WO2016040780A1 - Aminomethyl- and methyloxy-linked tricyclic compounds as inhibitors of protein aggregation - Google Patents

Abstract

The present invention relates to certain aminomethyl- and methyloxy-linked tricyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy.

Description

AMINOMETHYL- AND METHYLOXY-LINKED TRICYCLIC COMPOUNDS AS INHIBITORS OF PROTEIN AGGREGATION

Cross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 62/049,219, filed September 11, 2014, which is hereby incorporated by reference in its entirety.

Technical Field

[0002] The present invention relates to certain aminomethyl- and methyloxy-linked tricyclic derivatives, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer' s disease, Lewy body disease, Parkinson's disease dementia, fronto-temporal dementia, Huntington' s Disease, amyotrophic lateral sclerosis, and multiple system atrophy.

Background

[0003] Neurodegenerative disorders of the aging population such as Alzheimer' s disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD), affect over 20 million people in the United States and European Union alone and rank among the top causes of death for the elderly. A common feature among these neurological disorders is the chronic accumulation of proteins into neurotoxic aggregates. Each disease is characterized by the specific neuronal populations that are affected, the particular protein aggregates that are involved, and the clinical features that result from the neuronal degeneration.

[0004] Studies suggest that the initial stages of protein aggregation involve mutation or post- translational modification (e.g., nitrosilation, oxidation) of the target protein, which then adopts an abnormal conformation that facilitates interactions with similarly misfolded proteins. The abnormal proteins then aggregate to form dimers, trimers, and higher-order multimers, also termed "soluble oligomers," which may disrupt synaptic function. Additionally, the aggregates may then anchor in the cell membrane and form globular oligomers (which in turn can form pores in the membrane) and/or protofibrils or fibrils. These larger, insoluble fibrils may function as reservoirs of the bioactive oligomers.

[0005] Diverse lines of evidence support the notion that the progressive accumulation of amyloid-β (Αβ) protein is causally involved in the pathogenesis of AD. Αβ protein is a 38-42 amino acid (aa) transmembrane peptide derived from the cleavage of the amyloid precursor protein (APP). However, in addition to Αβ, a number of other proteins may accumulate in the brains of patients with AD, such as Tau, TDP43, and a-synuclein. The cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic systems and increasing levels of Αβ may contribute to this synaptic loss. Much research is focused on detailing the mechanisms through which accumulation of Αβ and other APP metabolites contributes to synaptic damage and neurodegeneration. Many studies support the hypothesis that formation of small Αβ aggregates, also known as oligomers, play a major role in AD neurotoxicity. Oligomers of Αβ peptides can organize into dimers, trimers, tetramers, pentamers, and other higher order arrays that can form annular structures. The levels of such oligomers are good predictors of dementia and synaptic loss in AD patients. In addition to the oligomers, Αβ can complex to form higher molecular weight aggregates with a fibrillar organization that includes hundreds or thousands of Αβ peptides. Such fibrillar aggregates are the main component of amyloid plaques, which are likewise useful diagnostic indicators for the neuropathological diagnosis of AD. However, while the smaller circular oligomers are considered the toxic array, the fibrillar aggregates in the plaques are not directly toxic and may even represent an endogenous mechanism to isolate oligomers.

[0006] Accumulation of toxic Αβ oligomers in the brains of patients with AD is the result of an imbalance between the rates of synthesis, aggregation, and clearance. Most therapies currently under development for AD aim to reduce Αβ synthesis by blocking beta- or gamma- secretase or to increase Αβ clearance with antibodies or molecular chaperones. The need for alternatives to these strategies has been underscored by disappointing Phase III results of gamma- secretase inhibitors including Tarenflurbil (Green, R.C. et al. JAMA 2009, 302, 2557-2564) and Eli Lilly's Semagacestat (LY450139) (Portelius, E. et al. J. Alzheimers Dis. 2010, 21, 1005-1012).

[0007] Inhibitors of Αβ aggregates (fibrils, protofibrils, and large oligomers) have been described, including relatively specific and non-specific Αβ inhibitors (Broersen, K. et al. Alzheimers Res. Ther. 2010, 2, 12). These compounds include Αβ "breakers," small peptides, phenolic compounds, and flavonoids such as curcumin. Such compounds tend to prevent amyloid formation and fibrillation and to display anti-oxidant properties. Most of the compounds of this type have less specific modes of action and target higher molecular weight aggregates and fibrils rather than the initial stages of the oligomerization process. Because evidence indicates the Αβ oligomers rather than the fibrils are the toxic species, compounds that target these early aggregation processes in a specific manner would be useful as potential new therapies for AD and related conditions.

[0008] Various other neurodegenerative diseases involve the accumulation of neurotoxic protein-based aggregates. In idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (LBD), Parkinson's disease dementia (PDD), and multiple system atrophy (MSA), the neurotoxic aggregates are composed of a-synuclein (SYN), which is a synaptic protein that is intracellular under normal conditions. In FTD and amyotrophic lateral sclerosis (ALS), neurotoxic aggregates originate from other intracellular proteins such as tau, TDP-43, or SOD1. For certain of these diseases, such as AD, SYN aggregates with the primary protein. Additional diseases that are associated with the accumulation of aggregated Αβ, include peripheral amyloidosis, Lewy body dementia, inclusion body myositis, and cerebral amyloid angiopathy.

[0009] Two mechanisms are implicated in these protein aggregation processes. In the first, the misfolded and/or aggregated proteins anchor to the various cell membrane structures. Binding of the misfolded or aggregated molecules to the plasma membrane or the membranes of organelles {e.g., mitochondria or lysosomes) may interfere with protein transcription, autophagy, mitochondrial function, and pore formation. By way of example, neurotoxic SYN aggregates and interacts with lipids in cell membranes, by a specific portion of the c-terminal region of the synuclein protein. Compounds that bind to this region can inhibit protein-protein or protein- lipid interactions and can therefore be used to block neurotoxic SYN oligomerization and membrane interaction. In the second process, aggregated protein is released from the anchored subunit and propagates to adjacent cells. This cell-to-cell propagation of toxic protein aggregates may then underlie the anatomic progression of neurodegeneration and worsening of symptoms. Small molecule drugs that interact with the target proteins may limit release and/or propagation, and therefore reduce the neurotoxic effects of aggregated proteins.

[0010] Compounds that are inhibitors of protein aggregation are described in PCT Publ. Nos. WO2011/084642, WO2013/134371, WO2013/148365, WO2014/014937, and WO2015/116663.

[0011] There remains a need for inhibitors of protein aggregation with desirable pharmaceutical properties. Certain aminomethyl- and methyloxy-linked tricyclic compounds have been found in the context of this invention to have protein aggregation modulating activity.

Summary of the Invention

[0012] In one aspect, the invention relates to a chemical entity of the following Formula (I):

wherein

Y is -NCR¹)- or -0-;

Y² is -N(R²)- or -0-;

where R 1 and R 2 are each independently H or C_1-4alkyl;

R³, R⁵, R⁶, and R⁸ are each independently C₁_₄alkyl, halogen, hydroxy, C₁_₄alkoxy, cyano,

amino, or -CF₃;

R⁴ and R⁷ are each independently H or C_1-4alkyl;

X 1¹ and X 2" are each independently N or CH; and A moiety is a 5-membered monocyclic cycloalkyl or heteroaryl ring, or a 5-, 6-, or 7-membered monocyclic heterocycloalkyl ring, wherein the cycloalkyl and heterocycloalkyl rings are optionally substituted with oxo;

or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the compound of Formula (I) is a compound selected from those species described or exemplified in the detailed description below, or a pharmaceutically acceptable salt thereof.

[0014] In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the invention may further comprise a pharmaceutically acceptable excipient. The invention is also a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0015] In another aspect, the invention is directed to a method of treating a disease or medical condition associated with protein or peptide aggregation, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof. The invention is also directed at use of a compound of Formula (I) in the preparation of a medicament for the treatment of such diseases and medical conditions, and the use of such compounds and salts for treatment of such diseases and medical conditions. In another aspect, the invention is directed to a method of treating a neurodegenerative disease or condition associated with protein or peptide aggregation comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In yet another aspect, the invention relates to a method of interfering with the accumulation of protein or peptide aggregates in a cell, or preventing, slowing, reversing, or inhibiting protein or peptide aggregation in a cell, comprising contacting the cell with an effective amount of at least one compound of Formula (I) or a salt thereof, and/or with at least one pharmaceutical composition of the invention, wherein the contacting is in vitro, ex vivo, or in vivo.

[0017] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

[0018] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference.

Brief Description of the Figures

[0019] FIG. 1 shows the effect of Example 1 on the formation of amyloid fibrils at various test concentrations, as described in Biological Example 1.

[0020] FIG. 2 shows the analysis of 6el0 immunolabeling of Abeta-protein in neuropil of frontal cortex in non-tg and APP tg mice treated with either vehicle or Example 1 as described in Biological Example 3. Data are expressed as the corrected optical densities and shown as the group mean + SEM. ( p<0.0001 vs. non-tg/vehicle control group; p<0.01 vs. APP tg/vehicle group).

[0021] FIG. 3 shows the hippocampal calbindin immunolabeling in the molecular layer of the dentate gyrus as described in Biological Example 3. Analysis of hippocampal calbindin immunolabeling in the molecular layer (ML) of the dentate gyrus (DG) in non-tg and APP tg mice treated with either vehicle or NPT-440-1 {right). Data are expressed as the corrected optical densities and shown as the group mean + SEM. (^***p<0.0001 vs. non-tg/vehicle control group, ^##p<0.01 vs. APP tg/vehicle group). Detailed Description of the Invention

[0022] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0023] Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties.

[0024] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley- Interscience, 2001.

[0025] The nomenclature used herein to name the subject compounds is illustrated in the Examples herein. This nomenclature has generally been derived using commercially-available AutoNom^® software (MDL, San Leandro, Calif.), Version 12.0.2.

[0026] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub -combination of chemical groups was individually and explicitly disclosed herein.

Representative Embodiments

[0027] In some embodiments of Formula (I), Y¹ is -NCR¹)- and Y² is -N(R²)-. In other

1 2

embodiments, one of Y and Y is -O- and the other is not -0-.

[0028] In some embodiments R 1 and R2 are each H. In other embodiments, R 1 and R2 are each

C_1-4alkyl. In other embodiments, R 1 and R2 are each methyl. In other embodiments, one of R 1 and R is H and the other is methyl or is C₁_₄alkyl.

[0029] In some embodiments, R³, R⁵, R⁶, and R⁸ are each independently C_1-4alkyl. In other embodiments, R³, R⁵, R⁶, and R⁸ are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In other embodiments, R³, R⁵, R⁶, and R⁸ are each methyl.

[0030] In other embodiments, R⁴ and R⁷ are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R⁴ and R⁷ are the same. In some embodiments, R⁴ and R⁷ are each H. In other embodiments, R⁴ and R⁷ are each C_1-4alkyl. In some embodiments, one of R⁴ and R⁷ is H and the other is C_1-4alkyl or is methyl.

[0031] In some embodiments, X 1 and X2 are each N. In other embodiments, X 1 and X2 are each

CH. In other embodiments, one of X 1¹ and X 2" is N and the other is CH. [0032] In some embodiments, A is a cyclopentyl or cyclopentadienyl ring. In other embodiments, A is a 5-membered heteroaryl ring. In other embodiments, A is a 5-membered heterocycloalkyl ring, optionally substituted with oxo. In other embodiments, A is a 6- or 7- membered heterocycloalkyl ring, each optionally substituted with oxo. In still other embodiments, A is tetrahydrofuran, tetrahydrothiophene, pyrrolidine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole, pyrrolidine-3- one, pyrrolidine-2-one, tetrahydropyran, 1,4-dioxane, morpholine, oxathiane, azepane, oxepane, oxazolidin-4-one, or 1,3,4-oxazolidine. In still other embodiments, A is tetrahydrofuran, furan, tetrahydrothiophene, or pyrrolidinone. In still other embodiments, A is tetrahydrofuran. In still other embodiments, A is a 5-membered ring with one heteroatom ring member, wherein the ring is optionally substituted with oxo. In still other embodiments, A is tetrahydrofuran, furan, or thiophene.

[0033] In one aspect, the invention relates to a chemical entity of the following Formula (II):

wherein

R 1ⁱ 8⁰ and X 1^1"2" are defined as for Formula (I) or for the representative embodiments described herein;

W is O, S, NH, or C(O); and

R^a and R^b taken together with the carbons to which they are attached form a 5-membered

heteroaryl ring, or a 5-, 6-, or 7-membered monocyclic heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with oxo;

or a pharmaceutically acceptable salt thereof.

[0034] In one aspect, the invention relates to a chemical entity of the following Formula (III):

(III) wherein

R 1ⁱ 8⁰ and X 1^1"2" are defined as for Formula (I) or for the representative embodiments described herein;

W is O, S, NH, or C(O); and

Y and Z are each independently CH, CH₂, N, NH, O, S, or C(O), as allowed by valency;

or a pharmaceutically acceptable salt thereof.

[0035] In one aspect, the invention relates to a chemical entity of the following Formula (IV):

wherein

R 1ⁱ 8⁰ and X 1^1"2" are defined as for Formula (I) or for the representative embodiments described herein;

W is O, S, NH, or C(O); and

Y and Z are each independently CH, N, O, or S;

or a pharmaceutically acceptable salt thereof.

[0036] In one aspect, the invention relates to a chemical entity of the following Formula (V):

wherein

R 1ⁱ 8⁰ and X 1^1"2" are defined as for Formula (I) or for the representative embodiments described herein;

W is O, S, NH, or C(O); and

Y and Z are each independently CH₂, NH, O, S, or C(O);

or a pharmaceutically acceptable salt thereof.

[0037] In other embodiments, the invention is directed to a compound selected from the group consisting of:

/ ^N H HN-NH H ^N \ 2-amine) N-((5-(((3,6-dimethylpyrazin-2-

30 yl)oxy)methyl)furan-2-yl)methyl)-3,6- dimethylpyrazin-2-amine and

N-((5-(((3,6-dimethylpyrazin-2-

31 yl)oxy)methyl)thiophen-2-yl)methyl)-3,6- dimethylpyrazin-2-amine and pharmaceutically acceptable salts thereof.

General Definitions

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0039] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0040] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0041] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

Chemical Definitions

[0042] The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0043] The term "alkoxy" refers to an alkyl group as defined above, bonded to an oxygen atom. The alkoxy group is connected to the parent structure via the oxygen atom.

[0044] The term "amino" refers to an -NH₂ group, or a mono- or dialkylamino group.

[0045] The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:

[0046] The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties:

[0047] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo' represents chloro, fluoro, bromo, or iodo.

[0048] The term "oxo" represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0049] The term "heterocycloalkyl" refers to a saturated or partially saturated, monocyclic or bicyclic (fused, bridged, or spiro) ring system that includes carbon atoms and at least one heteroatom (N, O, S) ring member. [0050] Those skilled in the art will recognize that the species listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0051] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency- allowed position on the system.

[0052] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

[0053] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ^UC, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P,

35 S, 18 F, 36 CI, and 125 I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies. PET and SPECT studies may be performed as described, for example, by Brooks, D.J., "Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development," NeuroRx 2005, 2(2), 226-236, and references cited therein. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0054] The nomenclature " -_j" with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C_1-3 refers independently to embodiments that have one carbon member (CO, embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

[0055] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.

[0056] The invention also includes pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0057] A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0058] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1 -sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0059] For a compound of Formula (I) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0060] The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0061] The present invention also relates to pharmaceutically active metabolites of compounds of Formula (I), and uses of such metabolites in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255- 331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

Pharmaceutical Compositions

[0062] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically- acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0063] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.

[0064] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0065] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0066] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0067] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0068] The inventive compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0069] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.

[0070] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.

[0071] As used herein, the terms "treat" and "treatment" encompass both "preventative" and "curative" treatment. "Preventative" treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0072] The term "subject" refers to a mammal in need of such treatment, such as a human.

[0073] Exemplary neurodegenerative diseases that are characterized by protein aggregation include Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease dementia, multiple system atrophy, amyotrophic lateral sclerosis, and Huntington's disease. In some embodiments, exemplary neurodegenerative diseases are those that are characterized by aggregation of amyloid beta. Other diseases that are characterized by amyloid aggregation include peripheral amyloidosis, inclusion body myositis, cerebral amyloid angiopathy, amyloid neuropathy, sensorimotor polyneuropathy, carpal tunnel syndrome, autonomic neuropathy, familial amyloid polyneuropathy, primary light chain amyloidosis, and dialysis-related amyloidosis.

[0074] In one aspect, the compounds and pharmaceutical compositions of the invention specifically target a-synuclein, β-amyloid, and/or tau protein aggregates. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit aggregation of a-synuclein, β-amyloid, and/or tau proteins, and are used in methods of the invention to treat degenerative neurological diseases related to or caused by aggregation, e.g., such as aggregation of a-synuclein, β-amyloid, and/or tau proteins. Preferably, the methods of the invention target neurodegenerative diseases associated with aggregation of α-synuclein, β- amyloid, and/or tau protein. In preferred embodiments, methods of treatment target Parkinson's disease, Alzheimer's disease, Lewy body disease, or multiple system atrophy. The compounds, compositions, and method of the present invention are also used to mitigate deleterious effects that are secondary to protein aggregation, such as neuronal cell death.

[0075] In alternative aspects, the compounds, compositions, and methods of the invention are used to target Αβ aggregation. While the invention is not limited by any particular mechanism of action, Αβ aggregation is thought to be caused by a mis-folding of the protein early in the disease process, which permits formation of abnormal protein multimers. As the number of monomer unites increases, the aggregated proteins can take on a pore-like shape, which can embed in the membrane of the neuron, disrupting ion flow and cell homeostasis.

[0076] In the inhibitory methods of the invention, an "effective amount" means an amount sufficient to reduce, slow the progression of, or reverse protein or peptide aggregation. Measuring the amount of aggregation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a nerve cell.

[0077] In treatment methods according to the invention, an "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about 1 μg to 2 mg of active agent per kilogram of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0078] Once improvement of the patient's disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

Drug Combinations

[0079] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of neurodegenerative disorders. For example, additional active ingredients are those that are known or discovered to be effective in treating neurodegenerative disorders, including those active against another target associated with the disease, such as but not limited to, a) compounds that address protein misfolding (such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation); b) compounds that treat symptoms of such disorders (e.g., dopamine replacement therapies); and c) drugs that act as neuroprotectants by complementary mechanisms (e.g., those targeting autophagy, those that are anti-oxidants, and those acting by other mechanisms such as adenosine A2A antagonists).

[0080] For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for a degenerative neurological disease related to or caused by protein aggregation, e.g., synuclein, beta-amyloid and/or tau protein aggregation, e.g., Parkinson's disease, Alzheimer's Disease (AD), Lewy body disease (LBD) and multiple system atrophy (MSA), or related symptoms or conditions. For example, the pharmaceutical compositions of the invention may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. In certain embodiments, additional active agents may be antibiotics (e.g., antibacterial or bacteriostatic peptides or proteins), e.g., those effective against gram positive or negative bacteria, fluids, cytokines, immunoregulatory agents, anti-inflammatory agents, complement activating agents, such as peptides or proteins comprising collagen-like domains or fibrinogen-like domains (e.g., a ficolin), carbohydrate -binding domains, and the like and combinations thereof. Additional active agents include those useful in such compositions and methods include dopamine therapy drugs, catechol- O-methyl transferase (COMT) inhibitors, monamine oxidase inhibitors, cognition enhancers (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta-secretase inhibitors, or gamma-secretase inhibitors. In particular embodiments, at least one compound of the present invention may be combined in a pharmaceutical composition or a method of treatment with one or more drugs selected from the group consisting of: tacrine (Cognex^®), donepezil (Aricept^®), rivastigmine (Exelon^®), galantamine (Reminyl^®), physostigmine, neostigmine, Icopezil (CP- 118954, 5,7- dihydro-3-(2-(l-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo-[3,2-f]-l,2-benzisoxazol-6-one maleate), ER- 127528 (2-fluoro-2-((l-((3-fluorophenyl)methyl)-4-piperidinyl)methyl)-2,3- dihydro-5,6-dimethoxy-lH-inden-l-one hydrochloride), zanapezil (TAK-147; 3-(l- benzylpiperidin-4-yl)-l-(2,3,4,5-tetrahydro-lH-l-benzazepin-8-yl)propan-l-one fumarate), metrifonate, T-588; ((lR)-l-benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan-l-ol hydrochloride), FK-960 (N-(4-acetyl-l-piperazinyl)-p-fluorobenzamide hydrate), TCH-346 (omigapil; dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynylamine), SDZ-220-581 ((S)- alpha-amino-2' -chloro-5-(phosphonomethyl)- [ 1,1' -biphenyl] -3-propionic acid), memantine (Namenda/Exiba), 1,3,3,5,5-pentamethylcyclohexan-l-amine (Neramexane), tarenflurbil (Flurizan), tramiprosate (Alzhemed), clioquinol, PBT-2 (an 8-hydroxyquinilone derivative), 1- (2-(2-naphthyl)ethyl)-4-(3-trifluoromethylphenyl)- 1 ,2,3,6-tetrahydropyridine, Huperzine A, posatirelin, leuprolide or derivatives thereof, ispronicline, (3-aminopropyl)(n-butyl)phosphinic acid (SGS-742), N-(2-hydroxy-3-sulfopropyl)-N-methyl-N-octyl-l-decanaminium (inner salt; zt-1), salicylates, aspirin, amoxiprin, benorilate, choline, magnesium salicylate, diflunisal, faislamine, methyl salicylate, salicyl salicylate, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indometacin, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, tiaprofenic acid, suprofen, mefenamic acid, meclofenamic acid, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinprazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, arylalkanoic acids, 2- arylpropionic acids (profens), N-arylanthranilic acids (fenamic acids), pyrazolidine derivatives, oxicams, COX-2 inhibitors, sulphonanilides, essential fatty acids, and minozac (2-(4-(4-methyl- 6-phenylpyridazin-3-yl)piperazin-l-yl)pyrimidine dihydrochloride hydrate), or a combination thereof. Such a combination may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention. Chemical Synthesis

[0081] Exemplary chemical entities useful in methods of the invention will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Isotopically labeled compounds as described herein are prepared according to the methods described below, using suitably labeled starting materials. Such materials are generally available from commercial suppliers of radiolabeled chemical reagents.

Scheme A

[0082] Compounds of Formula (I) may be prepared according to Scheme A. Dicarbaldehydes Al are commercially available or prepared according to known methods. Reductive amination of compounds Al with at least two equivalents of a suitably substituted amino-pyridine or amino-pyrazine provides compounds of Formula (I) where Y 1 and Y 2 are each NH. Alternatively bis-aminomethyl substituted compounds A2 may be used to displace a leaving group such as chloride from a suitably substituted chloro-pyridine or chloro-pyrazine to provide compounds of Formula (I) where Y 1 and Y 2 are each NH. Alkylation of one or both amino groups yields additional variants where R 1 and/or R 2 are C₁_₄alkyl.

Scheme B

1 ) (Activation)

2^{) DIS}P'^ACEMENT _{(! )}

[0083] Compounds of Formula (I) may also be prepared according to Scheme B. Dicarbaldehydes Al are reduced to the corresponding diols Bl. In one embodiment, the alcohol groups are activated and displaced with suitably substituted aminopyridines or aminopyrazines to generate compounds of Formula (I) in which Y 1 and Y2 are -N(R 1 )- and -N(R 2 ), respectively. Alternatively, the activated groups (such as a mesylate or tosylate) may be displaced with sodium azide, and the resulting azide reduced to form the corresponding primary amine. In other embodiments, the diol groups are used to displace a leaving group such as chloride from suitably substituted chloro-pyridines or chloro-pyrazines to yield compounds of Formula (I) in which Y 1 and Y 2 are each O. In still other embodiments, one diol group is used in each type of reaction, to produce compounds in which one of Y 1 and Y 2 is -N(R), and the other is O.

Examples

[0084] The following examples are offered to illustrate but not to limit the invention. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I).

[0085] Step 1. 2-Di(oxiran-2-yl)ethane. To a solution of hexa-l,5-diene (200 g, 2.43 mol) in anhydrous DCM (4000 mL) was added m-chloroperbenzoic acid (1235 g, 85% by wt, 6.09 mol) in 10 equal portions over 1 h at 4 °C. The mixture was stirred at rt for 18 h and water (2000 mL) was added. The organic layer was separated, washed with aqueous 1 N KOH (4000 mL x 3), dried over Na₂S0₄, filtered and evaporated to give the title compound (240 g, 86%) as a colorless oil. 1H NMR (400 MHz, CDC1₃) δ: 2.95-3.01 (m, 2H), 2.77-2.80 (m, 2H), 2.50-2.52 (m, 2H), 1.63-1.81 (m, 4H).

[0086] 2,2' -(2,5-Dihvdroxyhexane- 1 ,6-diyl)diisoindoline- 1 ,3-dione. To a mixture of phthalimide (742 g, 5.0 mol) in DMF (1400 mL) was added l,2-di(oxiran-2-yl)ethane (240 g, 2.1 mol) dropwise at 135 °C. The mixture was heated at 135 °C for 1 h and then cooled to 10 °C. The precipitate was filtered and successively washed with aqueous 1 N NaOH, H₂0, ethanol, and ether to give the title compound (531 g, 62.0%) as white solid. 1H NMR (400 MHz, DMSO-d₆) δ 7.82-7.88 (m, 8H), 4.87-4.90 (m, 2H), 3.68-3.78 (m, 2H), 3.34-3.57 (m, 4H), 1.29-1.66 (m, 4H).

[0087] Step 3. (Tetrahydrofuran-2,5-diyl)dimethanamine dihydrobromide. A suspension of 2,2'-(2,5-dihydroxyhexane-l,6-diyl)diisoindoline-l,3-dione (350 g, 0.86 mol) in aqueous 48% HBr (2300 mL) was heated at 120 °C for 24 h, then the mixture was cooled to 4 °C, and the precipitate removed by filtration. The aqueous filtrate was washed with ether (500 mL x 3) and concentrated in vacuum to give the title compound (246 g, 98.4%) as a brown solid. LC/MS: m/e 131 (MH⁺); 1H NMR (400 MHz, DMSO-d₆) δ 7.94 (br s, 6H), 4.05 - 4.25 (m, 2H), 2.80 - 3.10 (m, 4H), 1.98 - 2.12 (m, 2H), 1.63 - 1.79 (m, 2H). [0088] Step 4. A mixture of (tetrahydrofuran-2,5-diyl)dimethanamine dihydrobromide (200 g, 0.68 mol), 3-chloro-2, 5-dimethylpyrazine (244 g, 1.71 mol) and K₂C0₃ (728 g, 5.27 mol) in NMP (2000 mL) was stirred at 180 °C for 24 h. After cooling to rt, the mixture was diluted with water (3500 mL) and extracted with EtOAc (2000 mL x 3). The combined organic phase was washed with brine (5000 mL x 3), dried over Na₂S0₄ and evaporated. The residue was purified by flash column chromatography (DCM/MeOH 20/1) to give the title compound as a mixture of cis and trans isomers (140 g, 70%) as a white solid. LC/MS: m/e 343 (MH⁺); 1H NMR (400 MHz, CDC1₃) δ 7.58 (s, 2H), 4.62 (br s, 2H), 4.25-4.33 (m, 1H), 4.15-4.23 (m, 1H), 3.70-3.80 (m, 2H), 3.40-3.50 (m, 2H), 2.33 (s, 9.14H), 2.31 (s, 2.86H), 2.02- 2.15 (m, 2H), 1.69-1.78 (m, 2H).

[0089] Step 5. Salt Formation. A solution of N,N'-(tetrahydrofuran-2,5- diyl)bis(methylene)bis(3,6-dimethylpyrazin-2-amine) (111 g, 0.32 mol) andl2.28% HCl/ethanol solution (202.4 g) was stirred for 1 h at rt, then the solution was concentrated to give the hydrochloride salt of the title compound (131 g, 98%) as a pale yellow solid. LC/MS: m/e 343 [M+H]; 1H NMR (400 MHz, DMSO-d₆) δ 7.88 (br s, 2H), 7.64 (s, 2H), 4.27 (t, 1H), 4.13 (t, 1H), 3.52 (m, 4H), 2.51 (s, 6H), 2.37 (s, 6H), 1.91-2.03 (m, 2H), 1.68-1.76 (m, 2H).

Example 6: N,N'-(Furan-2,5-diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine).

[0090] To a stirred solution of 53 mg (0.427 mmol) of furan-2,5-dicarbaldehyde and 111 mg (0.901 mmol) of 3,6-dimethylpyrazin-2-amine in 5 mL of DCE was added 100 μΐ_^ of acetic acid and approximately 500 mg of anhydrous Na₂S0₄. After 30 min at rt under argon, the mixture was treated with 386 mg (1.82 mmol) of sodium triacetoxyborohydride, then was stirred further for 48 h. The mixture was treated with water (~ 3 mL), excess satd. aq. NaHC0₃, and EtOAc, and was stirred an additional 1 h at rt. The mixture was extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over Na₂S0₄, and concentrated in vacuo. Purification by preparative TLC (90% EtOAc/hexanes) provided 10 mg of the title compound. MS (ES⁺): [M + H] 339.3; [M+Na] 361.4; MS (ES^~): [M-H] 337.4. 1H NMR: (500 MHz, CDC1₃) δ 7.62 (2H, s), 6.2 (2H, s), 4.63 (4H, d, J = 5 Hz), 4.55 (2H, br s), 2.35 (6H, s), 2.31 (6H, s). Also obtained was (5-(((3,6-dimethylpyrazin-2-yl)amino)methyl)furan-2-yl)methanol as a side product (See Example 8).

Example 7: N,N'-(Thiophene- -diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine).

[0091] The title compound was prepared from 28.4 mg (0.202 mmol) of thiophene-2,5- dicarbaldehyde and 50 mg (0.405) of 3,6-dimethylpyrazin-2-amine using the method described for Example 6. Purification by column chromatography (50-100% EtOAc/hexanes) followed by preparative TLC (70% EtOAc/hexanes) provided 1.7 mg of the title compound. MS (ES⁺): [M+H] 355.4; [M+Na] 377.4; MS (ES^~): [M-H] 353.3. 1H NMR (500 MHz, CDC1₃) δ 7.63 (2H, s), 6.88 (2H, s), 4.77 (4H, d, J = 5 Hz), 4.55 (2H, br s), 2.38 (6H, s), 2.30 (6H, s).

[0092] Also obtained from this reaction was 17.1 mg of (5-(((3,6-dimethylpyrazin-2- yl)amino)methyl)thiophen-2-yl)methanol. MS (ES+): [M + H] 250.2; [M+Na] 272.1; (ES-): [M-H] 248.2. 1H NMR: (500 MHz, CDC1₃₎ δ 7.62(1H, s), 6.89 (1H, d, J=3.5 Hz), 6.85 (1H, d, J=3.5Hz), 4.78(2H, d, J= 5.5 Hz), 4.77 (2H, s), 4.55 (1H, br s), 2.37 (3H, s), 2.30 (3H, s), 2.01 (1H, br s).

Alternative Synthesis:

[0093] To a stirred solution of 280 mg (2.0 mmol) of thiophene-2,5-dicarbaldehyde in 6 mL of THF and 0.2 mL of water was added sodium borohydride (54 mg, 1.4 mmol). The reaction was stirred for 20 min at rt. Water (5 mL) was added and the mixture was stirred for 10 min and extracted with EtOAc (3 x). The combined organic layers were dried over Na₂S0₄, filtered and evaporated. The crude material was diluted with 10 mL of acetonitrile and cooled to 0 °C. Triethylamine (0.89 mL) and methanesulfonyl chloride (0.40 mL) were added and the mixture was stirred for 1 h at 0 °C and then 1 h at rt. The mixture was treated with satd. aq. NaHC0₃ and extracted with EtOAc (3 x). The combined organic layers were dried over Na₂S0₄, filtered and evaporated to provide 657 mg of crude thiophene-2,5-diylbis(methylene) dimethanesulfonate. A mixture of 62.1 mg of the crude mesylate, 114 mg of K₂C0₃, and 50 mg of 3,6-dimethylpyrazin-2-amine in 1 mL of DMF was heated at 110 °C in a sealed tube with stirring for 48 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc (3 x). The combined organic layers were dried over Na₂S0₄, filtered and evaporated. Purification by column chromatography (100% EtOAc) provided 7.3 mg of the title compound. MS (ES⁺): [M+H] 355.3; [M+Na] 377.4; MS (ES^~): [M-H] 353.3.

Example 30: N-((5-(((3,6-Dimethylpyrazin-2-yl)oxy)methyl)furan-2-yl)methyl)-3,6- dimethylp yrazin-2-amine .

[0094] Step 1. (5-(((3,6-Dimethylpyrazin-2-yl)amino)methyl)furan-2-yl)methanol. The title compound was obtained as a side-product from the preparation of Example 6. (MS⁺) m/z: [M + H] 234.1; [M+Na] 256.2; (MS^") [M-H] 232.2. 1H NMR (500 MHz, CDC1₃) δ 7.60 (1H, s), 6.23 (1H, d, J = 3 Hz), 6.214 (1H, d, J = 3 Hz), 4.63 (2H, d, J = 5.5 Hz), 4.59 (2H, s), 4.55 (1H, br s), 2.35 (3H, s), 2.33 (3H, s), 2.13 (1H, br s). ¹³C NMR (500 MHz, CDC1₃) δ 153.8, 152.9, 151.7, 148.8, 136.7, 131.2, 108.9, 108.4, 57.7, 38.4, 21.2, 19.7.

[0095] Step 2. To a solution of 29.2 mg of (5-(((3,6-dimethylpyrazin-2-yl)amino)methyl)furan- 2-yl)methanol in 1.25 mL of DMF was added 181 mg of Cs₂C0₃ and 17.5 μΐ_^ of 3-chloro-2,5- dimethylpyrazine. The mixture was heated at 120 °C in a sealed tube with stirring for 20 h and then cooled and stirred at rt for an additional 12 h. The reaction mixture was diluted with brine and extracted with EtOAc (3 x). The combined organic layers were dried over Na₂S0₄, filtered and evaporated. The crude product was purified by preparative TLC to provide 9.4 mg of the title compound. MS (ES⁺): [M+H] 340.3; [M+Na] 362.4; [M+K] 378.4; MS (ES^~): [M-H] 338.3. 1H NMR (500 MHz, CDC1₃) δ 7.88 (1H, s), 7.62 (1H, s), 6.39 (1H d, J = 3Hz), 6.25 (1H, d, J = 3 Hz), 5.31 (2H, s), 4.67 (2H, d, J = 5.5 Hz), 4.55 (1H, br s), 2.41 (6H, s), 2.36 (3H, s), 2.33 (3H, s).

Example 31 : N-((5-(((3,6-Dimethylpyrazin-2-yl)oxy)methyl)thiophen-2-yl)methyl)-3,6- dimethylpyrazin-2-amine .

[0096] The title compound was prepared using methods analogous to those described for Example 30. MS (ES⁺): [M+H] 378.1. 1H NMR (500 MHz, CDC1₃) δ 7.88 (1H, s), 7.64 (1H, s), 7.00 (1H d, J = 3Hz), 6.91 (1H, d, J = 3.5 Hz), 5.49 (2H, s), 4.79 (2H, d, J = 5 Hz), 4.55 (1H, br s), 2.41 (6H, s), 2.37 (3H, s), 2.31 (3H, s).

[0097] The remaining examples and other embodiments of compounds of Formula I are prepared using methods analogous to those described herein.

Biological Example 1: Beta-amyloid (Ap)-protein oligomer formation

[0098] The seeded fibrillation assay measures the time-dependent formation of amyloid fibrils from monomeric amyloid beta and protofibril seeds using thioflavin T (ThT). The principle of this assay is that ThT has little fluorescence on its own or in the presence of protofibril or monomers but becomes highly fluorescent when bound to amyloid beta fibrils.

[0099] Amyloid beta protofibrils seeds were prepared from amyloid beta fibrils by sonication. The initial amyloid beta fibrils were generated by incubating monomeric amyloid beta at 37 °C for 4 days in Tris buffered saline - TBS (20 mM Tris buffer, 0.9% sodium Chloride, pH 7.4). A stock solution of 2 mg/mL amyloid beta fibrils (150 μί) was sonicated on ice using a probe type sonicator (amplitude 40, 20 cycles of 5 seconds on and 5 seconds off). Following sonication dynamic light scattering was used to confirm that the protofibrile seeds had an approximate diameter of 100 nM. [0100] Monomeric amyloid beta was dissolved in TBS (1 mg/mL) and filtered (Ulter-c centrifugal filter units with an Ultracel-30 membrane). Dynamic light scattering was then used to confirm a radius of approximately 3 nM for the monomers. To initiate seeded fibrillation monomeric amyloid beta monomer (lOuM) was incubated with 1 μΜ of amyloid beta protofibril seeds in the presence or absence of a test compound for varying lengths of time in 1.7 mL Eppendorf tubes. Monomer alone and proto fibrils alone constituted the negative controls. Reactions were terminated by the addition of ThT (100 μΜ in TBS). To quantify the fibril- dependent fluorescence of ThT, 40 μΐ_^ of incubations sample was combined with 30 μΐ_^ of TBS and 20 μΐ_^ of 100 μΜ ThT in a 384 black well plate. Samples were incubated in the dark for 5-6 minutes and then ThT fluorescence was determined (emission -450 nM and excitation - 485 nM). Standard curves were generated by measuring ThT fluorescence with different

concentrations of amyloid beta fibrils.

[0101] In this assay, the time-dependent formation of amyloid fibrils was measured in the presence of increasing concentrations of Example 1. At concentrations as low as 50 nM, the test compound produced a marked reduction in the formation of amyloid fibrils from monomeric amyloid beta and amyloid beta protofibrils. Example 1 decreased the formation of aggregates of amyloid beta in a concentration-dependent manner (Figure 1). This finding indicates that Example 1 can directly interact with amyloid beta monomers or oligomers to prevent further aggregation.

Biological Example 2: In vivo pharmacokinetic assays

[0102] The pharmacokinetics and brain distribution of Ex. 1 in male C57BL/6 mice were studied following administration of a single intravenous, intraperitoneal, or oral dose. A group of 81 male C57BL/6 mice (8-12 weeks old, weighing between 20 to 35 g) were divided into three groups with each group comprising 27 mice. Animals in Group 1 (i.v.) and Group 2 (i.p.) were dosed with an Ex. 1 solution formulation at a dose of 10 mg/kg. Animals in Group 3 (p.o.) were dosed with an Ex. 1 suspension formulation at a dose of 10 mg/kg. Blood samples were collected at pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h post dose (i.v. and i.p.) and at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hr (p.o.). Blood was collected from sets of three mice at each time point in labeled micro centrifuge tube containing K2EDTA as anticoagulant. Plasma samples were separated by centrifugation of whole blood and stored below -70 °C until bioanalysis.

[0103] After collecting blood samples, mice were humanely euthanized by C0₂ asphyxiation and brain was collected at pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h (Group land Group 2) and at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h (Group 3) post dose. Following collection, the brain samples were washed in ice-cold phosphate buffer saline (pH 7.4), gently dried on filter paper, weighed and placed in polypropylene tubes. Further brain samples were homogenized using phosphate buffer saline pH 7.4 and the total homogenate volume was thrice the brain weight. The samples were then stored below -70 °C until bioanalysis. All samples were processed for analysis by protein precipitation using acetonitrile and glipizide as internal standard and analyzed with developed LC-MS/MS method (LLOQ = 1.03 ng/mL for both plasma (P) and brain(B)). Pharmacokinetic parameters were calculated using the non- compartmental analysis tool of WinNonlin® Enterprise software (version 5.2).

[0104] The data obtained from this assay are presented in Table 1. The density of brain homogenate was considered as 1, which is equivalent to plasma density (1). Brain concentration and exposure figures are expressed as ng/g and hr*ng/g, respectively. Brain to plasma exposure rations are provided in Table 2.

Table 1.

P - 1255.17 353.12 356.03 1.51 468.12 20.03 i.v.

B 14378.62 2576.55 2580.01 0.26 64.60 0.68

P 0.08 629.65 170.74 170.82 - - - 48 i.p.

B 0.08 6637.96 1390.17 1426.33

-100

P 0.25 3054.41 1363.21 1364.15 - - - p.o. (314)

B 0.25 2910.74 1069.96 1071.75

a extrapolated cone, for i.v. group

b AUCi_ast considered for calculating bioavailability Table 2.

C_max ratio Brain to plasma

Matrix Cm_ax (ng/mL) AUCi_ast (tu-ng/mL)

(B P) exposure ratio

B - 2576.55

i.v. - 7.30

P 353.12

B 6637.96 10.54 1390.17

i.p. 8.14

P 629.65 170.74

B 2910.74 0.95 1069.96

p.o. 0.78

P 3054.41 1363.21

[0105] The chemical, ADMET, and pharmacokinetic data for Example 1 as compared to the pharmacokinetic properties for Comparative Example 1 (CEl), N,N'-((lr,4r)-cyclohexane- l,4- diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine):

(see PCT Publ. No. WO2013/ 134371, para. 19) are reported in Tables 3 and 4.

Table 3.

Table 4.

Biological Example 3: In vivo efficacy assay

[0106] A chronic administration study was conducted to evaluate the biochemical and neuropathological effects of Example 1 in mThyl-APP transgenic (tg) mice. The objective of this study was to determine whether Example 1 (1 month, 5 mg/kg; p.o.) administration would produce decreases in Αβ-protein and improvements in markers of CNS integrity in a transgenic mouse model of AD. Transgenic (tg) mice expressing hAPP751 cDNA containing the London (Lon, V717I) and Swedish (Swe, K670N/M671L) mutations under the regulatory control of the mThyl gene (mThyl- hAPP751) (Rockenstein et al, J. Neurosci. Res. 2001, 66(4), 573-582) were used in the present studies. Male tg and non-tg controls (7.5-8.5 months of age at start of treatment; N=3-5/group) were used in this study, and animals were housed 2-4 per cage and received free access to food and water prior to and during the experiment. The vivarium was maintained on a 12 h light cycle (lights on at 7 a.m.).

[0107] Example 1 was prepared as a 1 mg/mL solution in a vehicle consisting of 0.9% sterile saline solution (pH adjusted to 3.5) and was administered in a volume of 0.1 mL per 20 grams of body weight by oral gavage (PO) injection. Subjects received a daily administration (MWF) of either vehicle or 5 mg/kg dose of test compound. Animals were weighed prior to treatment and evaluated daily for signs of toxicity with any treatment. On Day 30, all subjects received a final injection and then were euthanized and brain and blood samples were collected. Whole brains were extracted and then divided sagitally, with one half drop fixed in 4% paraformaldehyde (for neuropathological evaluations) and the other hemisphere collected in cryovials, snap frozen in a dry ice-ethanol bath, and then stored at -80 °C. Blood was collected into EDTA tubes, centrifuged, and plasma was collected and stored at -80 °C. Frozen brains were homogenized and then either processed for Western Blot or ELISA analysis.

[0108] For Western Blots, processing of the cytosolic and membrane fractions of mouse brain homogenates was performed as previously described (Rockenstein, 2001, supra). Briefly, one hemisphere from each subject was weighed and the volume of buffer to be added was calculated at three times brain weight for a dilution factor of four. The buffer solution (pH 8.8) was comprised of 1.0 mM HEPES, 5.0 mM benzamidine, 2.0 mM 2-mercaptoethanol, 3.0 mM EDTA, 0.5 mM magnesium sulfate, and 0.05% sodium azide. The sample was then

homogenized using a handheld ultrasonic homogenizer wand (Branson, Model 4C15) and stored at -80 °C. For ELISA analysis, the protein concentrations of homogenized samples were quantified using the Thermo Scientific Pierce BCA Protein Assay (Fisher Scientific, catalog # PI-23227). Twenty micrograms of protein was used in the Αβ 42 Human ELISA Kit (Life Technologies, catalog # KHB3442). The protocol provided by the manufacturer was followed. Tissue collection, processing, and imaging methods for neuropathological evaluations were conducted as described by Masliah et ah, Science 2000, 287, 1265-1269.

[0109] Immunolabeling studies of Αβ-protein were conducted using methods described by Pham et ah, FEBS J. 2010, 277(14), 3051-3067. Immunolabeling studies of neurodegeneration- relevant markers utilized commercially available antibodies including synaptophysin (1: 100, MAB5258, (Millipore, Temecula, CA), GFAP (1:500, MAB3402, (Millipore, Temecula, CA), and calbindin (1:500, C-8666, Sigma- Aldrich, St. Louis, MO)). All sections were processed simultaneously under the same conditions. Sections were imaged with a Zeiss 63X (N.A. 1.4) objective on an Axiovert 35 microscope (Zeiss, Germany) with an attached MRC1024 LSCM system (BioRad). To confirm the specificity of primary antibodies, control experiments were performed where sections were incubated overnight in the absence of primary antibody (deleted) or preimmune serum and primary antibody alone. For each region and marker, triplicate measures were averaged per subject. The data are expressed as mean values + standard error of the mean (SEM). Statistical analysis was performed using a one-way analysis of variance (ANOVA). In the event of statistically significant ANOVA, post hoc comparisons were made using Dunnett's multiple comparisons test. The significance level was set at p<0.05. [0110] The principal findings from this study were that Example 1 reduced concentrations of amyloid beta protein in the cerebral cortex and improved hippocampal levels of calbindin.

These key neuropathological findings for frontal cortex and hippocampus are shown in Figures 2 and 3.

[0111] As shown in Figure 2, there was a statistically significant increase in Abeta (6el0) immunolabeling in the frontal cortices of vehicle-treated APP tg mice as compared to vehicle- treated non-transgenic control mice. Treatment with Example 1 (5 mg/kg) produced statistically significant decreases in Abeta immunoreactivity in the APP tg mice.

[0112] Examination of hippocampal calbindin immunolabeling in the molecular layer of the dentate gyrus revealed statistically significant decreases in vehicle-treated APP tg mice versus vehicle-treated non-transgenic control mice (Figure 3). Calbindin is a key molecule in hippocampal calcium homeostasis, and is decreased the brains of Alzheimer's disease (AD) patients and mouse models of AD. Treatment with Example 1 produced statistically significant increases in calbindin in the APP tg mice.

[0113] The results from this study demonstrate that one month of daily treatment with 5 mg/kg of Example 1 produced statistically significant decreases in Abeta levels and normalized a key hippocampal marker of calcium homeostasis in an APP transgenic mouse model of AD.

Moreover, no overt adverse effects of the compound were observed.

Claims

Claims

1. A compound of Formula I:

Y¹ is -NCR¹)- or -0-;

Y² is -N(R²)- or -0-;

where R 1 and R 2 are each independently H or C_1-4alkyl;

R³, R⁵, R⁶, and R⁸ are each independently C₁_₄alkyl, halogen, hydroxy, C^alkoxy, cyano, amino, or -CF₃;

R⁴ and R⁷ are each independently H or C_1-4alkyl;

X 1¹ and X 2" are each independently N or CH; and

A moiety is a 5-membered monocyclic cycloalkyl or heteroaryl ring, or a 5-, 6-, or 7-membered monocyclic heterocycloalkyl ring, wherein the cycloalkyl and heterocycloalkyl rings are optionally substituted with oxo;

or a pharmaceutically acceptable salt thereof.

The compound of claim 1, wherein the compound is a compound of Formula (II):

wherein

R 1ⁱ 8⁰ and X 1^1"2" are defined as for Formula (I);

W is O, S, NH, or C(O); and

R^a and R^b taken together with the carbons to which they are attached form a 5-membered

heteroaryl ring, or a 5-, 6-, or 7-membered monocyclic heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with oxo;

or a pharmaceutically acceptable salt thereof.

3. The compound of Formula (I), wherein the compound is a compound of Formula (III):

wherein

1 8 1 2

R^{i 0} and X^1"" are defined as for Formula (I);

W is O, S, NH, or C(O); and

Y and Z are each independently CH, CH₂, N, NH, O, S, or C(O), as allowed by valency; or a pharmaceutically acceptable salt thereof.

4. The compound of Formula (I), wherein the compound is a compound of Formula (IV):

wherein

1 8 1 2

R^{i 0} and X^1"" are defined as for Formula (I);

W is O, S, NH, or C(O); and

Y and Z are each independently CH, N, O, or S;

or a pharmaceutically acceptable salt thereof.

5. The compound of Formula (I), wherein the compound is a compound of Formula (V):

wherein

1 8 1 2

R^{i 0} and X^1"" are defined as for Formula (I);

W is O, S, NH, or C(O); and

Y and Z are each independently CH₂, NH, O, S, or C(O);

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein Y 1 is -N(R1 )- and Y2 is -N(R 2 )-.

7. The compound of claim 1, wherein one of Y 1 and Y 2 is -O- and the other is not -O-

8. The compound of any one of claims 1-6, wherein R 1 and R 2 are each H.

9. The compound of any one of claims 1-6, wherein R 1 and R 2 are each C₁_₄alkyl.

The compound of claim 9, wherein R 1 and R 2 are each methyl.

11. The compound of any one of claims 1-10, wherein R³, R⁵, R⁶, and R⁸ are each independently C_1-4alkyl.

The compound of claim 11, wherein R³, R⁵, R⁶, and R⁸ are each methyl.

13. The compound of any one of claims 1-12, wherein R⁴ and R⁷ are each H.

The compound of any one of claims 1-12, wherein R⁴ and R⁷ are each C_1-4alkyl.

15. The compound of any one of claims 1-14, wherein X 1 and X 2 are each N.

The compound of any one of claims 1-14, wherein X 1 and X 2 are each CH.

17. The compound of any one of claims 1-16, wherein A is:

(a) a cyclopentyl or cyclopentadienyl ring;

(b) a 5-membered heteroaryl ring;

(c) a 5-membered heterocycloalkyl ring, optionally substituted with oxo;

(d) a 6- or 7-membered heterocycloalkyl ring, each optionally substituted with oxo;

(e) tetrahydrofuran, tetrahydrothiophene, pyrrolidine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole, pyrrolidine-3-one, pyrrolidine-2-one, tetrahydropyran, 1,4-dioxane, morpholine, oxathiane, azepane, oxepane, oxazolidin-4-one, or 1,3,4-oxazolidine;

(f) tetrahydrofuran, furan, tetrahydrothiophene, or pyrrolidinone;

(g) tetrahydrofuran; or

(h) tetrahydrofuran, furan, or thiophene.

A compound selected from the group consisting of:

amine)

dimethylpyrazin-2-amine and pharmaceutically acceptable salts thereof.

19. A pharmaceutical composition comprising (a) at least one compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.

20. A method of treating a disease associated with protein aggregation, a neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's diseases dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, or multiple system atrophy, comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof.

21. A compound as in any one of claims 1-18 for use in preventing, reversing, slowing, or inhibiting protein aggregation or in treating a disease associated with protein aggregation, a neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's diseases dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, or multiple system atrophy.