mild cognitive impairment due to AD (MCI due to AD, n=20), mixed dementia (n=3), Lewy body disease (LBD; n=1), frontotemporal lobar degeneration (FTLD; n=18), mild cognitive impairment of other etiology (MCI other; n=7) and progressive supranuclear palsy (n=3). Vascular disease was considered when confluent vascular changes on MRI were present (Fazekas scale 2 and 3). 12ml of CSFwaswithdrawnby lumbar puncture in supine position between vertebral body L3-L5 using atraumatic needle. The lumbar puncture was done between 8 am and 11 am and effectuated immediately after serum sample collection. CSFwas transferred to theCSF lab, located at the same floor where spinning during 5minutes at 2000RPMat room temperaturewas done. After centrifugation, theCSFwas aliquoted using 0.5ml tubes and stored immediately at ‑80 °C. Only polypropylene tubes were used for CSF withdrawal and storage. Processing time between CSF withdrawal, spinning and freezing was standardized and in total did not exceed 45 minutes.

[0079] Thesampleswerewithdrawn from the freezerandshippedondry ice toNextcea Inc (Woburn,MA)andstored ina freezer set to maintain ‑80 °C after receipt. The CSF collection and storage were carried out after subjects signed an informedconsent inaccordancewith theethical guidelines in theCzechRepublic andgoodclinical practice, andaccording to thewidely recognized consensusprotocol for the standardizationofCSFcollectionandbiobanking (Viola et al., Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 2015; 129:183‑206; and Vanderstichele et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement 2012;8(1):65‑73).CommercialELISAkits (InnogeneticsNV,Ghent,Belgium)wereused for dementiabiomarkeranalyses (Aβ1‑42, tau protein, and phospho-tau), and cut off values derived froma validation studywere used. CSF concentrations of 3-SPAwerealsoquantified in12patients receiving the150mgBIDdoseof tramiprosateatWeek78of thePhase3North American AD trial. Identification and quantitation of 3-SPA in human CSF by LC-MS / MS

[0080] The CSF sample analysis was performed by Nextcea, using LC-MS and LC-MS / MS methods. A total of 64 human CSF samples were received at Nextcea for analysis. Derivatization and LC-MS / MS method

[0081] The 3-SPA reference material and human CSF samples were mixed with N-ethyl-N’‑(3-dimethylaminopropyl) carbodiimide (EDC) and 2,2,2-trifluro ethylamine (TFEA). The samples were vortexed and reacted at room temperature for 30minutes. The reactions were centrifuged at 4500 rpm for 5minutes. The supernatant was transferred to a new plate for analysis. 3-SPA was identified and characterized using LC-MS and LC-MS / MS. Injections were made onto a Thermo ScientificAQUASIL5µm,50x2.1mmcolumnusingaShimadzuautosampler andUPLCpump.MobilephaseAwas0.1% trifluoroacetic acid in water (v / v). Mobile phase Bwas 0.1% formic acid in 90 / 10 acetonitrile / water (v / v). The flow rate was 0.35mL / min. The total running timeper samplewas4min.AnAPI 6500 triple quadrupolemass spectrometerwasused for detection. Data were acquired in negative LC-MS and LC-MS / MS modes. Representative chromatograms of 3-SPA in crude native material and human CSF derivatized with EDC and TFEA are shown in FIG. 7, FIG. 8 Panel A, and FIG. 8 Panel B. LC-MS and LC-MS / MS data were acquired using Analyst software (AB Sciex, Foster City, CA). LOQ for the LC- MS / MSmethodwas 0.1 ng / mlwith a dynamic rangeof 0.1 to 1000 ng / ml (r=0.99688 and%CV5.8%± 2.0; data on file). 3- SPA was identified in human CSF by matching the chromatographic retention time and by co-elution of the LC-MS / MS transition ions to the authentic 3-SPA reference standard (synthesized by Paraza Pharma, Montreal, Canada). 3-SPA molecular modeling and molecular dynamics simulations

[0082] All molecular modeling was performed using the Schrödinger suite (Schrödinger Suite, 2015‑3; Schrödinger, LLC,NewYork,NY).Molecular dynamics simulationswere runusingDesmond.SeeVanderstichele et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement 2012; 8(1):65‑73. The simulations were run on GeForce GTX Titan Black GPU (graphics processing unit) cards. The OPLS 3.0 (Optimized Potential for Liquid Simulations) force field (Hort et al., The liquor tau protein and beta amyloid in Alzheimer’s disease. Cesk Slov Neurol N 2007; 70(1):30‑36) was used to model all interactions, and the SPC model was used for waters. The 1IYT Aβ42 NMR 23 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 structure from theProteinDataBank (PDB)wasusedasastartingpoint formolecular dynamicssimulations. This structure is primarily alpha helical and is representative of the peptide in an apolar environment. A 20 Angstrom box of water or a mixed solvent box of 1% 3-SPA in water was added around the peptide using Schrödinger system setup tools. Ions were added toneutralize the chargeof the entire system.Simulationswereequilibrated and rununderNPTconditions (constant number (N) pressure (P) and temperature (T) with periodic boundary conditions. The Nose-Hoover Thermostat and Martina-Tobias-Klein barostat were used to control temperature and pressure, respectively. Simulations were run in replicates of 3 for 100 nanoseconds each, and the results were compiled for analysis. Principal component analysis was performed using ProDy (Shivakumar et al., Improving the Prediction of Absolute Solvation Free Energies Using the Next Generation OPLS Force Field. J. Chem. Theory Comput 2012; 8:2553‑8) and plotted using custom python scripts. Ion Mobility Mass Spectrometry (IMS MS)

[0083] The conditions used for mass spectrometry, using a Waters Synapt G2-S, were as follows: positive polarity in sensitivity mode, capillary = 2.5 kV, nebulizer = 2 mbar, source temperature = 80 °C, desolvation temperature = 60 °C, sample cone setting = 35 V, source offset setting = 60 V, and mass range = 500 to 4000 m / z. These conditions were maintained throughout the study to ensure consistency of the data and to avoid influencing the detection of oligomers due to preferential ionization conditions.

[0084] Samples were directly infused into the mass spectrometer at a flow rate of 10 µL / min using a Protea PM‑1000 Syringe Pump and Hamilton 1 mL Syringe. The data acquisition of the amyloid peptide was performed using a Waters Synapt G2-S quadrupole time of flight mass spectrometer (Q-TOF MS) with traveling wave ion mobility (Waters Corp., Milford, MA). The data were acquired using the systems sensitivity mode to allow for the detection of the less abundant oligomers. Sampleswere infusedat room temperature. The IMSMSstudieswere conductedat Protea, Inc. (Morgantown, WV). Sample preparation

[0085] 1mgof recombinant humanAβ42peptide fromBioLegend (99%purity, cat#843801)was reconstituted in200µL of FisherOptimaLC / MSgradewater (cat#W6‑1) and vortexed vigorously for 2minutes to solubilize the peptide creating a 5 mg / mL solution. Samples were then diluted to a final concentration of 22 pmol / µL prior to incubation. The sample mixtures were then incubated at room temperature for 0, 4 and 24 hours. After the acquisition of incubated samples was completed, the raw datawere analyzed using theWatersMassLynx v2.4 suite withDriftScover v2.7 to visualize drift times for the peptide. Aβ42 species characterization

[0086] Aβ42 species characterization using IMS MS was performed by direct infusion at 22 pmol / µLin water. The peptidewasprepared inwater tomaintain thenativestateconformationof thepeptideand ionmobility dataacquisitionwas performed todetect andcharacterize the conformational changesof thenative statemonomerandanyoligomers thatmay have formed during the incubation. 3-SPA IMS MS binding study

[0087] Thedata acquisition for Aβ42peptidewasperformedusing aWatersSynaptG2-Squadrupole timeof flightmass spectrometer (Q-TOFMS) with traveling wave ionmobility (Waters Corp., Milford, MA). The data were acquired using the systems sensitivity mode to allow for the detection of the less abundant oligomers. Samples were infused at room temperature as above.

[0088] 1 mg of 3-SPA was reconstituted in 1 mL of Fisher Optima LC / MS grade water (cat# W6‑1) and vortexed vigorously for 2 minutes until completely dissolved. The sample was then diluted to create 220 pmol / µL, and 22,000 pmol / µLsolutions to perform a 100-fold, and 1,000-fold molar excess for the binding experiments with Aβ42 peptide.

[0089] 1mg of recombinant humanAβ42 peptide was reconstituted in 200µL of Fisher Optima LC / MSgradewater and vortexed vigorously to solubilize to a 5 mg / mL solution. Samples were then diluted to their final concentrations prior to incubation. The sample mixtures were incubated at room temperature for 0, 4 and 24 hours, followed by analysis as described above. Pharmacokinetics, oral absorption and brain exposure of 3-SPA in Sprague-Dawley (SD) rats

[0090] The oral and iv pharmacokinetics of 3-SPA was evaluated in male Sprague-Dawley fasted rats at a dose of 30 mg / kg and 10 mg / kg respectively (n=3 per groups). Animals were housed in a standard facility, with water and food was 24 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 providedad libitum to theexperiment. 3-SPAwasdissolved in saline,wasadministeredorally bygavageand intravenously asabolus.Serial bloodsamples (approximately1.0mLeach)werecollected fromeachanimal at 0.25, 0.5, 1, 2, 4, 8and24 hours after dosing into tubes containing K2EDTA and processed for plasma by centrifugation. Plasma samples were stored at ‑80 °C until bioanalyses.

[0091] A separate group of animals was dosed orally at 30 mg / kg and terminal brain, CSF and plasma samples were collectedat1, 2, 6,and24hr (3animals foreach timepoint) for bioanalysesof3-SPA inbrainandCSF,and toestimatebrain penetration relative to plasma concentrations. The in-life study was performed at Agilux Laboratories (Worcester, MA) followingquality standards in linewithGoodLaboratoryPractice.Bioanalysesof rat plasma,CSFandbrainwaspreformed using LC-MS / MS at Nextcea. Prior to processing rat brains for bioanalysis, the brains were perfused to remove pooled blood. Pharmacokinetic data analyses were conducted using Winnonlin Professional v5.0.1 (Pharsight, Mountain View, CA). 2. Results Identification and quantitation of 3-SPA in CSF of drug naïve subjects and tramiprosate-treated AD patients

[0092] 3-SPAwas identified and quantitated in humanCSFby LC-MS / MS. The sampleswere derivatizedwith EDCand TFEA before analysis. LC-MS / MS transition ions were selected for monitoring based on 2‑[(2,2,2-trifluoroethyl)carba- moyl]ethane‑1-sulfonicacid, theproduct ionspectraof thederivatized3-SPAreferencestandard.The [M-H]‑of3-SPAwas detected in human CSF atm / z 234.1 at retention time 1.55 min. Structural match of 3-SPA in human CSF with authentic sample as standard was performed by matching the molecular peak of the acid as well as the molecular peaks of the 2‑[(2,2,2-trifluoroethyl)‑carbamoyl]ethane‑1-sulfonic acid derivative including the MS-MS fragmentation pattern by monitoring two LC-MS / MS transition ions. The transition ions and retention time of 3-sulfopropanoic acid in human CSFmatchedwith theauthentic 3-sulfopropanoic acid reference standard. The transition ions of themolecular peak of the diacid (234.1 / 80.9) was selected for quantitation. The LLOQ of the LC-MS / MS assay was 0.1 ng / mL for 3-SPA. The concentrations of 3-SPA in human CSF are provided in Table 1. In a separate analysis, the presence of 3-SPA was also confirmed by LC-MS / MS in drug naive samples of human CSF obtained from Bioreclamation, Westbury, NY (n=27 and n=88 respectively). See FIG. 2 Table 1 ‑ Concentrations of 3-SPA in human CSF in drug naive patients with memory deficits Descriptive Statistics of patients with memory deficits Concentration of 3-SPA in CSF ng / ml (nM) Combined Gender Concentration of 3- SPA inCSFng / ml (nM) Male Concentration of 3-SPA in CSF ng / ml (nM) Female n 64 27 37 Age 68.6 ± 8.5 yr 69.0 ± 8.7 yr 68.1 ± 8.5 yr Clinical diagnosis-n* AD‑14 MCI due to AD‑20 AD‑14 MCI due to AD‑11 AD‑10 MCI due to AD‑9 MCI (other)‑7 FTLD‑18 Other- MCI (other)‑2 FTLD‑9 Other‑1 MCI (other)‑5 FTLD‑9 Other‑4 MMSE range 25.0 ± 3.2 25.4 ± 2.5 24.6 ± 3.7 Mean ± SD 1.8 ± 0.7 (11.7 ± 4.3) 1.9 ± 0.6 (12.3 ± 3.9) 1.7 ± 3.7 (11.0 ± 4.5) Median 1.7 (11.0) 1.7 (11.0) 1.6 (10.3) Minimum - maximum 0.64 - 4.27 (4.15 - 27.7) 0.85 - 2.8 (5.6 - 18.5) 0.64 - 4.27 (4.2 - 27.7) *AD-Alzheimer’s disease, MCI-mild cognitive impairment, FTLD-frontotemporal lobular degeneration, Other-Lewy body disease, vascular dementia, mixed disease

[0093] The levels of 3-SPAof in patientswith a variety of cognition impairing diseases, includingAD, ranged from4.15 to 27.7 nM (0.64 - 4.27 ng / ml) (Table 1).When related to theCSF concentrations of Aβ42monomers in ADpatients (0.04 nM to 0.1 nM) (Bakan et al., ProDy: protein dynamics inferred from theory and experiments. Bioinformatics 2011; 27:1575‑7; Shaw et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 2009; 65:403‑13; Pannee et al. Reference measurement procedure for CSF Abeta1‑42 and the CSF Abeta1‑42 / Abeta1‑40 ratio - a crossvalidation study against Amyloid PET. J. Neurochem 2016; and Lambert et al. Diffusible, nonfibrillar ligands derived fromA1‑42are potent central nervous systemneurotoxins. PNAS. 1998; 95:6448‑53), there is 25 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 an approximately 40‑700 fold excess of 3-SPAover soluble Aβ42monomers, which falls within the rangewhere partial Aβ anti-oligomeraggregationactivitymayoccur insomepatients (Table3).Furthermore, retrospectiveanalysesof theCSFof a subset of patients from the tramiprosatePhase 3 trial were also evaluated for presence of 3-SPA, the primarymetabolite of tramiprosate. Table 2 presents descriptive summaries of 3-SPA concentrations in CSF. The concentrations of metabolite were quantified in 6 patients for whomCSF samples atWeek 78 were available. ThemeanCSF concentration of 3-SPAwas147nM (range=114.3 - 235.8 nM), thus representinga12.6-fold increaseover levels observed in drugnaive patients. Table 2. CSF concentrations (ng / mL) of 3-SPA at Week 78 in North American Phase 3 tramiprosate trial Descriptive Statistics 150 mg BID dose of tramiprosate, Week 78 of Phase 3 NA study (nM) n 6 Mean ± SD 22.3 ± 7.9 ng / ml (147 ± 51.3 nM) Median 19.3 ng / ml (127.5 nM) Minimum - maximum 17.3 - 35.7 ng / ml (114.3 - 235.8 nM) Anti-Aβ42 oligomeric activity of 3-SPA

[0094] To address the high conformational flexibility of Aβ42 and to characterize its interaction with 3-SPA, we used ion mobilitymass spectrometry (IMS),with a quadrupole timeof flightmass spectrometer (Q-TOFMS)with travelingwave ion mobility.Resulting effect ofmodulation of Aβ conformational space is the prevention of oligomer formation.Wehave found not only concentration dependency but also time-dependency of this anti-Aβ42 oligomeric effect of 3-SPA as indicated in FIG.3andFIG.4.Thesummaryof the concentrationexcessdependencyof 3-SPAoverAβ42 is presented inTable3. 100‑ vs 1,000-fold molar excess of 3-SPA over Aβ42 results in a different sub-species profile of inhibition of Aβ42 oligomer formation. The activity is also compared with the same excess dependency of tramiprosate. Near complete prevention of formation of Aβ42 oligomers except for pentamers is shown for 3-SPA. Table 3 ‑ Comparison of anti-Aβ42 oligomer activity of 3-SPA vs tramiprosate at 100:1 and 1,000:1 excess ratios of compound:protein Oligomer Species Aβ42 alone Tramiprosate 100:1 3-SPA 100:1 Tramiprosate 1000:1 3-SPA 1000:1 Dimer Y N Y N N Trimer Y Y Y N N Tetramer Y Y Y N N Pentamer Y Y Y N Y Hexamer Y Y Y N N Decamer Y N N N N Y = yes, presence of oligomer species; N = no presence of oligomer species.

[0095] While functional end results, i.e. inhibition of Aβ42 oligomer formation, are the same for both tramiprosate and its metabolite, 3-SPA, the conformational landscape of the process is not. 3-SPA as dianion under physiological conditions interacts with cations on amino acids side chains of Aβ42 (FIG. 5). These are protonated amino groups of Asp1, Lys16, Lys28, His13,14. At the same time repulsive forces of 3-SPA dianion and carboxylate groups of Aβ42 are at work. This interplay of ionic interactions contributes to significant conformational changes of Aβ42 monomer species.

[0096] Both ionmobility MS data andmolecular dynamics (FIGs. 3, 4, 7, 8 Panel A, and 8Panel B) displaymulti-ligand binding interaction of 3-SPA with Aβ42 monomers. 3-SPA interacts with Aβ42 via different ionic interactions than tramiprosate. Interestingly, although employing different ionic binding patterns, under the same conditions, data from IMS MS and molecular dynamics show qualitatively the same anti-Aβ42 oligomeric result from both compounds. Tramiprosate has shown complete inhibition of formation of Aβ42 oligomers after 24 hours in vitro, while 3-SPA has shown the same results with the exception of inhibition of formation of pentamers at the same time scale. However, a detailed time course investigation also shows a time-dependent course of oligomers inhibition. After 4 hours, 3-SPA inhibits the formationofoligomerswith theexceptionofdimers, trimersandpentamers.After sustained24hoursexposure, theonly oligomeric speciesnot inhibitedwerepentamersofAβ42.Thesedata suggest that the first anti-oligomeric effect of 26 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 tramiprosate is followed by the second anti-oligomeric effect of tramiprosate metabolite 3-SPA. Pharmacokinetics and brain penetration of orally administered 3-SPA in rats

[0097] The plasma concentration of a single dose of 3-SPA, dissolved in saline as a clear solution, administered orally and intravenously to rats at a dose level of 30 mg / kg and 10 mg / kg, respectively, are shown in FIG. 9. Brain, CSF and correspondingplasma levels after a single oral doseof doseof 30mg / kgof 3-SPAat 1, 2, 6, and24hr are shown inFIG. 10. Mean PK curves were used for calculation of pharmacokinetic parameters. The resulting pharmacokinetic parameters, oral bioavailability and brain penetration of 3-SPA in rats are shown in Tables 4‑6. Table 4 ‑ Pharmacokinetic parameters of oral 3-SPA in male SD rats (n=3) Oral PK parameters (30 mg / kg) Parameter Unit Value Lambda_z 1 / h 0.16 t1 / 2 h 4.40 Tmax h 0.50 Cmax ng / ml 8943 AUC 0-t ng / ml*h 18894 AUC 0-inf obs ng / ml*h 19061 Table 5 - Pharmacokinetic parameters of iv 3-SPA in male SD rats (n=3) IV PK parameters (10 mg / kg) Parameter Unit Value t1 / 2 h 10.99 Tmax h 0.08 Cmax ng / ml 7484 C0 ng / ml 13599 AUC 0-t ng / ml*h 3407 AUC 0-inf obs ng / ml*h 3638 Vz_obs L / kg 43.6 Cl_obs L / kg / h 2.7 Vss_obs L / kg 12.9 Oral Bioavailability % ~ 100 Table 6 - Brain Penetration of Oral 3-SPA (30 mg / kg) in male SD rats PK Parameter Unit Plasma Brain CSF t1 / 2 h 3.03 64.07 3.56 Cmax ng / ml 5714.6 649.8 159.2 AUC 0-t ng / ml*h 30001.7 7586.5 463.6 AUC 0-inf obs ng / ml*h 30099.2 33224.4 726.2 Brain / Plasma (AUC%) 25.3% CSF / brain AUC% 6.1% 3. Preparation of Compounds of Formula I 27 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 General synthesis of alkyl esters of 3-sulfopropanoic‑1-alkyl esters

[0098] The following reagents are added in this sequence: olefin (0.20 mmol), MeOH (2.0 mL), triethylamine (5.5 µL, 0.04mmol) and 0.5Maqueous sodiumbisulfite (0.6mL, 0.3mmol) in a test tubeequippedwith amagnetic stirring bar. The reaction mixture is stirred at 22 °C for 14 hours.

[0099] Alternatively, thesealkyl esters canbeprepared frombeta-bromopropionic acid by reactingwithNa2SO3and the corresponding alcohol. Alternative procedure for preparation of 3-sulfopropanoic‑1-alkyl esters.

[0100] Reaction of 3-chloro‑3-oxopropane‑1-sulfonic acidwith the correspondingC1‑C20 alcohol in acetonitrile at room temperature affords the corresponding C1‑C20 ester of 3-sulfopropanoic acid Preparation of alpha-sulfocarboxylic acid halide

[0101] The sulfocarboxylic acid chloride can be prepared by treating the sulfocarboxylic acid with a halogenating agent e.g. SOCl2 in diethylether and a necessary amount of dimethylformamide for dissolution at 30° for 45 hrs. General synthesis of 3-sulfopropanoic esters derived from amino acids linked via hydroxyl functional group in their side chain

[0102] Reaction of 1 eq of N-protected amino acid or N-protected and carboxyl-derivatized amino acid with 1 eq of 3- chloro‑3-oxopropane‑1-sulfonic acid in organic solvent e.g. acetonitrile (with DMF as needed for solubilization or reactants) is mixed in room temperature. Depending on amino-protecting group triethyl amine or N-methypiperidine is added. Reaction is monitored until disappearance of starting amino acid. Reaction mixture is evaporated followed with typical work-up. Synthesis of (2S)‑2‑[(tert-butoxycarbonyl)amino]‑3‑[(3-sulfopropanoyl)oxy]‑propanoic acid

[0103] Reaction of 1 eq of Boc-L-serine with 1 eq of 3-chloro‑3-oxopropane‑1-sulfonic acid in organic solvent e.g. acetonitrile (with DMF as needed for solubilization or reactants) and N-methylpiperidine is mixed in room temperature. Reaction is monitored until disappearance of starting Boc-L-serine. Reaction mixture is evaporated with typical work-up affords (2S)‑2‑[(tert-butoxycarbonyl)amino]‑3‑[(3-sulfopropanoyl)oxy]propanoic acid. 28 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 Preparation of (2S)‑2-amino‑3‑[(3-sulfopropanoyl)oxy] propanoic acid

[0104] (2S)‑2‑[(tert-butoxycarbonyl)amino]‑3‑[(3-sulfopropanoyl)oxy]propanoic acid is deprotected in trifluoroacetic acid or in a mixture if dichloromethane with trifluoroacetic acid (1:1) in the presence of thioanizole for 30 min. General procedure for synthesis of compounds with core structure of 2‑(carbamoylmethylcarbamoyl)ethane- sulfonic acid, (3-sulfopropanamido)acetic acid, [2‑(3-sulfopropanamido)acetamido]acetic acid, and 2‑[(carba- moylmethylcarbamoyl)methylcarbamoyl]ethanesulfonic acid

[0105] 1 eq of appropriately N-protected and side-chainO-protected amino acid or amino acid derivative or N-protected and side-chain O-protected dipeptide or dipeptide derivative is added to 1 eq of 3-chloro‑3-oxopropane‑1-sulfonic acid in acetonitrile with DMF (depending on solubility of the reactants) and then 1 eq of terciary base e.g. trimethylamine or N- methylpiperidine is added. Reaction is run at room temperature andmonitored until disappearance of starting amino acid or dipeptide component. Typical work-up affords the corresponding product.

[0106] The activity and / or pharmaceutical properties of the aforementioned compounds described herein can be obtained using biological and / or ADME assays know to those skilled in the art. 4. Discussion

[0107] From our studies we have discovered the presence of 3-SPA in human cerebrospinal fluid (CSF) of drug-naive subjects. See e.g., FIG. 2. Also, as exemplified above (see e.g., Table 1), we have identified the presence of 3-SPA in the CSF of 64 naive patients with cognitive defects. The mean 3-SPA concentration from the study was 11.7 ± 4.3 nM. We have also shown that 3-SPA elicits anti-Aβ42 oligomeric effect in both a time and concentration dependent manner. See "Anti-Aβ42 oligomeric activity of 3-SPA" section presented above. We have further shown that that 3-SPA displays 100% oral bioavailability and 25% brain penetration indicating that 3-SPA is well absorbed and crosses the blood brain barrier. See Tables 4‑6. Taken together, these data suggest that the higher CSF concentrations in human brain after oral administration of ALZ‑801 or tramiprosate result from the penetration of the metabolite 3-SPA into the CNS.

[0108] We have also identified an inverse correlation between the concentration of 3-SPA in CSF and the severity of cognitive impairment. For example, as the severity of AD decreases, higher concentrations of 3-SPA were found in CSF. See FIG 6. In contrast, as the severity of AD increases, lower concentrations of 3-SPAwere found in CSF. See FIG 6. This data suggests that the levels of 3-SPA in the brain play an important role in reducing the likelihood of, or delaying the onset of, disease progression.

[0109] From these findings,wehypothesize that increasing 3-SPACSF levels can provide therapeutic benefit to subject suffering from AD. We also hypothesize that such an increase will provide additional benefit to AD subjects with the least cognitive impairment (i.e., MMSE= 30) (a "baseline threshold level") andmaintaining such elevated levels should protect those subjects from further cognitive decline or reduce the rate of cognitive decline as compared to a placebo treatment. Increasing 3-SPA CSF levels to above such baseline threshold level can be achieved by administering a compound of Formula I as described herein. This new therapeutic approach provides means for reducing amyloid beta oligomer neurotoxicity, and provides clinical routes for treating cognitive disorders such as AD.

[0110] While we have described a number of embodiments of this invention, it is apparent that our basic examplesmay be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0111] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) that may be cited throughout this application are hereby expressly incorporated herein in 29 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. Claims 1. A pharmaceutical composition comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from ‑O-R3, ‑O-R4‑CH(NHR6)‑C(O)‑R5, and ‑[N(R6)‑CH(R7)‑C(O)]1‑2‑R5; R2 is selected from hydrogen, R3, and R4‑CH(NHR6)‑C(O)‑O-R5; each R3 is independently selected from C1‑C20 alkyl, ‑C2‑C20 alkenyl, ‑C2‑C20 alkynyl, - (C0‑C20 alkylene)‑aryl, ‑(C0‑C20 alkylene)‑carbocyclyl, ‑(C0‑C20 alkylene)‑heterocyclyl, ‑(C0‑C20 alkylene)‑heteroaryl, ‑(C2‑C20 alkeny- lene)‑aryl, ‑(C2‑C20 alkenylene)‑carbocyclyl, ‑(C2‑C20 alkenylene)‑heterocyclyl, ‑(C2‑C20 alkenylene)‑heteroar- yl, ‑(C2‑C20 alkynylene)‑aryl, ‑(C2‑C20 alkynylene)‑carbocyclyl, ‑(C2‑C20 alkynylene)‑heterocyclyl, and ‑(C2‑C20 alkynylene)‑heteroaryl; each R4 is an independently selected derivatized side chain of a natural or unnatural α-amino acid wherein the side chain has been derivatized through a free ‑OH group present on the side chain prior to derivatization; each R5 is independently selected from ‑OH, ‑O-C1‑C4 alkyl and ‑NH2; each R6 is independently selected from hydrogen and ‑C(O)R8; R7 is a side chain of an α-amino acid; and eachR8 is independently selected fromhydrogen,C1‑C4alkyl, ‑O-C1‑C4alkyl, ‑(C1‑C4alkylene)‑aryl, and (C1‑C4 alkoxy)‑aryl; wherein: each alkyl, alkylene, alkenyl, alkenylene, alkynyl or alkynylene portion of R3 is optionally substituted with up to 6 substituents independently selected fromhalo, ‑OH, ‑O‑(C1‑C4 alkyl), ‑O‑(C1‑C4 haloalkyl), carbocyclyl, aryl, heterocyclyl, and heteroaryl; each carbocyclyl, aryl, heterocyclyl, or heteroaryl portion of R3 is optionally substituted with up to four substituents independently selected from halo, ‑OH, ‑O‑(C1‑C4 alkyl), ‑O‑(C1‑C4 haloalkyl), C1‑C18 alkyl, C2‑C18 alkenyl, and C2‑C18 alkynyl, wherein the alkyl, alkenyl, or alkynyl portions of the C1‑C18 alkyl, C2‑C18 alkenyl, or C2‑C18 alkynyl, respectively, are optionally substituted with up to six substituents independently selected from halo, ‑OH, ‑O‑(C1‑C4 alkyl), and -O‑(C1‑C4 haloalkyl); R1 comprises no more than 2 cyclic moieties; and R2 comprises no more than 2 cyclic moieties. 2. The pharmaceutical composition of claim 1, wherein R2 is selected from hydrogen and C1‑C6 alkyl. 3. The pharmaceutical composition of claim 1 or 2, wherein R2 is selected from hydrogen and ‑CH3. 4. The pharmaceutical composition of any one of claims 1 to3, wherein: R1 is selected from ‑O-R3, ‑O-R4‑CH(NHR6)‑C(O)‑R5, and ‑O-R4‑CH(NHR6)‑CH(OH)‑R5; R3 is C1‑C4 alkyl; and R4 is selected from ‑CH(CH3)‑, ‑CH2‑, and 30 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 5. Thepharmaceutical compositionofanyoneof claims1 to4,whereinR6 is selected fromhydrogen, ‑C(O)H, ‑C(O)CH3, ‑C(O)O-C(CH3)3, and ‑C(O)O-benzyl. 6. Thepharmaceutical composition of anyoneof claims1 to5,whereinR5 is selected from ‑OH, ‑OCH3, and ‑OCH2CH3. 7. The pharmaceutical composition of claim 1, wherein the compound is selected from any compound in the following table, or a pharmaceutically acceptable salt thereof: Compound Structure 100 102 104 106 108 110 112 31 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 114 116 118 120 122 124 126 128 130 32 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 132 134 136 138 140 142 143 145 146 147 33 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 149 151 153 154 155 156 158 160 162 164 166 168 34 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 170 172 174 176 178 180 182 184 186 188 35 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 190 192 194 196 197 198 199 200 201 207 36 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 208 209 210 211 217 218 219 220 221 37 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Structure 227 228 229 230 231 232 233 234 235 38 EP 4 671 757 A2 5 10 15 20 25 30 35 40 45 50 55 39 EP 4 671 757 A2 40 EP 4 671 757 A2 41 EP 4 671 757 A2 42 EP 4 671 757 A2 43 EP 4 671 757 A2 44 EP 4 671 757 A2 45 EP 4 671 757 A2 46 EP 4 671 757 A2 47 EP 4 671 757 A2 48 EP 4 671 757 A2 49 EP 4 671 757 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 62713056

[0001] Non-patent literature cited in the description • SALLOWAY et al. Two Phase 3 Trials of Bapineu- zumab in Mild-to-Moderate Alzheimer’s Disease. N Engl J Med, 2014, vol. 370, 322-33

[0003] • SEVIGNY et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease.Nature, 2016, vol. 537, 50-6

[0003] • CASELLI et al. Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med, 2009, vol. 361, 255-263

[0003] • VIGLIETTA et al. Aducanumab titration dosing regimen: 12-month interim analysis from prime, a randomized double blind, placebo-controlled phase Ibstudy inpatientswithprodromalormildAlzheimer’s disease. J Prev Alzheimers Dis, 2016, vol. 3 (1), 378

[0003] • ESPARZA et al. Amyolid beta oligomerization in Alzheimer’s dementia vs. high pathology controls. Ann Neurol, 2013, vol. 73 (1), 104-119

[0004] • HASHIMOTO et al. Apolipoprotein E, especially apolipoprotein E4, increases t peptide. J Neurosci, 2012, vol. 32, 15181-15192

[0004] • ONO et al. Low-n oligomers as therapeutic targets of Alzheimer’s disease. J. Neurochem, 2011, vol. 117, 19-28

[0004] • TOWNSEND et al. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plas- ticity: a potent role for trimers. J. Physiol, 2006, vol. 572, 477-92

[0004] • LAMBERT et al. Diffusible, nonfibrillar ligands derived from A 1‑42 are potent central nervous system neurotoxins. PNAS, 1998, vol. 95, 6448-53

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[0093] • USUI et al. Site-specific modification of Alzheimer’s peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity. PNAS, 2009, vol. 106, 18563-8

[0004] • GAUTHIER, S et al.Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: explora- tory analyses of the MRI sub-group of the Alphase study. J Nutr Health Aging, 2009, vol. 13, 550-557

[0005] • SAUMIER,D. ;DUONG,A. ;HAINE,D. ;GARCEAU, D ; SAMPALIS, J. Domain-specific cognitive effects of tramiprosate in patients with mild to moderate Alzheimer’s disease: ADAS-cog subscale results from the Alphase Study. J Nutr Health Aging, 2009, vol. 13, 808-812

[0005] • AISEN, P. S et al. Tramiprosate in mild-to-moderate Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci, 2011, vol. 7, 102-111

[0005] • HEY et al. Clinical Pharmacokinetics and Safety of ALZ‑801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease. Clin Pharmacokinetics, 2018, 315-333

[0006] • KOCIS et al. Elucidating the Abeta42 Anti-Aggrega- tion Mechanism of Action of Tramiprosate in Alzhei- mer’s Disease: Integrating Molecular Analytical Methods. Pharmacokinetic and Clinical Data. CNS Drugs, 2017, vol. 31, 495-509

[0006] • ABUSHAKRAet al.Clinical effectsof tramiprosate in APOE 4 / 4 homozygous patients with mild Alzhei- mer’s disease suggest disease modification poten- tial. J Prev Alzheimers Dis, 2017, vol. 4, 149-56

[0006] • PANGMAN et al. Applied Nursing Research, vol. 13 (4), 209-213

[0009] • KOCIS et al. Pharmacokinetic and Clinical Data. CNS Drugs, 2017, vol. 31, 495-509

[0015] • E. GROBER ; R.B LIPTON ; C. HALL et al. Neurology, 2000, vol. 54, 827-832

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[0059] • VIOLA et al. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol, 2015, vol. 129, 183-206

[0079] • VANDERSTICHELE et al. Standardization of pre- analytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: A con- sensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement, 2012, vol. 8 (1), 65-73

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[0082] 50 EP 4 671 757 A2 • SHIVAKUMAR et al. Improving the Prediction of Absolute Solvation Free Energies Using the Next Generation OPLS Force Field. J. Chem. Theory Comput, 2012, vol. 8, 2553-8

[0082] • BAKAN et al. ProDy: protein dynamics inferred from theory and experiments. Bioinformatics, 2011, vol. 27, 1575-7

[0093] • SHAWet al.Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative sub- jects. Ann Neurol, 2009, vol. 65, 403-13

[0093] • PANNEE et al. Reference measurement procedure for CSF Abeta1‑42 and the CSF Abeta1‑42 / Abe- ta1‑40 ratio - a crossvalidation study against Amyloid PET. J. Neurochem, 2016

[0093] (19) *EP004671757A3* (11) EP 4 671 757 A3 (12) EUROPEAN PATENT APPLICATION (88) Date of publication A3: 04.03.2026 Bulletin 2026 / 10 (43) Date of publication A2: 31.12.2025 Bulletin 2026 / 01 (21) Application number: 25210213.2 (22) Date of filing: 30.07.2019 (51) International Patent Classification (IPC): A61K 31 / 221 (2006.01) A61K 31 / 222 (2006.01) A61K 31 / 223 (2006.01) A61K 31 / 225 (2006.01) A61K 31 / 255 (2006.01) A61P 25 / 28 (2006.01) G01N 33 / 50 (2006.01) G01N 33 / 52 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 31 / 222; A61K 31 / 221; A61K 31 / 223; A61K 31 / 225; A61K 31 / 255; A61P 25 / 28; G01N 33 / 50; G01N 33 / 52; G01N 2800 / 2821 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 01.08.2018 US 201862713056 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 23188362.0 / 4 296 670 19752609.8 / 3 829 568 (71) Applicant: Alzheon, Inc. Framingham, MA 01701 (US) (72) Inventors: • Kocis, Petr Framingham, 01701 (US) • Hey, John Framingham, 01701 (US) • Tolar, Martin Framingham, 01701 (US) (74) Representative: Potter Clarkson Chapel Quarter Mount Street Nottingham NG1 6HQ (GB) (54) SULFOPROPANOIC ACID DERIVATIVES FOR TREATING NEURODEGENERATIVE DISORDERS (57) Provided herein is the use of a compound of Formula I: or a pharmaceutically acceptable salt thereof, for treating a disease characterized by amyloid and amyloid-like aggre- gates, e.g., Alzheimer’s disease. EP 4 67 1 75 7 A 3 Processed by Luminess, 75001 PARIS (FR) 2 EP 4 671 757 A3 5 10 15 20 25 30 35 40 45 50 55 3 EP 4 671 757 A3 5 10 15 20 25 30 35 40 45 50 55 4 EP 4 671 757 A3 5 10 15 20 25 30 35 40 45 50 55 5 EP 4 671 757 A3 5 10 15 20 25 30 35 40 45 50 55 6 EP 4 671 757 A3 5 10 15 20 25 30 35 40 45 50 55 摘 要 本發明涉及式I化合物： 或其藥學上可接受的鹽 的用途，用於治療特徵為澱粉樣蛋白和澱粉樣蛋白樣聚集體的疾病，例如阿 爾茨海默氏病。

Claims

1. A pharmaceutical composition comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from -O-R3, -O-R4-CH(NHR6)-C(O)-R5, and -[N(R6)-CH(R7)-C(O)]1-2-R5; R2 is selected from hydrogen, R3, and R4-CH(NHR6)-C(O)-O-R5; each R3 is independently selected from C1-C20 alkyl, -C2-C20 alkenyl, -C2-C20 alkynyl, - (C0-C20 alkylene)-aryl, -(C0-C20 alkylene)-carbocyclyl, -(C0-C20 alkylene)-heterocyclyl, -(C0-C20 alkylene)-heteroaryl, -(C2-C20 alkenylene)-aryl, -(C2-C20 alkenylene)-carbocyclyl, -(C2-C20 alkenylene)-heterocyclyl, -(C2-C20 alkenylene)-heteroaryl, -(C2-C20 alkynylene)-aryl, -(C2-C20 alkynylene)-carbocyclyl, -(C2-C20 alkynylene)-heterocyclyl, and -(C2-C20 alkynylene)-heteroaryl; each R4 is an independently selected derivatized side chain of a natural or unnatural α-amino acid wherein the side chain has been derivatized through a free -OH group present on the side chain prior to derivatization; each R5 is independently selected from -OH, -O-C1-C4 alkyl and -NH2; each R6 is independently selected from hydrogen and -C(O)R8; R7 is a side chain of an α-amino acid; and each R8 is independently selected from hydrogen, C1-C4 alkyl, -O-C1-C4 alkyl, -(C1-C4 alkylene)-aryl, and (C1-C4 alkoxy)-aryl; wherein: each alkyl, alkylene, alkenyl, alkenylene, alkynyl or alkynylene portion of R3 is optionally substituted with up to 6 substituents independently selected from halo, -OH, -O-(C1-C4 alkyl), -O-(C1-C4 haloalkyl), carbocyclyl, aryl, heterocyclyl, and heteroaryl; each carbocyclyl, aryl, heterocyclyl, or heteroaryl portion of R3 is optionally substituted with up to four substituents independently selected from halo, -OH, -O-(C1-C4 alkyl), -O-(C1-C4 haloalkyl), C1-C18 alkyl, C2-C18 alkenyl, and C2-C18 alkynyl, wherein the alkyl, alkenyl, or alkynyl portions of the C1-C18 alkyl, C2-C18 alkenyl, or C2-C18 alkynyl, respectively, are optionally substituted with up to six substituents independently selected from halo, -OH, -O-(C1-C4 alkyl), and -O-(C1-C4 haloalkyl); R1 comprises no more than 2 cyclic moieties; and R2 comprises no more than 2 cyclic moieties.

2. The pharmaceutical composition of claim 1, wherein R2 is selected from hydrogen and C1-C6 alkyl.

3. The pharmaceutical composition of claim 1 or 2, wherein R2 is selected from hydrogen and -CH3.

4. The pharmaceutical composition of any one of claims 1 to3, wherein: R1 is selected from -O-R3, -O-R4-CH(NHR6)-C(O)-R5, and -O-R4-CH(NHR6)-CH(OH)-R5; R3 is C1-C4 alkyl; and R4 is selected from -CH(CH3)-, -CH2-, and 5. The pharmaceutical composition of any one of claims 1 to 4, wherein R6 is selected from hydrogen, -C(O)H, -C(O)CH3, -C(O)O-C(CH3)3, and -C(O)O-benzyl.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein R5 is selected from -OH, -OCH3, and -OCH2CH3.

7. The pharmaceutical composition of claim 1, wherein the compound is selected from any compound in the following table, or a pharmaceutically acceptable salt thereof: CompoundStructure100 102 104 106 108 110 112 114 116 118 120 122 124 126 128 130 132 134 136 138 140 142 143 145 146 147 149 151 153 154 155 156 158 160 162 164 166 168 170 172 174 176 178 180 182 184 186 188 190 192 194 196 197 198 199 200 201 207 208 209 210 211 217 218 219 220 221 227 228 229 230 231 232 233 234 235

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