Compounds, compositions, and method of use to detect islet amyloid polypeptide (IAPP) and inhibit IAPP, alpha-synuclein and TAU protein aggregation

Abstract

Compounds comprising a rhodanine scaffold, compositions comprising same, method of using such compounds find compositions to inhibit tubulin-associated unit (tau) protein aggregation or alpha-synuclein (α-syn) protein aggregation in a subject having, or at risk for, tau protein aggregation or α-syn protein aggregation, respectively; and methods of using such compounds and compositions to inhibit islet amyloid polypeptide (LAPP) fibril formation and to detect LAPP fibrils.

Description

70836-02^ COMPOUNDS, COMPOSITIONS, AND METHOD OF USE TO DETECT ISLET AMYLOID POLYPEPTIDE (IAPP) AND INHIBIT IAPP, ALPHA-SYNUCLEIN AND TAU PROTEIN AGGREGATION ^^ CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from U.S. Appl. No. 63 / 685,317, filed August 21, 2024, which is incorporated by reference as if fully set forth herein. ^^^ TECHNICAL FIELD

[0002] This disclosure relates to compounds comprising a rhodanine scaffold, compositions comprising same, and the use of such compounds and compositions to inhibit tubulin- associated unit (tau) protein and alpha-synuclein (^-syn) protein aggregation, including, but not limited to, neurofibrillary tangles (NFTs), associated with tauopathies (e.g., Alzheimer’s ^^^ disease, Downs syndrome, progressive supranuclear palsy, and traumatic brain injury) and Lewy bodies, associated with synucleinopathies (e.g., Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)). This disclosure also relates to the use of such compounds and compositions to inhibit islet amyloid polypeptide (IAPP) fibril formation and to detect IAPP fibrils. ^^^ BACKGROUND

[0003] Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the first and second most prevailing neurodegenerative diseases that affect ever-growing millions of the elderly population.1,2The molecular pathology of AD is identified by the aggregation of extracellular ^^^ senile plaques of amyloid-^ (A^) accompanied by intracellular deposition of neurofibrillary tangles (NFTs) of hyperphosphorylated tau.3,4In comparison to A^, Braak staging highlighted the higher significant correlation between tau propagation and the degree of cognitive decline in AD.5,6Tau is mainly present in human brains as six different isoforms counting on the alternative mRNA splicing of a microtubule-associated protein tau (MAPT) gene.7,8Isoforms ^^^ are classified by the existence or the lack of one or two 29-amino-acid in the N-terminal side (0N, 1N, or 2N) and 31-amino-acid domain in the carboxy-terminus (3R, or 4R).9–11Owing to its comparatively high aggregation kinetics, the 4R tau isoform is believed to participate significantly in AD and other tau-aggregate disorders, such as progressive supranuclear palsy and Down’s syndrome, known as tauopathies.12In AD, the monomeric tau is first misfolded to ^^^ form oligomers before aggregation to paired helical filaments (PHFs) and neurofibrillary ^70836-02^ tangles (NFTs).13Recent reports showed that tau oligomers and protofibrils are significantly more associated with cognitive impairment than are the large NFTs.14–17Braak stage I demonstrated the presence of granular tau oligomers in the brain cortex, while NFTs are detected in the later Braak stage V.18,19Thus, targeting the neurotoxic early-stage tau 4R ^^ oligomer formation would be more advantageous in designing potential neuroprotective agents. A rhodanine-benzimidazole compound was reported to highlight significant inhibitory activity against tau aggregation in a cell-based assay (70% reduction in tau aggregates at 15 µM compound) without showing any marked cytotoxicity.20

[0004] Abnormal ^-synuclein (^-syn) aggregates play a fundamental role in the pathology ^^^ of PD, dementia with Lewy bodies (DLB), and other sporadic neurodegenerative diseases.21–23^-syn is an acidic protein that mainly exists in two forms: unfolded monomer (14 kDa) and folded tetramer (58 kDa) with imbalanced ratios that result in pro-aggregation forms.24The protein is composed of three important segments: a) amphipathic repetitions in the N-terminus that form the ^-helix, which is responsible for interaction with cell membranes,25b) a ^^^ hydrophobic non-A^ component (NAC), which is recognized as the aggregation-prone domain,26and c) a Ca++-binding domain of acidic amino acids in the C-terminal region.27Aggregation of ^-syn is mainly present as neuronal cytosolic inclusions of Lewy bodies (LBs) in dementia and PD patients.28In line with tau pathology, the transient ^-syn oligomeric intermediates resulting from the folding of monomeric protein are neurotoxic in vivo and ^^^ proposed to be in charge of neuronal death.29,30A peptidomimetic pyrimido-pyrazine compound II, NPT100-18A, with an indole-3-yl substituent has been designed and synthesized to target the C-terminus domain of ^-syn.31NPT100-18A inhibited the formation of toxic ^- syn oligomers and reduced the behavioral motor deficits in transgenic mice.

[0005] The co-existence of NFTs and LBs was clinically observed in the brains of AD and ^^^ PD patients supporting the evidence of strong crosstalk between tau and ^-syn.32–34Both proteins synergistically enhance the oligomerization of each other in animal models.35The NAC domain of ^-syn can promote tau polymerization, while tau facilitates fibril inclusions of ^-syn.36Therefore, the design of multitargeted directed ligands (MTDLs) has emerged as a promising tool to develop potential neuroprotective agents in managing and controlling the ^^^ progression of neurodegenerative diseases. Recently, an indole nitrophenyl urea derivative has been reported to be a powerful inhibitor against both ^-syn and 2N4R tau fibrils.37

[0006] Existing treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) mainly target symptom alleviation without addressing the root causes of these neurodegenerative disorders. As a result, while they may provide temporary relief, they fail to deliver long-term ^70836-02^ improvements in overall health and quality of life. An antibody, which apparently stimulates the clearance of amyloid plaques has been approved by the Food and Drug Administration for the treatment of AD. However, it is the formation of the neurofibrillary tangles and the spatiotemporal distribution of the tangles that correlate with the loss of cognition. In view of ^^ the foregoing, there is an unmet need for a small molecule that can inhibit the formation of oligomers, i.e., early-stage aggregation. Accordingly, it is an object of the present disclosure to provide such small molecules and related compositions, which can be used to inhibit tau protein aggregation and alpha-synuclein (^-syn) protein aggregation (e.g., Lewy bodies and Lewy neurites). The compounds and compositions also can be used to inhibit islet amyloid ^^^ polypeptide (IAPP) fibril formation and to detect IAPP fibrils. These and other objects, as well as inventive features, will be apparent from the detailed description provided herein. SUMMARY

[0007] Provided is a compound of formula (I): ^^^or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is^70836-02^a compound of formula (II):^^In an embodiment of the compound of formula (II), R1 isand n = 1 or 2. In an embodiment of the compound of formula

[0009] In view of the above, further provided is a pharmaceutical composition comprising an above-described compound of formula (I), or a pharmaceutically acceptable salt or hydrate ^^^ thereof, and a pharmaceutically acceptable carrier. Also in view of the above, provided is a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0010] In further view of the above, a method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation is provided. ^^^ The method comprises administering to the subject an effective amount of (i) a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB). ^70836-02^

[0011] Another method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, is also provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition ^^ comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB).

[0012] A method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation is further provided. The method comprises administering to the ^^^ subject an effective amount of (i) a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0013] Another method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation is also provided. The method comprises administering to ^^^ the subject an effective amount of (i) a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0014] A method of decreasing A^-plaques or their density in a subject having, or at risk for, ^^^ A^-plaque formation is still further provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0015] Another method of decreasing A^-plaques in a subject having, or at risk for, A^- ^^^ plaque formation is also provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0016] Still further provided is a method of inhibiting islet amyloid polypeptide (IAPP) fibril ^^^ formation in a subject having, or at risk for, IAPP fibril formation. The method comprises administering to the subject an effective amount of (i) a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a ^70836-02^ pharmaceutically acceptable carrier. In an embodiment of the method, the subject is a human. In another embodiment of the method, the subject is a feline.

[0017] Even still further provided is a method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation. The method comprises (i) ^^ administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) detecting fluorescence, whereupon IAPP fibrils in a subject are detected. In an embodiment of the method, the subject is a diabetic human and the presence of IAPP fibrils indicates the diabetic human has pancreatic amyloidosis. In an embodiment of the method, the subject is a diabetic feline and the presence ^^^ of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis. BRIEF DESCRIPTION OF THE FIGURES

[0018] Figs.1A-1G: For Figs.1A-1B: The ThT fluorescence kinetic curves of the synthesized compounds (100 ^M) with ^-syn (6 µM) fibrils. Compounds 3a-d, 4a-d, and 5a-l (Fig. 1A). ^^^ Compounds 5m-s (Fig. 1B). The standard error of the mean (SEM) has been represented by error bars for each measurement. For Figs. 1C-1D: The dose-dependent inhibition curves of compounds 5l (Fig.1C) and 5r (Fig.1D) at different concentrations (3.125, 6.25, 12.5, 25, 50, 100 ^M) on ^-syn (6 µM) fibrils. Triplicate data were scored for each concentration from five successive time points at the plateau phase. For Figs. 1E-1F: The ThS fluorescence kinetic ^^^ curve of 5r (100 ^M) with 2N4R tau (12 µM) (Fig. 1E), 1N4R p-tau (6 µM) (Fig. 1F), and 0N4R (6 µM) (Fig. 1G). The error bars represent the SEM for each measurement.

[0019] Figs. 2A-2J: PICUP assay to monitor the ability of rhodanines to suppress oligomer formation (oligomeric band between 35 and 40 kDa) of: ^-syn (30 µM) (Figs. 2A-2F) and 2N4R tau (6 µM) (Figs. 2G-2J). The control consisted of no light exposure and no tris(2,2^- ^^^ bipyridyl)ruthenium(II) chloride (Ru(BPY)3), a cross-linking agent).

[0020] Fig. 2K: Validation of ^-syn anti-oligomer effects provided by compounds 5l and 5r. A solution of ^-syn (30 ^M) in 10 mM PBS (pH 7.4) was incubated with 0.25 % DMSO or 100 ^M of compound 5l, 5r, or III for 3 days at 37 ^C. Samples were then loaded in a 16% SDS-PAGE gel. Western blot was performed using antisyn-33 to detect the ^-syn oligomer ^^^ (between 35 and 40 kDa) and monomer (located at 15 kDa). Compound III has the structure: ^70836-02^.

[0021] Figs. 3A-3C: Excitation and emission of 5l and 5r (10 µM) (Fig. 3A). Fluorescence binding profile of 5l (1 µM) (Fig.3B) and 5r (1 µM) (Fig.3C) in the presence and absence of ^-syn (50 µg / mL) and 2N4R tau (50 µg / mL) fibrils at ^ex = 450 nm. ^^

[0022] Figs.3D-3E: Fluorescence binding profile of 5l (1 ^M) (Fig. 3D) and 5r (1 ^M) (Fig. 3E) in the presence and absence of ^-syn (50 ^g / mL) and 2N4R tau (50 ^g / mL) fibrils at ^ex= 450 nm. The buffer consisted of 10 mM PBS (pH 7.4) with 10 % ethylene glycol.

[0023] Figs. 4A-4D: Rhodanine prototype 5l enhancement of fluorescence upon binding to fIAPP and hIAPP fibrils, but not ^-syn and tau. Fig. 4A: Fluorescence binding profile of 5l ^^^ (500 nM) in the presence and absence of fIAPP, hIAPP, ^-syn, 2N4R tau (50 µg / mL) fibrils at ^ex = 450 nm after 1h of incubation with shaking at 300 rpm at 37ºC. Fig. 4B: Similar experiments were performed using ^ex = 440 nm, ^em = 528 nm. Fig.4C: Competition dialysis confirmed the binding of 5l to hIAPP and fIAPP. Fibrils (0.1 mg / ml) were placed in mini- dialysis cassettes with a MW cutoff of 3500 Daltons. 5l (10 µM) was incubated in PBS and ^^^ allowed to reach equilibrium at 25 °C for 48 hours. Probe was separated from fibrils by slight agitation in a detergent (0.5 mM SDS). Measurements of fluorescence and UV-spectral absorbance were done to assess Kd. Fig. 4D: Fibrillar conformation for each protein was validated by TEM. Buffer in A-D: 10 mM PBS (pH 7.4) + 0.5 mM SDS + 300 mM NaCl.

[0024] Fig. 5: TEM analyses of the anti-fibril activity of 5l, 5r, 5j, and 3b (100 µM) toward ^^^ ^-syn (2 µM, upper row) and 2N4R tau (6 µM, lower row). Both proteins were incubated with: A-B. Control (DMSO, 0.25%) (A; B); compound 5l (C; D); compound 5r (E; F); compound 5j (G; H); and compound 3b (I; J). Incubation time was 3 days and 5 days for ^-syn and 2N4R tau, respectively, at 37° C. Scale bars: 200 nm, magnification: 40K.

[0025] Fig. 6: Ex vivo TEM analyses of A^-plaques extracted from AD brains after 5 days ^^^ incubation at 37° C with: (A) DMSO (control vehicle, 1.5%); (B) 5l (50 ^M); and (C) 5r (50 ^M). Scale bars: 200 nm, magnification: 2.5K.

[0026] ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ !^^^^^^^^"^^^^^^^#^ ^$^^^^^^^^^^^%^^^^^^^^%&'(()*+^^^^^^^^^^^^^^^^,^^"%^^^^^^-^^.^ / ^^^^^^^^^^^^ / ^^$^0^^1^!^^2^ ,^^$^^^^3^ 40^^^5.^^^^ / ^^^^ ^^^^^6^7^6^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^ ^^^ ^^8^69^$^^^^^^^^^^ ^^^^^^#^^^^^^^^ / ^^^^^^^^^^^^ / ^^$^^^":^:^^^^^^^^^^^8^9;^$^^,^^^^^^^.^<^^^^:^^%-^^^^^^^^^:^^^^^^^ ^70836-02^ punctate YFP signals relative to 0.1% DMSO was done at t = 96 h. N = 3 independent experiments, n = 12-18 individual wells total (0 ^^7^^^8^^;3^^^^^^^$^^^^^^^^^^^^^^^^^7^^^8^^6.^^ (Fig.7B) Same as panel A, but confluence fold changes relative to DMSO vehicle (0 ^M) were plotted. (Fig. 7C) Representative IncuCyte images of reporter cells treated with vehicle vs 5 ^^ and 2.5 ^M of compound 3b and 5j (t = 96 h), green channel. Arrows indicate ^S-rich YFP- positive inclusions. Scale bar, 50 ^m. All data are presented as fold-changes relative to DMSO control + / - standard deviation. Brown-Forsythe and Welch ANOVA plus Dunnett’s T3 post- hoc test (Fig.7A.3^^^^-way ANOVA plus Dunnett’s post-hoc test (Fig.7B.3^^, p < 0^0^3^====7^ p < 0.001. ^^^

[0027] Fig.8: TEM analyses of the anti-fibril activity of 4c and 4d (100 µM) toward ^-syn (2 µM). Incubation time was 3 days at 37° C. Scale bars: 200 nm, magnification: 40K.

[0028] Figs. 9A-9B:^Compound 5l and 5r inhibited the aggregation of A^ 1–40. A. Kinetics of aggregation of A^ 1–40 (21 ^M) in the presence of DMSO (0.25 %) and compound (100 ^M) in 10 mM PBS supplemented with 0.5 mM SDS and 300 mM NaCl. B. The maximum ^^^ fluorescence intensity extracted from the plateau phase of the kinetics of aggregation were plotted for control (DMSO) and compounds III, 3b, 5l, and 5r. Difference of treatments in comparison to the control DMSO are significant at p < 0.001 as assessed by one-way ANOVA plus Dunnett’s post-hoc test.

[0029] Figs. 10A-10C: Compounds 5l and 5r disaggregated the A^-plaques isolated from ^^^ Alzheimer’s disease (AD) brains. Ex vivo TEM analyses were done after 5 days of incubation at 37 ^C of A^-plaques (0.37 mg / ml) in 10 mM PBS (pH 7.4) with: (A) DMSO (control vehicle, 0.125 %); (B) 5l (50 ^M); (C) 5r (50 ^M). Scale bars: 200 nm, magnification: 40 K.

[0030] Figs. 11A-11B: In vitro ThT fluorescence assay of rhodanine probes (100 ^M) with: A. hIAPP (7 µM); B. fIAPP (7 µM). The error bars correspond to each entry’s standard error ^^^ of the mean (SEM).

[0031] Figs. 12A-12H: Anti-fibrillar activity of 5l, DM-3a, and DM-3b (100 µM) against hIAPP (7 µM, upper row) and fIAPP (7 µM, lower row) using TEM analyses. Both aggregates were incubated for x hr at 37 °C with: A-B. Control (DMSO, 0.25%); C-D. 5l; E-F. DM-3a; and G-H. DM-3b. Scale bars: 200 nm, magnification: 40K. ^^^

[0032] Fig. 13. Compound 5l (AAE-II-35) stained cat pancreatic amyloid deposits as good as thioflavin S (ThS, positive control). Compound 5l (AAE-II-35) and thioflavin S (ThS, a non- specific amyloid dyes) were tested at 10 µM. Control consisted of PBS alone. The fluorescence signals from the probes (Ex / Em 440 / 558 nm) will be detectable by fluorescence microscopy. ^70836-02^ As an example of application, the probe 5l (AAE-II-35) was able to bind to the IAPP amyloid deposits in the islets of Langerhans of pancreatic cat using paraffin fixed tissues in Fig. 13. DETAILED DESCRIPTION

[0033] The present disclosure is based on the design and synthesis of rhodanine-based ^^ compounds as MTDLs to tackle the oligomers and fibrils of tau and ^-syn. Unlike single- targeted candidates, dual proteinaceous-aggregate inhibitors could have a synergistic response and eliminate target-related toxicity.

[0034] Provided is a compound of formula (I):^^^ or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is selected from, and. In an embodiment of the compound of formula (I), R1^^^

[0035] Also provided is a compound of formula (II):^70836-02^ or a pharmaceutically acceptable salt or hydrate thereof, wherein R is selected from^^

[0036] In particular, the indole derivatives 5l (Table I) and 5r (Table II) exhibited the most promising inhibitors against the oligomers and fibrils of ^-syn and 2N4R tau. Compounds5l and 5r showed a powerful in vitro reduction of ^-syn fibril formation. The fluorescence binding assay of 5l showed a remarkably higher binding to the 2N4R tau fibrils than that with ^-syn aggregates at 520 and 530 nm, respectively. Moreover, 5l and 5r were strongly able to ^^^ disaggregate amyloid plaques in the human AD brain. Although both inhibitors showed no observed activity towards ^-syn inclusion in neuroblastoma cells, compound 5j (Table I) demonstrated significantly high reduction of ^-syn inclusion at 5 µM without changes in cell confluence.

[0037] Provided is also a compound of the formula (III): ^^^or a pharmaceutically acceptable salt or hydrate thereof, wherein: R3 is 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) substituted with (R5)n; n is 0, 1, 2 or 3;^^^R4 is carboxy-6- to 10-membered aryl substituted with (R5)n, carboxy alkyl substituted with (R5)n, -C1-C6alkyl-C(O)O-alkyl or -C1-C6alkyl-C(O)NR7R8, wherein R7and R8are each independently, H or C1-C6alkyl or R7and R8, together with the nitrogen atom to which they are attached, form a 5- to 10-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S); and ^70836-02^ R5 in each instance is independently OH, halo, S(O)xR6 (wherein R5 is H, C1-C6 alkyl or 6- to 10-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S) and x is 0, 1 or 2), -SCN, -NCS, C1-C6-alkyl, C1-C6-alkoxy, C1- C6-haloalkyl, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 5- to 10-membered ^^ heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), or two R4groups, together with carbon atoms to which they are attached, form a 5- to 6- membered heterocycloalkyl (wherein 1 or 2 heterocycloalkyl members are independently selected from N, O, and S).

[0038] In one example, R3can be selected from: ^^^of which is substituted with (R5)n; such as:each of which is substituted with (R5)n;^^^each of which is substituted with (R5)n; ^70836-02^each of which is substituted with (R5)n;each of which is substituted with (R5)n; ^^each of which is substituted with (R5)n;andeach of which is substituted with (R5)n.^^^

[0039] In the compounds of the formula (III) wherein R4 can be -(CH2)pCO2H, -(CH2)pCO2 C1-C6-alkyl or -(CH2)pCONR7R8, wherein p is 1, 2, 3, 4, 5, 6 or from 1 to 6, 1 to 3, 1 to 4, 1 to 2, 2 to 3, 3 to 6 or 2 to 5; and R7 and R8, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl. Thus, for example, compounds of ^70836-02^ formula (III) can have R4 be -CH2CO2H, -CH2CH2CO2H, -CH2 CH2CH2CO2H, - CH2CH2CH2CH2CO2H, - CH2CH2CH2CH2CH2CO2H, - CH2CH2CH2CH2CH2CH2CO2H, - CH2CO2CH3, -CH2CO2CH2CH3, -CH2CH2CO2CH3, -CH2CH2CO2CH2CH3 in combination with any of the foregoing options for R3. In another example, in compounds of the formula ^^ (III) R4 can be:any of the foregoing options for R3.

[0040] Alternatively, in the compounds of the formula (III) R4 can be carboxy-6- to 10- membered aryl substituted with (R5)n, such as: ^^^In one example, R4can be:substituted with (R5)n in combination with any of the foregoing options for R3. ^^^

[0041] The above compounds include isotopic variants and compounds in which one or more hydrogen atoms have been substituted with deuterium. The compounds may contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. In one ^70836-02^ embodiment, the compounds are not limited to any particular stereochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. Such mixtures of ^^ stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

[0042] Similarly, the compounds may include geometric centers, such as cis, trans isomers, diastereomers, enantiomers, and E and Z double bonds. In another embodiment, the compounds are not limited to any particular geometric isomer requirement, and that the compounds, and ^^^ compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. Such mixtures of geometric isomers may include a single configuration at one or more double bonds and chiral carbons, while including mixtures of geometry at one or more other double bonds and chiral carbons.

[0043] The above compounds, and pharmaceutically acceptable salts and solvates, such as ^^^ hydrates, thereof, can be synthesized in accordance with methods known in the art and exemplified herein. See, e.g., Example 1.

[0044] The compounds can be used to inhibit the aggregation of proteins prone to aggregate in a state of disease. The ability of such compounds to inhibit aggregation can include, but is not limited to, inhibition of oligomer formation, inhibition of fibril formation, and / or inhibition of ^^^ the formation of ^-syn inclusions. “Aggregation” and its derivatives are used herein to refer to all such inhibitory actions for ease of reference. Proteins prone to aggregate include, but are not limited to, islet amyloid polypeptide, amyloid-^, ^-synuclein (^-syn), tubulin associated unit (tau), and transthyretin. The tau can be tau isoform 0N4R, 1N4R, 2N4R, 0N3R, 1N3R, and / or 2N3R with and without post-translational changes (such as phosphorylation). The ^^^ compounds described herein can be used to inhibit the aggregation of ^-syn. Diseases involving protein aggregation include, but are not limited to, AA amyloidosis, Alzheimer's disease, monoclonal immunoglobulin light-chain amyloidosis, Huntington's disease, Parkinson's disease, Creutzfeldt-Jacob disease, prion disorders, amyotrophic lateral sclerosis, type 2 diabetes, or transthyretin amyloidosis. The compounds described herein can be used to ^^^ inhibit the aggregation of ^-syn in a subject having, or at risk for, Alzheimer’s disease, dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). The compounds described herein also can be used to inhibit the formation of ^-syn inclusions in a subject with a neuroblastoma. The compounds also can be used to inhibit islet amyloid polypeptide (IAPP) fibril formation and to detect IAPP fibrils. ^70836-02^

[0045] The compounds can be used to inhibit tau protein aggregation in tauopathies. Tauopathies are a group of disorders that result from abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, and mutations in the tau gene, for example. Neurodegenerative diseases have been classified based on this protein accumulation. ^^ Tauopathies encompass more than 20 clinicopathological conditions, including Alzheimer’s disease (AD), which is the most common tauopathy. Other tauopathies include, but are not limited to, familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, cortico-basal degeneration (CBD), Picks disease (PiD), progressive supranuclear palsy (also ^^^ known as Steele, Richardson, and Olszewski disorder), Down syndrome, Parkinsonism with dementia, myotonic dystrophy, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism ^^^ linked to chromosome 17 (FTDP-17), Haller-vorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), ^^^ familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6- related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson’s disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ^^^ ischemic stroke, psychosis in AD, Huntington’s disease, and prion diseases with tangles. The majority of neurodegenerative diseases are characterized by the deposition of insoluble protein in cells of the neuromuscular system.

[0046] The compounds can be formulated as pharmaceutical compositions comprising a pharmaceutically acceptable carrier using methods well-known in the art. “Carrier” is used ^^^ generically herein to refer to pharmaceutically acceptable carriers, diluents, adjuvants, and excipients. See, e.g., Remington: The Science and Practice of Pharmacy, 23rdedition, October 30, 2020, Adeboye Adejare, ed. In view of the foregoing, also provided is a pharmaceutical composition. The composition comprises an above-described compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. ^70836-02^

[0047] In further view of the above, a method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation is provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical ^^ composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB).

[0048] Another method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, is also provided. The method ^^^ comprises administering to the subject an effective amount of (i) a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB). ^^^

[0049] A method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation is further provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. ^^^

[0050] Another method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation is also provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically ^^^ acceptable carrier.

[0051] A method of decreasing A^-plaques or their density in a subject having, or at risk for, A^-plaque formation is still further provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a ^^^ pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0052] Another method of decreasing A^-plaques in a subject having, or at risk for, A^- plaque formation is also provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (II), or a pharmaceutically acceptable salt or ^70836-02^ hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0053] Still further provided is a method of inhibiting islet amyloid polypeptide (IAPP) fibril formation in a subject having, or at risk for, IAPP fibril formation. The method comprises ^^ administering to the subject an effective amount of (i) a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject is a human. In another embodiment of the method, the subject is a feline. ^^^

[0054] Even still further provided is a method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation. The method comprises (i) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) detecting fluorescence, whereupon IAPP fibrils in a subject are detected. In an embodiment of the method, the subject is a diabetic ^^^ human and the presence of IAPP fibrils indicates the diabetic human has pancreatic amyloidosis. In an embodiment of the method, the subject is a diabetic feline and the presence of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis.

[0055] In further view of the above, a method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation is provided. ^^^ The method comprises administering to the subject an effective amount of (i) a compound of formula (III), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB). ^^^

[0056] A method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation is further provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (III), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically ^^^ acceptable carrier.

[0057] A method of decreasing A^-plaques or their density in a subject having, or at risk for, A^-plaque formation is still further provided. The method comprises administering to the subject an effective amount of (i) a compound of formula (III), or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the ^70836-02^ compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0058] Still further provided is a method of inhibiting islet amyloid polypeptide (IAPP) fibril formation in a subject having, or at risk for, IAPP fibril formation. The method comprises ^^ administering to the subject an effective amount of (i) a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. In an embodiment of the method, the subject is a human. In another embodiment of the method, the subject is a feline. ^^^

[0059] Even still further provided is a method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation. The method comprises (i) administering to the subject an effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) detecting fluorescence, whereupon IAPP fibrils in a subject are detected. In an embodiment of the method, the subject is a diabetic ^^^ human and the presence of IAPP fibrils indicates the diabetic human has pancreatic amyloidosis. In an embodiment of the method, the subject is a diabetic feline and the presence of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis.

[0060] Any suitable route of administration can be used in the above methods. Examples include, but are not limited to, oral, parenteral, intravenous, intracranial, ^^^ intracerebroventricular, and intracerebral. An effective amount can be determined by one of ordinary skill in the art using dosage range determining methods known in the art. Typically, a physician (or veterinarian for non-human subjects) will determine the actual dosage, which will be most suitable for an individual subject. The specific dose level and frequency of dosage for an individual may be varied and will depend upon a variety of factors including the activity ^^^ of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, gender, diet, mode and time of administration, rate of excretion, other administered drugs, and the severity of the particular condition. The compound / compositions described herein can be administered with other biologically active compounds as appropriate. ^^^

[0061] The terms “substituted,” “substituent,” and “functional group” refer to a group that can be or is substituted onto a molecule or onto another group (e.g., on an aryl or an alkyl group). Examples of substituents include, but are not limited to, a halogen (e.g., F, Cl, Br, and I), OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, -(CH2)0-^70836-02^ 2P(O)(OR)2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)C(O)OR, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, ^^ N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, or C(=NOR)R wherein each R can be, independently, hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl, which can be mono- or independently multi- ^^^ substituted.

[0062] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms (C1-C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (C1-C8), or, in some embodiments, from 1 to 6 carbon atoms (C1-C6). Examples of ^^^ straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n- alkyl, isoalkyl, and ante-isoalkyl groups as well as other branched chain forms of alkyl. ^^^ Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0063] The term “alkenyl” as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkenyl groups and cycloalkenyl groups having at least one^^^ double bond and having from 1 to 40 carbon atoms (C1-C40), 1 to about 20 carbon atoms (C1- C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (C1-C8), or, in some embodiments, from 1 to 6 carbon atoms (C1-C6). Examples of straight chain alkenyl groups include those with from 1 to 8 carbon atoms such as -CH=CH-, -CH=CHCH3, and -CH2CH=CHCH2- groups, wherein the double bonds can have an E- or Z-configuration. And when there are multiple bonds, each ^^^ double bond can, independently, have an E- or a Z-configuration. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and CH2C=CH(CH3) groups. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. ^70836-02^

[0064] The term “cycloalkyl” as used herein refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms ^^ range from 3 to 4, 5, 6, or 7. Cycloalkyl groups can have any number of carbon atoms, e.g., 3 to 8 carbon atoms (C3-C8), 3 to 6 carbon atoms (C3-C6), and 4 to 8 carbon atoms (C4-C8). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. ^^^

[0065] The term “cycloalkylalkyl” as used herein refers to substituted or unsubstituted alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a cycloalkyl group as defined herein. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylalkyl.

[0066] The term “alkylcycloalkyl” as used herein refers to substituted or unsubstituted ^^^ cycloalkyl groups as defined herein in which a hydrogen of a cycloalkyl group as defined herein is replaced with a bond to an alkyl group as defined herein. Representative alkylcycloalkyl groups include, but are not limited to, alkylcyclopropyl.

[0067] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to ^^^ another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a “formyl” group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-40, 6-10, 1-5 or 2-5 additional carbon atoms bonded to the carbonyl ^^^ group. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the ^^^ group is termed a “haloacyl” group. An example is a trifluoroacetyl group.

[0068] The term “heterocyclylcarbonyl” is an example of an acyl group that is bonded to a substituted or unsubstituted heterocyclyl group, as the term “heterocyclyl” is defined herein. An example of a heterocyclylcarbonyl group is a prolyl group, wherein the prolyl group can be a D- or an L-prolyl group. ^70836-02^

[0069] The term “aryl” as used herein refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl ^^ groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (C6-C14) or from 6 to 10 carbon atoms (C6-C10) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. “Aryl” and the phrase “aryl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Accordingly, “aryl” and the phrase “aryl group” include groups of the formula: ^^^or unsubstituted, such as hydroxy substituted.

[0070] Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those ^^^ listed herein.

[0071] The terms “aralkyl” and “arylalkyl” refer to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as ^^^ defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0072] “Heterocycloalkyl” is a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system that has from 3 to 14 members, such as 6 to 10 and 3 to 6 members, in which 1 to 3 carbon atoms in the ring are replaced by heteroatoms of ^^^ O, S or N. The ring heteroatoms can also include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of a tertiary ring nitrogen. A heterocycloalkyl can be fused to another ring system, such as with an aryl or heteroaryl of 5-6 ring members. The point of attachment of the heterocycloalkyl ring is at a carbon or heteroatom such that a stable ring is retained. Examples of heterocycloalkyl groups include without limitation morpholino, ^^^ tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, ^70836-02^ dihydrobenzofuryl, and dihydroindolyl. A heterocycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0073] “Heteroaryl,” alone or in combination with any other moiety described herein, is a monocyclic aromatic ring structure containing 6 to 10, such as 5 or 6 ring atoms, or a bicyclic ^^ aromatic group having 8 to 10 atoms, containing one or more, such as 1-4, 1-3, or 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or heteroatom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, ^^^ but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. A heteroaryl group can be unsubstituted or optionally substituted with one or more substituents as described herein. ^^^

[0074] The term “alkoxy” refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert- butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include, but are ^^^ not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a ^^^ methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0075] The terms “amine,” “amine group,” “amino,” and “amino group” refer to a substituent of the form -NH2, -NHR, -NR2, or -NR3+, wherein each R is defined herein, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any ^^^ compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.

[0076] An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. An example of a “alkylamino” is -NH-alkyl and -N(alkyl)2. ^70836-02^

[0077] An example of a “cycloalkylamino” group is -NH-cycloalkyl and -N(cycloalkyl)2.

[0078] An example of a “cycloalkyl heterocycloamino” group is -NH-(heterocyclo cycloalkyl), wherein the heterocyclo group is attached to the nitrogen and the cycloalkyl group ^^ is attached to the heterocyclo group.

[0079] An example of a “heterocyclo cycloamino” group is -NH-(cycloalkyl heterocycle), wherein the cycloalkyl group is attached to the nitrogen and the heterocyclo group is attached to the cycloalkyl group.

[0080] The term “amido” refers to a group of the formula -C(O)NR2, wherein R is ^^^ defined herein.

[0081] The terms “halo,” “halogen,” and “halide” group, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0082] The term “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl ^^^ groups, wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, -CF(CH3)2and the like.

[0083] The terms “treat,” “treating,” “treated,” or “treatment” (with respect to a disease ^^^ or condition) is an approach for obtaining beneficial or desired results including and preferably clinical results and includes, but is not limited to, one or more of the following: improving a condition associated with a disease, curing a disease, lessening severity of a disease, delaying progression of a disease, alleviating one or more symptoms associated with a disease, increasing the quality of life of one suffering from a disease, prolonging survival and / or ^^^ prophylactic or preventative treatment.

[0084] An “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active conjugates or compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of ^^^ administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the ^70836-02^ art can empirically determine the effective amount of a particular compound and / or other therapeutic agent without necessitating undue experimentation. A maximum dose can be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day can be used to achieve appropriate systemic levels of compounds. Appropriate systemic levels can ^^ be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

[0085] Generally, daily oral doses of a compound are, for human subjects, from about 0.01 milligrams / kg per day to 1,000 milligrams / kg per day. Oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, can yield therapeutic results. ^^^ Dosage can be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, intravenous administration can vary from one order to several orders of magnitude lower dose per day. If the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) can be employed to the extent that patient tolerance permits. Multiple ^^^ doses per day are contemplated to achieve appropriate systemic levels of the compound.

[0086] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, such as a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions ^^^ according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0087] For any compound a therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are ^^^ known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. ^^^

[0088] The formulations can be administered in pharmaceutically acceptable solutions, which can routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a ^70836-02^ pharmaceutical composition can be accomplished by any means known to the skilled artisan. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. ^^

[0089] For intravenous and other parenteral routes of administration, a compound can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome- intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. ^^^

[0090] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. A pharmaceutical preparation for oral use can be obtained as a solid excipient, optionally ^^^ grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium ^^^ carboxymethylcellulose, and / or polyvinyl pyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross-linked PVP, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations can also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions, or can be administered without any carriers. ^^^

[0091] Also contemplated are oral dosage forms of the compounds. The compounds can be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the compound itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall ^^^ stability of the compounds and increase in circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, PVP and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts,” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl ^70836-02^ Biochem 4:185-189 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[0092] The location of release of a compound hereof can be the stomach, the small ^^ intestine (e.g., the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations, which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. The release can avoid the deleterious effects of the stomach environment, either by protection of the compound or by release of the compound beyond the stomach environment, such as in the intestine. ^^^

[0093] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be ^^^ used as mixed films.

[0094] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell can be used. ^^^ The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0095] The compound can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as ^^^ tablets. Therapeutic agent could be prepared by compression.

[0096] Colorants and flavoring agents may all be included. For example, the compound can be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. ^^^

[0097] One may dilute or increase the volume of the compound with an inert material. These diluents can include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts also can be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some ^70836-02^ commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0098] Disintegrants can be included in the formulation of therapeutic agent into a solid dosage form. Materials used as disintegrates include, but are not limited to, starch, including ^^ the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrant is the insoluble cationic exchange resin. Powdered gums can be used as disintegrants and as binders, and these can include powdered gums such as agar, Karaya or ^^^ tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0099] Binders can be used to hold the compound together to form a hard tablet and can include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). PVP and hydroxypropylmethyl cellulose (HPMC) can both be used in alcoholic ^^^ solutions to granulate therapeutic agent.

[0100] An anti-frictional agent can be included in the formulation of therapeutic to prevent sticking during the formulation process. Lubricants can be used as a layer between therapeutic agent and the die wall, and these can include, but are not limited to, stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, ^^^ vegetable oils and waxes. Soluble lubricants can also be used, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[0101] Glidants, which can improve the flow properties of the drug during formulation and aid rearrangement during compression, can be added. The glidants can include starch, ^^^ talc, pyrogenic silica and hydrated silicoaluminate.

[0102] To aid dissolution of therapeutic agent into the aqueous environment a surfactant can be added as a wetting agent. Surfactants can include anionic detergents, such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents, which can be used, include benzalkonium chloride and benzethonium chloride. ^^^ Potential non-ionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound or derivative thereof either alone or as a mixture in different ratios. ^70836-02^

[0103] Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc ^^ or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. Such microspheres have been well-defined in the art. All formulations for oral administration should be in dosages suitable for such administration. ^^^

[0104] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

[0105] For topical administration, the compound can be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, ^^^ intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0106] For administration by inhalation, compounds can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, ^^^ dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator, can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch. ^^^

[0107] Also contemplated is pulmonary delivery of the compounds (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) ^^^ (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (a1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins," Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant hepatocyte growth hormone); Debs et al., 1988, J Immunol 140:3482- 3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. ^70836-02^ 5,284,656 (granulocyte colony stimulating factor; incorporated herein by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (specifically incorporated herein by reference for its disclosure regarding same), issued Sep. 19, 1995, to Wong et al. ^^

[0108] Contemplated for use are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products including, but not limited to, nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0109] Nasal delivery of a pharmaceutical composition is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition to the blood stream directly after ^^^ administering therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0110] The compounds, when it is desirable to deliver them systemically, can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous ^^^ infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0111] Pharmaceutical formulations for parenteral administration include aqueous ^^^ solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium ^^^ carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0112] Alternatively, the active compounds can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. ^^^

[0113] The compounds can also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0114] In addition to the formulations described above, a compound can also be formulated as a depot preparation. Such long-acting formulations can be formulated with ^70836-02^ suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0115] The pharmaceutical compositions also can comprise suitable solid or gel phase ^^ carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0116] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto ^^^ microscopic gold particles, contained in liposomes, nebulized, aerosolized, pelleted for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives ^^^ and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-1533 (1990).

[0117] The compound and optionally one or more other therapeutic agents can be ^^^ administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene^^^ sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2- sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0118] Suitable buffering agents include acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt ^^^ (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v); and thimerosal (0.004-0.02% w / v).

[0119] Pharmaceutical compositions contain an effective amount of a compound as described herein and optionally one or more other therapeutic agents included in a ^70836-02^ pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents or encapsulating substances, which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is ^^ combined to facilitate the application. The components of the pharmaceutical compositions also can be commingled with the compounds, and with each other, in a manner such that there is no interaction, which would substantially impair the desired pharmaceutical efficiency.

[0120] Therapeutic agent(s), including specifically, but not limited to, a compound, can be provided in particles. “Particles” means nanoparticles or microparticles (or in some ^^^ instances larger particles) that can consist in whole or in part of the compound or the other therapeutic agent(s). The particles can contain therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. Therapeutic agent(s) also can be dispersed throughout the particles. Therapeutic agent(s) also can be adsorbed into the particles. The particles can be of any order release kinetics, including zero-order release, first- ^^^ order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle can include, in addition to therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles can be microcapsules which contain the compound in a ^^^ solution or in a semi-solid state. The particles can be of virtually any shape.

[0121] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering therapeutic agent(s). Such polymers can be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described ^^^ in Sawhney et al., Macromolecules 26:5823-2787 (1993), the teachings of which are specifically incorporated by reference herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl ^^^ methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0122] Therapeutic agent(s) can be contained in controlled-release systems. The term “controlled release” refers to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non- ^70836-02^ immediate release formulations, with non-immediate release formulations including, but not limited to, sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that can result in substantially constant ^^ blood levels of a drug over an extended time period. The term “delayed release” refers to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0123] Use of a long-term, sustained-release implant can be particularly suitable for ^^^ treatment of chronic conditions. “Long-term” release means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and up to 30-60 days. Long-term sustained-release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0124] The term “salts” and “pharmaceutically acceptable salts” refer to derivatives of ^^^ the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound ^^^ formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, ^^^ sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0125] Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these ^^^ compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, the disclosure of which is hereby incorporated by reference. ^70836-02^

[0126] The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0127] The term “prodrug” means a derivative of a compound that can hydrolyze, ^^ oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and ^^^ biohydrolyzable phosphate analogues. Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ^^^ ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0128] Further, in each of the foregoing and following embodiments, it is to be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and / or solvates of the compound ^^^ formulae or salts thereof. It is to be appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and / or coordination compounds with water and / or various solvents, in the various physical forms of the compounds. Accordingly, the above formulae are to be understood to include and represent those various hydrates and / or solvates. In each of the foregoing and following embodiments, it is also to be understood that ^^^ the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non-crystalline and / or amorphous forms of the compounds. ^^^

[0129] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the ^70836-02^ patient. Some examples of materials, which may serve as pharmaceutically acceptable carriers, include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; ^^ (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; ^^^ (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0130] The term “administering” includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ^^^ ocular, sublingual, vaginal, rectal, and the like. The compounds and compositions may be administered in unit dosage forms and / or formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles.

[0131] Illustrative formats for oral administration include tablets, capsules, elixirs, syrups, and the like. Illustrative routes for parenteral administration include intravenous, ^^^ intraarterial, intraperitoneal, epidural, intraurethral, intrasternal, intramuscular and subcutaneous, as well as any other art recognized route of parenteral administration.

[0132] Illustrative means of parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically ^^^ aqueous solutions, which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH in the range from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, ^^^ may readily be accomplished using standard pharmaceutical techniques well-known to those skilled in the art. Parenteral administration of a compound is illustratively performed in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound, itself, is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied. ^70836-02^

[0133] The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the ^^ pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage regimen used.

[0134] In the methods the individual components of a co-administration, or combination, can be administered by any suitable means, contemporaneously, simultaneously, sequentially in either order, separately or in a single pharmaceutical formulation. Where the ^^^ co-administered compounds or compositions are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The compounds or compositions may be administered via the same or different routes of administration. The compounds or compositions may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the ^^^ therapy, concurrently in divided or single forms.

[0135] The term “therapeutically effective amount” refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being ^^^ treated. In one aspect, the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular ^^^ patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender 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 coincidentally with the ^^^ specific compound employed; and like factors well-known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.

[0136] Depending upon the route of administration, a wide range of permissible dosages are contemplated, including doses falling in the range from about 1 ^g / kg to about 1 g / kg. The dosages may be single or divided and may administered according to a wide variety ^70836-02^ of protocols, including q.d. (once a day), b.i.d. (twice a day), t.i.d. (three times a day), or even every other day, once a week, once a month, once a quarter, and the like. In each of these cases the described therapeutically effective amounts correspond to the instance of administration, or alternatively to the total daily, weekly, month, or quarterly dose, as determined by the ^^ dosing protocol.

[0137] An effective amount of any one or a mixture of the compounds can be determined by the attending diagnostician or physician by the use of known techniques and / or by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician or ^^^ physician, including, but not limited to, the species of mammal, including human, its size, age, and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and ^^^ other relevant circumstances.

[0138] The term “patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human. ^^^

[0139] The following enumerated Embodiments are also part of the disclosure and are listed in no particular order of importance:

[0140] Embodiment A1 relates to a compound of formula (I):or a pharmaceutically acceptable salt or hydrate thereof, wherein: ^^^ R1 is selected fromR2 is selected from^70836-02^

[0141] Embodiment A2 relates to the compound of Embodiment A1, wherein:

[0142] Embodiment A3 relates to the compound of Embodiment A1, wherein: when^^

[0143] Embodiment A4 relates to the compound of Embodiment A1, wherein:

[0144] Embodiment A5 relates to a compound of formula (II):or a pharmaceutically acceptable salt or hydrate thereof, wherein: ^^^ R is selected fromn = 1 or 2.

[0145] Embodiment A6 relates to the compound of Embodiment A5, wherein: ^^^

[0147] Embodiment A8 relates to a compound of the formula:^70836-02^ or a pharmaceutically acceptable salt or hydrate thereof, wherein: R3 is 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) substituted with (R5)n; n is 0, 1, 2 or 3; ^^ R4 is carboxy-6- to 10-membered aryl substituted with (R5)n, carboxy alkyl substituted with (R5)n, -C1-C6alkyl-C(O)O-alkyl or -C1-C6alkyl-C(O)NR7R8, wherein R7and R8are each independently, H or C1-C6alkyl or R7and R8, together with the nitrogen atom to which they are attached, form a 5- to 10-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S); and ^^^ R5 in each instance is independently OH, halo, S(O)xR6 (wherein R5 is H, C1-C6 alkyl or 6- to 10-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S) and x is 0, 1 or 2), -SCN, -NCS, C1-C6-alkyl, C1-C6-alkoxy, C1- C6-haloalkyl, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S),^^^ or two R4 groups, together with carbon atoms to which they are attached, form a 5- to 6- membered heterocycloalkyl (wherein 1 or 2 heterocycloalkyl members are independently selected from N, O, and S).

[0148] Embodiment A9 relates to the compound of Embodiment A8, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3is selected from: ^^^of which is substituted with (R5)n.

[0149] Embodiment A10 relates to the compound of Embodiment A8 or A9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from: ^70836-02^each of which is substituted with (R5)n.

[0150] Embodiment A11 relates to the compound of Embodiment A8 or A9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from: ^^each of which is substituted with (R5)n.

[0151] Embodiment A12 relates to the compound of Embodiment A8 or A9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3is selected from:^^^each of which is substituted with (R5)n.

[0152] Embodiment A13 relates to the compound of Embodiment A8 or A9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from:each of which is substituted with (R5)n. ^70836-02^

[0153] Embodiment A14 relates to the compound of Embodiment A8 or A9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from:^^

[0154] Embodiment A15 relates to the compound of Embodiment A8 or A9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from:

[0155] Embodiment A16 relates to the compound of any of Embodiments A8-A15, or ^^^ a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is carboxy alkyl substituted

[0156] Embodiment A17 relates to the compound of Embodiment A16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4is carboxy C1-C6alkyl substituted with (R5)n. ^^^

[0157] Embodiment A18. The compound of Embodiment A16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is -(CH2)pCO2H, -(CH2)pCO2 C1-C6-alkyl or - (CH2)pCONR7R8, wherein p is 1, 2, 3, 4, 5, 6 or from 1 to 6, 1 to 3, 1 to 4, 1 to 2, 2 to 3, 3 to 6 or 2 to 5; and R7 and R8, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl. ^^^

[0158] Embodiment A19. The compound of any of Embodiments A8-A16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is carboxy-6- to 10- membered aryl substituted with (R5)n.

[0159] Embodiment A20 relates to the compound of Embodiment A19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4is: ^70836-02^substituted with (R5)n.

[0160] Embodiment A21 relates to the compound of Embodiment A19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is selected from:^^

[0161] Embodiment A22 relates to the compound of Embodiment A19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is selected from:(R5)n.

[0162] Embodiment A23 relates to the compound of Embodiment A19, or a ^^^ pharmaceutically acceptable salt or hydrate thereof, wherein R4is selected from:substituted with (R5)n.

[0163] Embodiment A24 relates to the pharmaceutical composition comprising a compound of any one of Embodiments A1-A23, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. ^^^

[0164] Embodiment A25 relates to a method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of any one of Embodiments A1-A23, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a ^70836-02^ pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0165] Embodiment A26 relates to a method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, ^^ which method comprises administering to the subject an effective amount of (i) a compound of any one of Embodiments A2-A4, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0166] Embodiment A27 relates to the method of Embodiment A25 or A26, wherein ^^^ the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB).

[0167] Embodiment A28 relates to the method of Embodiment A26 or A27, wherein the compound is a compound of Embodiment A 4 in which R2 is, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate ^^^ thereof, and a pharmaceutically acceptable carrier, and the compound also inhibits ^-syn oligomers.

[0168] Embodiment A29 relates to the method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, which method comprises administering to the subject an effective amount of (i) a compound ^^^ of Embodiment A6 or A7, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0169] Embodiment A30 relates to the method of Embodiment A29, wherein the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB). ^^^

[0170] Embodiment A31 relates to the method of Embodiment A29 or A30, wherein the compound is the compound of Embodiment A 7, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, and the compound also inhibits ^-syn oligomers. ^^^

[0171] Embodiment A32 relates to a method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation, which method ^70836-02^ comprises administering to the subject an effective amount of (i) a compound of Embodiment A4 in which R2 is, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically ^^ acceptable carrier.

[0172] Embodiment A33 relates to a method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation, which method comprises administering to the subject an effective amount of (i) a compound of Embodiment A7, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a ^^^ pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0173] Embodiment A34 relates to a method of decreasing A^-plaques or their density in a subject having, or at risk for, A^-plaque formation, which method comprises administering to the subject an effective amount of (i) a compound of Embodiment A4 in ^^^ which R2 is, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0174] Embodiment A35 relates to a method of decreasing A^-plaques in a subject having, or at risk for, A^-plaque formation, which method comprises administering to the ^^^ subject an effective amount of (i) a compound of Embodiment A7, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0175] Embodiment A36 relates to a method of inhibiting islet amyloid polypeptide ^^^ (IAPP) fibril formation in a subject having, or at risk for, IAPP fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of formula (I): ^70836-02^or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is selected from^^ or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0176] Embodiment A37 relates to the method of Embodiment A36, wherein the subject is a human.

[0177] Embodiment A38 relates to the method of Embodiment A36, wherein the ^^^ subject is a feline.

[0178] Embodiment A39 relates to a method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation, which method comprises (i) administering to the subject an effective amount of a compound of formula (I):^^^ or a pharmaceutically acceptable salt or hydrate thereof, wherein:(ii) detecting fluorescence, whereupon IAPP fibrils in a subject are detected.

[0179] Embodiment A40 relates to the method of Embodiment A39, wherein the subject is a diabetic human and the presence of IAPP fibrils indicates the diabetic human has ^^^ pancreatic amyloidosis. ^70836-02^

[0180] Embodiment A41 relates to the method of Embodiment A39, wherein the subject is a diabetic feline and the presence of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis.

[0181] Embodiment A42 relates to a method of inhibiting tau 2N4R oligomer ^^ formation in a subject having, or at risk for, 2N4R oligomer formation, which method comprises administering to the subject an effective amount of (i) a compound of any of Embodiments A8-A22, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. ^^^

[0182] Embodiment A43 relates to a method of decreasing A^-plaques in a subject having, or at risk for, A^-plaque formation, which method comprises administering to the subject an effective amount of (i) a compound of any of Embodiments A8-A22, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a ^^^ pharmaceutically acceptable carrier.

[0183] Embodiment A44 relates to a method of inhibiting islet amyloid polypeptide (IAPP) fibril formation in a subject having, or at risk for, IAPP fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of any of Embodiments A8-A22, or a pharmaceutically acceptable salt or hydrate thereof; or (ii) a ^^^ pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

[0184] Embodiment A45 relates to the method of Embodiment A44, wherein the subject is a human.

[0185] Embodiment A46 relates to the method of Embodiment A44, wherein the ^^^ subject is a feline.

[0186] Embodiment A47 relates to a method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation which method comprises administering to the subject an effective amount of (i) a compound of any of Embodiments A8-A22, or a pharmaceutically acceptable salt or hydrate thereof; or (ii) a ^^^ pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier; and detecting fluorescence, whereupon IAPP fibrils in a subject are detected. ^70836-02^

[0187] Embodiment A48 relates to the method of Embodiment A47, wherein the subject is a diabetic human and the presence of IAPP fibrils indicates the diabetic human has pancreatic amyloidosis.

[0188] Embodiment A49 relates to the method of Embodiment A47, wherein the ^^ subject is a diabetic feline and the presence of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis. EXAMPLES

[0189] The following examples serve to illustrate the present disclosure. The examples are ^^^ not intended to limit the scope of the claimed invention in any way. Example 1 Design and Synthesis

[0190] All reagents and solvents were commercially available (Sigma Aldrich, St. Louis, MO; Thermo Scientific (formerly Alfa Aesar), Waltham, MA; Matrix Scientific, Columbia, ^^^ SC; Ambeed, Arlington Hts, IL) and were used without further purification. Thin-layer chromatography (TLC) was used to monitor the reaction progress. Organic solutions were dried over anhydrous sodium sulfate. The solvents were evaporated on a Büchi rotavapor R-100 equipped with a Büchi V-100 vacuum controller. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker spectrometer at a frequency of 500 MHz forand at 126 ^^^ MHz for13C. Proton chemical shifts are reported in parts per million (ppm) with the solvent reference relative to tetramethyl silane (TMS) employed as the internal standard (CDCl3, > 7.26; DMSO^d6 > 2.54). The multiplicities of NMR signals are designated as s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), m (multiplet, for unresolved lines). High resolution mass spectrometry (HRMS) of the compounds was carried out on Advion Mass ^^^ Spectrometer (Advion Expression CMS) at the Analytical Mass Spectrometry Facility within the Purdue Institute for Drug Discovery. Uncorrected melting points (m.p.) were scored using electrothermal apparatus (Barnstead International, Dubuque, Iowa, USA).

[0191] The targeted compounds were prepared using the Knoevenagel condensation of equimolar amounts of the rhodanine and fused heterocyclic aldehydes in the presence of ^^^ dimethylamino pyridine (DMAP) as a base (Schemes 1 and 2). The rhodanines 2a and 2b were easily achieved by reacting bis(carboxymethyl) trithiocarbonate with 4-amino benzoic acid and 4-amino salicylic acid, respectively, while the other rhodanines (2c and 2d) and the aromatic aldehydes were commercially available. The final compounds were produced in moderate to excellent yields. ^70836-02^Scheme 1: Synthetic procedure for the target compounds 3a-d, 4a-d, and 5a-l. Reagents and conditions: (a) water, 100°C, 4-6 h, 63-75%; (b) DMAP, DCM, r.t., overnight, 63-92%. ^70836-02^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ ^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^!Scheme 2: Synthetic procedure for the optimized anti-oligomer compounds 5m-s. Reagents and conditions: (a) DMAP, DCM, r.t., overnight, 65-92%; (b) K2CO3, DMF, r.t., 3 h, 94%; (c) 2c or 2d, DMAP, DCM, r.t., overnight, 82-93% ^^

[0192] General procedure for the synthesis of rhodanine benzoic acid derivatives (2a-b). A constantly stirred suspension of 4-amino benzoic acid or 4-amino salicylic acid (1 equiv.) in water (5 mL) was heated at 100˚C for 30 minutes. Bis (carboxyl methyl) trithiocarbonate (1.2 equiv.) was gradually added and the reaction mixture was stirred at 100˚C for 4-6 h. After cooling, 1 N HCl was added and the precipitated solid was filtered and washed several times ^^^ with cold water affording 2a and 2b at good yields. ^70836-02^

[0193] 4-(4-Oxo-2-thioxothiazolidin-3-yl)benzoic acid (2a). 63%, pale yellow solid.1H NMR (500 MHz, DMSO) ? 8.07 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 4.38 (s, 2H).13C NMR (126 MHz, DMSO) ? 203.9, 174.4, 167.1, 139.8, 132.0, 130.7, 130.4, 129.6, 122.5, 37.8.

[0194] 2-Hydroxy-4-(4-oxo-2-thioxothiazolidin-3-yl)benzoic acid (2b) as a salt. 75%, ^^ pale yellow solid.1H NMR (500 MHz, DMSO) ? 9.78 (s, 1H), 7.28 (t, J = 8.0 Hz, 1H), 6.90 – 6.79 (m, 1H), 6.68 – 6.56 (m, 2H), 4.34 (s, 2H).13C NMR (126 MHz, DMSO) ? 204.0, 174.5, 158.5, 136.9, 130.4, 119.6, 116.7, 116.1, 37.5.

[0195] General procedure for the synthesis of target compounds 3a-d, 4a-d, and 5a-s. The appropriate rhodanine derivative (2a-d, 1.0 equiv.) and dimethylamino pyridine (DMAP, ^^^ 1.2 equiv.) were dissolved in dry dichloromethane (DCM, 10 mL). To this solution was added the aldehyde (quinoline-2-carbaldehyde for 3a-d, benzothiazole-2-carboxaldehyde for 4a-d, benzothiophene-2-carbaldehyde for 5a-d, benzofuran-3-carbaldehyde for 5e-h, indole-3- carbaldehyde for 5i-l, indole-2-carbaldehyde for 5m-n, indole-7-carbaldehyde for 5o-p, N- ethyl indole-3-carbaldehyde for 5q, and 6-methoxy indole-3-carbaldehyde for 5r-s, 1.0 eq.) ^^^ and stirred overnight at room temperature under nitrogen atmosphere. The precipitate was then filtered and washed with hexane (10 mL), DCM (2 x 10 mL) and diethyl ether (10 mL). The desired pure products were obtained either by crystallization from methanol or flash column chromatography in moderate to excellent yields.

[0196] (Z)-4-(4-Oxo-5-(quinolin-2-ylmethylene)-2-thioxothiazolidin-3-yl)benzoic acid ^^^ (3a). 63%, yellow solid, m.p.: >300°C.;1H NMR (500 MHz, DMSO) ? 8.51 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.15 – 8.08 (m, 2H), 8.06 – 7.99 (m, 3H), 7.89 – 7.84 (m, 1H), 7.74 – 7.67 (m, 1H), 7.61 – 7.53 (m, 2H).13C NMR (126 MHz, DMSO) ? 201.1, 167.3, 167.1, 152.3, 147.6, 139.5, 138.1, 132.2, 131.4, 130.7, 130.0, 129.8, 128.9, 128.6, 128.3, 127.5, 125.2.

[0197] (Z)-2-Hydroxy-4-(4-oxo-5-(quinolin-2-ylmethylene)-2-thioxothiazolidin-3- ^^^ yl)benzoic acid (3b). 91%, brown solid, m.p.: 275.4 – 277.5°C.;1H NMR (500 MHz, DMSO) ? 9.86 (s, 1H), 8.55 – 8.43 (m, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.07 – 7.92 (m, 3H), 7.89 – 7.80 (m, 1H), 7.74 – 7.62 (m, 1H), 7.39 – 7.29 (m, 1H), 6.91 (dd, J = 8.6, 2.4 Hz, 1H), 6.89 – 6.76 (m, 2H).13C NMR (126 MHz, DMSO) ? 201.1, 167.4, 158.5, 152.3, 147.6, 138.0, 136.5, 131.3, 130.4, 130.0, 128.9, 128.6, 128.5, 128.0, 127.5, 125.1, 119.6, 116.9, 116.2. ^^^

[0198] (Z)-2-(4-Oxo-5-(quinolin-2-ylmethylene)-2-thioxothiazolidin-3-yl)acetic acid (3c). 66%, yellow solid, m.p.: 286.2 – 287.1°C.;1H NMR (500 MHz, DMSO) ? 8.50 (d, J = 8.3 Hz, 1H), 8.16 (dd, J = 8.5, 1.1 Hz, 1H), 8.04 – 7.98 (m, 3H), 7.85 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.69 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.75 (s, 2H).13C NMR (126 MHz, DMSO) ? ^70836-02^ 200.5, 167.9, 166.9, 152.0, 147.5, 138.1, 131.4, 129.3, 128.9, 128.7, 128.6, 128.5, 127.6, 125.3, 45.1.

[0199] (Z)-3-(4-Oxo-5-(quinolin-2-ylmethylene)-2-thioxothiazolidin-3-yl)propanoic acid (3d).80%, yellow solid, m.p.: 258.8 – 260.5°C.;1H NMR (500 MHz, DMSO) ? 8.49 (dd, ^^ = 8.5, 0.8 Hz, 1H), 8.16 – 8.14 (m, 1H), 8.05 – 7.97 (m, 2H), 7.96 (s, 1H), 7.84 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.68 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 4.29 – 4.18 (m, 2H), 2.67 – 2.59 (m, 2H). 13C NMR (126 MHz, DMSO) ? 200.5, 172.3, 167.2, 152.2, 147.5, 138.0, 131.4, 129.1, 128.9, 128.6, 128.6, 128.4, 127.5, 125.2, 40.5, 31.4.

[0200] (Z)-4-(5-(Benzo[d]thiazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3- ^^^ yl)benzoic acid (4a). 81%, yellow solid, m.p.: >300°C.;1H NMR (500 MHz, DMSO) ? 8.22 (dd, J = 8.4, 4.8 Hz, 2H), 8.15 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.68 – 7.57 (m, 2H), 7.59 – 7.49 (m, 2H).13C NMR (126 MHz, DMSO) ? 198.5, 167.1, 166.7, 161.7, 153.5, 139.3, 136.6, 132.3, 131.2, 130.7, 129.7, 128.0, 127.1, 124.0, 123.4, 121.2.

[0201] (Z)-4-(5-(Benzo[d]thiazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)-2- ^^^ hydroxy benzoic acid (4b).71%, dark red solid, m.p.: 218.9 – 221.1°C.;1H NMR (500 MHz, DMSO) ? 9.86 (s, 1H), 8.26 – 8.18 (m, 2H), 8.12 (s, 1H), 7.63 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.54 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.32 (t, J = 8.3 Hz, 1H), 6.93 – 6.87 (m, 1H), 6.86 – 6.77 (m, 2H).13C NMR (126 MHz, DMSO) ? 198.5, 166.8, 161.8, 158.5, 153.6, 139.5, 136.6, 136.4, 131.3, 130.4, 128.0, 127.1, 124.0, 123.4, 120.9, 119.6, 117.0, 116.2, 107.4. ^^^

[0202] (Z)-2-(5-(Benzo[d]thiazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (4c). 67%, canary yellow solid, m.p.: 269.1 – 270.9°C.;1H NMR (500 MHz, DMSO) ? 8.25 – 8.16 (m, 3H), 7.66 – 7.58 (m, 1H), 7.58 – 7.50 (m, 1H), 4.73 (s, 2H).13C NMR (126 MHz, DMSO) ? 197.9, 167.8, 166.3, 161.5, 153.5, 136.7, 129.5, 128.0, 127.2, 124.1, 123.4, 122.3, 45.4. ^^^

[0203] (Z)-2-(5-(Benzo[d]thiazol-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3- yl)propanoic acid (4d). 72%, yellow solid, m.p.: 257.4 – 258.6°C.;1H NMR (500 MHz, DMSO) ? 8.23 – 8.16 (m, 2H), 8.09 (s, 1H), 7.61 (ddd,= 8.3, 7.1, 1.3 Hz, 1H), 7.53 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 4.26 – 4.18 (m, 2H), 2.67 – 2.61 (m, 2H).13C NMR (126 MHz, DMSO) ? 197.9, 172.2, 166.7, 161.7, 153.5, 136.6, 130.3, 128.0, 127.1, 124.0, 123.4, 121.3, 40.5, 31.3.^^^

[0204] (Z)-4-(5-(Benzo[b]thiophen-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3- yl)benzoic acid (5a). 78%, orange solid, m.p.: >300°C.;1H NMR (500 MHz, DMSO) ? 8.28 (s, 1H), 8.21 – 8.17 (m, 1H), 8.11 (d, J = 8.2 Hz, 2H), 8.09 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.52 (m, 2H).13C NMR (126 MHz, DMSO) ? 194.0, 167.1, 167.0, 139.7, 139.5, 138.1, 133.0, 132.3, 130.7, 129.8, 129.7, 126.2, 126.0, 125.0, 123.7, 123.1, 122.3. ^70836-02^

[0205] (Z)-4-(5-(Benzo[b]thiophen-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)-2- hydroxybenzoic acid as a salt (5b).83%, orange solid, m.p.: 254.6 – 255.4°C;1H NMR (500 MHz, DMSO) ? 9.86 (s, 1H), 8.24 (s, 1H), 8.21 – 8.15 (m, 1H), 8.14 – 8.08 (m, 1H), 8.03 (s, 1H), 7.55 – 7.46 (m, 2H), 7.33 (t, J = 8.1 Hz, 1H), 6.93 – 6.86 (m, 1H), 6.81 (dd, J = 7.2, 1.4 ^^ Hz, 2H).13C NMR (126 MHz, DMSO) ? 194.1, 167.0, 158.6, 139.6, 138.1, 136.6, 132.8, 130.5, 129.8, 126.2, 125.9, 125.0, 123.7, 122.8, 122.3, 119.6, 117.0, 116.2.

[0206] (Z)-2-(5-(Benzo[b]thiophen-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3- yl)acetic acid (5c).86%, yellow solid, m.p.: 282.0 – 283.4°C.;1H NMR (500 MHz, DMSO) ? 8.26 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.0 Hz, 2H), 7.57 – 7.44 (m, 2H), 4.74 (s, ^^^ 2H).13C NMR (126 MHz, DMSO) ? 193.5, 167.8, 166.5, 139.6, 138.1, 133.5, 129.7, 126.3, 126.0, 124.2, 123.7, 123.4, 122.4, 45.6.

[0207] (Z)-2-(5-(Benzo[b]thiophen-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3- yl)propanoic acid (5d). 84%, orange solid, m.p.: 207.3 – 208.8°C.;1H NMR (500 MHz, DMSO) ? 8.22 – 8.14 (m, 2H), 8.13 – 8.07 (m, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.55 – 7.46 (m, ^^^ 2H), 4.28 – 4.21 (m, 2H), 2.67 – 2.62 (m, 2H).13C NMR (126 MHz, DMSO) ? 193.5, 172.3, 166.9, 139.6, 138.1, 133.0, 129.7, 126.2, 125.9, 124.0, 123.7, 123.2, 122.3, 40.5, 31.3.

[0208] (Z)-4-(5-(Benzofuran-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid (5e). 77%, dark brown solid, m.p.: >300°C.;1H NMR (500 MHz, DMSO) ? 8.59 (s, 1H), 8.10 (t, J = 8.5 Hz, 3H), 8.00 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 – ^^^ 7.36 (m, 2H).13C NMR (126 MHz, DMSO) ? 193.4, 167.1, 166.7, 155.1, 148.6, 139.5, 132.3, 130.7, 129.7, 126.6, 125.8, 124.7, 124.6, 121.8, 120.9, 117.1, 112.4.

[0209] (Z)-4-(5-(Benzofuran-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)-2-hydroxy benzoic acid (5f). 62%, brown solid, m.p.: 242.6 – 245.1°C.;1H NMR (500 MHz, DMSO) ? 9.85 (s, 1H), 8.56 (d, J = 0.8 Hz, 1H), 8.12 – 8.02 (m, 1H), 7.95 (d, J = 0.9 Hz, 1H), 7.75 – ^^^ 7.64 (m, 1H), 7.43 (ddd, J = 20.5, 7.9, 1.0 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 6.94 – 6.87 (m, 1H), 6.80 (dd, J = 7.4, 1.3 Hz, 2H).13C NMR (126 MHz, DMSO) ? 193.4, 166.7, 158.5, 155.1, 148.5, 136.6, 130.5, 126.6, 125.8, 124.8, 124.6, 122.0, 121.4, 120.8, 119.6, 117.1, 117.0, 116.2, 112.3.

[0210] (Z)-2-(5-(Benzofuran-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid ^^^ (5g).92%, red solid, m.p.: 280.6 – 282.3°C.;1H NMR (500 MHz, DMSO) ? 8.50 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.47 – 7.36 (m, 2H), 4.42 (s, 2H). 13C NMR (126 MHz, DMSO) ? 192.9, 167.8, 166.4, 157.2, 155.1, 148.8, 140.2, 126.6, 124.6, 120.8, 117.0, 112.3, 107.4, 46.5. ^70836-02^

[0211] (Z)-2-(5-(Benzofuran-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (5h).82%, orange solid, m.p.: >300°C.;1H NMR (500 MHz, DMSO) ? 8.50 (s, 1H), 8.07 – 8.02 (m, 1H), 7.94 (d, J = 0.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.44 (ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.41 – 7.39 (m, 1H), 4.24 – 4.19 (m, 2H), 2.62 – 2.60 (m, 2H).13C NMR (126 MHz, ^^ DMSO) ? 192.9, 166.6, 155.1, 148.6, 126.6, 125.7, 124.6, 123.9, 121.9, 120.8, 117.0, 112.3, 42.8, 31.7.

[0212] (Z)-4-(5-((1H-Indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid (5i). 72%, dark brown solid, m.p.: 253.6 – 255.1°C.;1H NMR (500 MHz, DMSO) ? 10.40 (s, 1H), 8.29 – 8.02 (m, 2H), 8.02 – 7.93 (m, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, ^^^ 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.29 – 7.18 (m, 1H).13C NMR (126 MHz, DMSO) ? 193.2, 179.6, 167.4, 144.0, 139.9, 139.6, 136.9, 130.7, 130.4, 129.8, 126.5, 122.4, 119.1, 115.7, 113.1, 111.6, 107.4.

[0213] (Z)-4-(5-((1H-Indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-2- hydroxybenzoic acid (5j). 66%, brown solid, m.p.: 267.4 – 269.1°C.;1H NMR (500 MHz, ^^^ DMSO) ? 9.85 (s, 1H), 8.08 (s, 1H), 8.01 – 7.90 (m, 2H), 7.55 – 7.48 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.25 – 7.18 (m, 1H), 6.93 – 6.84 (m, 1H), 6.80 – 6.70 (m, 2H). 13C NMR (126 MHz, DMSO) ? 193.3, 167.1, 158.5, 136.9, 136.9, 131.0, 130.4, 127.3, 126.4, 123.9, 122.0, 119.6, 119.1, 116.8, 116.2, 115.8, 113.1, 111.6.

[0214] (Z)-2-(5-((1H-Indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid ^^^ (5k).71%, orange solid, m.p.: 280.7 – 282.4°C.;1H NMR (500 MHz, DMSO) ? 12.42 (s, 1H), 8.15 (d, J = 7.2 Hz, 1H), 8.02 – 7.91 (m, 2H), 7.51 (d, J = 7.9 Hz, 1H), 7.28 – 7.21 (m, 2H), 4.72 (s, 2H).13C NMR (126 MHz, DMSO) ? 193.3, 168.0, 166.0, 136.9, 131.5, 127.5, 124.0, 123.1, 122.2, 119.1, 114.4, 113.1, 111.6, 45.5.

[0215] (Z)-2-(5-((1H-Indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic ^^^ acid (5l).65%, dark brown solid, m.p.: 246.3 – 247.1°C.;1H NMR (500 MHz, DMSO) ? 12.36 (s, 1H), 8.07 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 3.1 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.28 – 7.23 (m, 1H), 7.23 – 7.17 (m, 1H), 4.23 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H).13C NMR (126 MHz, DMSO) ? 192.7, 172.3, 166.9, 136.9, 131.1, 127.2, 126.7, 123.9, 122.0, 119.0, 114.9, 113.1, 111.6, 40.5, 31.4. ^^^

[0216] (Z)-2-(5-((1H-Indol-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (5m) as a salt.71%, orange solid, m.p.: 242.2– 243.6°C.;1H NMR (500 MHz, DMSO) ? 11.79 (s, 1H), 8.22 – 8.15 (m, 1H), 7.82 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 8.3, 1.0 Hz, 1H), 7.29 – 7.22 (m, 1H), 7.12 – 7.05 (m, 1H), 6.98 – 6.89 (m, 2H), 4.69 (s, 2H).13C NMR ^70836-02^ (126 MHz, DMSO) ? 193.1, 167.8, 166.6, 138.6, 132.4, 129.1, 125.6, 123.9, 122.3, 120.1, 112.6, 108.8, 107.4, 45.8.

[0217] (Z)-2-(5-((1H-Indol-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (5n) as a salt. 92%, brown solid, m.p.: 200.2– 201.6°C.;1H NMR (500 MHz, DMSO) ? ^^ 11.79 (s, 1H), 8.16 – 8.07 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.87 (s, 1H), 6.68 (d, J = 5.6 Hz, 1H), 4.20 (t, J = 7.9 Hz, 2H), 2.70 – 2.53 (m, 2H).13C NMR (126 MHz, DMSO) ? 193.0, 172.6, 166.9, 155.5, 146.0, 138.5, 1326, 129.1, 123.1, 122.1, 112.5, 108.4, 107.2, 40.8, 31.8.

[0218] (Z)-2-(5-((1H-Indol-7-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid ^^^ (5o).65%, brick red solid, m.p.: 184.0– 185.6°C.;dc1H NMR (500 MHz, DMSO) ? 12.03 (s, 1H), 8.46 (s, 1H), 8.19 (d, J = 6.9 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.47 (t, J = 2.8 Hz, 1H), 7.30 – 7.17 (m, 1H), 6.56 (dd, J = 3.0, 1.6 Hz, 1H), 4.76 (s, 2H).13C NMR (126 MHz, DMSO) ? 194.0, 167.8, 166.7, 139.4, 136.3, 130.2, 127.2, 124.9, 121.4, 120.3, 117.5, 107.4, 102.7, 45.5. ^^^

[0219] (Z)-2-(5-((1H-Indol-7-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (5p). 82%, orange solid, m.p.: 207.3– 208.6°C.;1H NMR (500 MHz, DMSO) ? 12.00 (s, 1H), 8.40 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 2.9 Hz, 1H), 7.22 (m, 2H), 6.56 (dd, J = 3.1, 1.7 Hz, 1H), 4.39 – 4.09 (t, J = 7.6 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H).13C NMR (126 MHz, DMSO) ? 194.0, 172.3, 167.1, 136.3, 129.5, 129.1, 127.1, 124.6, 122.0, 121.9, 120.3, ^^^ 117.6, 102.7, 40.5, 31.3.

[0220] (Z)-2-(5-((1-(2-Hydroxyethyl)-1H-indol-3-yl)methylene)-4-oxo-2- thioxothiazolidin-3-yl)acetic acid (5q) as a salt.82%, dark red solid, m.p.: 216.4– 217.2°C.; 1H NMR (500 MHz, DMSO) ? 8.19 (d, J = 6.9 Hz, 1H), 8.11 (s, 1H), 8.00 – 7.97 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.97 – 6.88 (m, 1H), ^^^ 4.71 (s, 2H), 4.69 (brs, 1H), 4.4.39 (t, J = 5.3 Hz, 2H), 3.77 (t, J = 5.3 Hz, 2H).13C NMR (126 MHz, DMSO) ? 168.0, 166.6, 140.2, 137.1, 134.6, 126.9, 123.9, 122.4, 119.3, 114.2, 111.9, 110.7, 107.4, 60.4, 49.7, 45.9.

[0221] (Z)-2-(5-((6-Methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3- yl)acetic acid (5r) as a salt.93%, dark red solid, m.p.: 251.4– 253.0°C.;1H NMR (500 MHz, ^^^ DMSO) ? 12.25 (s, 1H), 8.08 (s, 1H), 7.88 – 7.79 (m, 1H), 7.19 (s, 2H), 6.98 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.7, 2.3 Hz, 1H), 4.71 (s, 2H), 3.78 (s, 3H).13C NMR (126 MHz, DMSO) ? 168.0, 166.6, 157.4, 137.9, 130.6, 127.7, 124.7, 121.2, 119.9, 114.2, 112.1, 111.7, 96.0, 55.8, 45.5. ^70836-02^

[0222] (Z)-2-(5-((6-Methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3- yl)propanoic acid (5s) as a salt. 91%, dark red solid, m.p.: >300°C.; 1H NMR (500 MHz, DMSO) ? 12.17 (s, 1H), 8.19 (d, J = 6.8 Hz, 2H), 8.01 (s, 1H), 7.86 – 7.71 (m, 1H), 6.99 – 6.91 (m, 2H), 6.91 – 6.76 (m, 1H), 4.26 – 4.18 (m, 2H), 3.78 (s, 3H), 2.64 – 2.59 (m, 2H).To ^^ synthesize the hydroxyethyl indole derivative (compound 5q), the indole-3-carbaldehyde was first treated with 2-bromoethanol in the presence of anhydrous potassium carbonate. The alkylated indole was then reacted with rhodanine 2c to produce 5q in a good yield (83% overall the two steps). ^^^ Example 2 Thioflavin-T (ThT) and Thioflavin-S (ThS) Fluorescence Assays

[0223] ThT was purchased from Alfa Aesar (Ward Hill, MA) for the ^-syn and ThT assays while ThS was obtained from Sigma Aldrich (St. Louis, MO) for the 2N4R ThS assays. Heparin sodium salt was purchased from Millipore-Sigma. Procuration of recombinant ^-syn and tau 2N4R was from rPeptide (WatKinsville, GA). The recombinant p-tau isoform 1N4R ^^^ was prepared as published previously.51–53The fluorescence emission experiments were performed with the excitation and emission wavelengths set at 440 and 485 nm, respectively, with a Synergy HT multi-mode microplate reader (BioTek, Winooski, VT). Air-dried grids were analyzed using a transmission electron microscope JEOL 1400 Flash (Japan). Amyloid- ^ plaques were purified from post-mortem human AD brains obtained from patients diagnosed ^^^ with advanced Alzheimer’s (Braak stage V or VI) (Tissue Biobank at Case Western Reserve University-Cleveland Clinic) using ultracentrifugation with a sucrose gradient and cell sorting, as previously published.54,55

[0224] Thioflavin fluorescence assays were used to monitor the effect of different rhodanine compounds on the fibril formation of recombinant ^-syn (6 µM) and 2N4R tau (12 µM). ^^^ Kinetics of ^-syn fibril formation were performed using ThT following our reported procedures.56The experiments were repeated three times, and the samples were measured in three replicates. Arbitrary units of fluorescence were calculated from the mean values normalized against the maximum value in each completed assay. All results were presented as mean ± SEM. On the other hand, the kinetics of aggregation of 2N4R tau was performed using ^^^ ThS. Fluorescence measurements were scored using a solution of the protein diluted to a final concentration of 6 µM and 12 µM in PBS (pH 7.4) for ^-syn and 2N4R tau, respectively, supplemented with 0.15 mM heparin, 40 µM of either ThT or ThS, 5 mM DTT, 0.92 µg / mL of arachidonic acid, and 100 µM compound. PBS was pe-treated with chelex beads (0.5 ml, Biosciences, cat # BTNM-0024). Solution total volume consisted of 10 µL and assay was ^70836-02^ completed using a 384-well plate. The plate was incubated at 37º C and shaked for 30 seconds prior each fluorescence measurement. Fluorescence was measured every 5 min with excitation and emission wavelengths of 440 nm and 480 nm, and the data were plotted using GraphPad Prism. ^^

[0225] Kinetic fluorescence studies using either Thioflavin-T or Thioflavin-S (ThT, or ThS) dyes are widely used techniques to demonstrate the activity against ^-syn and tau fibrils.41The fluorescence quantum yields of these dyes are highly increased upon binding to the late-stage protein fibrils. After equilibrium between aggregation and disaggregation, the kinetic curve is achieved with a plateau phase where the dense fibrils are located. All rhodanines (100 µM) ^^^ were first screened against ^-syn protein (6 µM) using the ThT assay (Figs.1A-1B, Table 1). Generally, the ability of the compound to reduce the ^-syn ThT fluorescence is a good measure for its high anti-fibrillar activity. Analyzing the activity with respect to the structure of compound, structure-activity relationship (SAR), has been intensively studied. Except 5j, the aromatic benzoic-acid or salicylic-acid containing derivatives in the R2 position displayed^^^ moderate to weak activity on reducing ThT fluorescence in comparison to the aliphatic acetic- acid or propanoic-acid containing counterparts. Moreover, investigating the activity of the fused heterocyclic ring in the R1 part clearly showed that the derivatives with the indole, benzothiophene, and benzothiazole moieties had superior anti-fibrillar activity than that with the benzofuran or quinoline scaffolds. Due to its complete inactivity towards the ^-syn fibrils, ^^^ compound 3b was set as a negative control. Compounds 4c, 5c-d, and 5l significantly decreased the ThT fluorescence to lower than 5% on ^-syn aggregates and consequently expected to show the highest ^-syn anti-fibrillar activity.

[0226] To find out a powerful two-stage inhibitor against both protein fibrils and oligomers, the anti-oligomer activity of the most promising anti-fibril derivatives was investigated. Only ^^^ the indole-containing rhodanines 5k and 5l exhibited remarkable inhibition of ^-syn oligomers (discussed later). Therefore, the indole scaffold with aliphatic rhodanines were chosen for further optimization (Table 2). Changing the attachment of rhodanine from the 3-indolyl methylene to 2-indolyl methylene, compounds 5m-n, significantly improved the ThT fluorescence reduction while changing the attachment to the 7-position, compounds 5o-p, ^^^ strongly decreased the activity. In addition, alkylating the indole moiety with an aliphatic water-soluble hydroxyethyl group, compound 5q, led to moderately active inhibitor. Importantly, introduction of a 6-methoxy group to the indole ring coupled with the rhodanine acetic acid, compound 5r, gave similar anti-fibrillar activity to that in 5l with a great improvement in the anti-oligomer activity (discussed later). The superior inhibitory activity of ^70836-02^ 5r over 5l was also confirmed by the dose-dependent inhibition curves (Figs.1C-1D). The log EC50 value of 5r was 8.66 µM, which is 1.5 higher than that of the 5l. Intriguingly, 5r displayed a strong anti-fibrillar activity towards 2N4R tau and phosphorylated tau 1N4R (p-tau) as depicted by the significant reduction in the ThS fluorescence to approximately 30% and 21%, ^^ respectively (Figs. 1E-1F). Table 1. ThT fluorescence assay of rhonanine derivatives (100 µM) on ^-syn fibrils (6 µM).^70836-02^^^ Table 2. ThT fluorescence assay of the optimized indole rhonanine derivatives (100 µM) on ^-syn fibrils (6 µM).^70836-02^Table 3. Inhibition of islet amyloid polypeptide fibrils with different compounds with ThT assays. Results are expressed in terms of average ± SEM. Most of compounds reduced the ^^ aggregation of IAPP fibrils, 3a, 3b, 5f, being the weakest compounds.^70836-02^^70836-02^^70836-02^^70836-02^^70836-02^Example 3 Photo-Induced Cross-Linking of Unmodified Protein (PICUP) Assay

[0227] Rhodanine compounds of varying concentrations (50, 100, 200, 300 µM) were added to the protein solution (30 µM ^-syn or 6 µM 2N4R tau). The controls consisted of samples ^^ without light exposition, without the cross linking agent, Ru(BPY)3, or without the compound (i.e. 0.125% DMSO). The cross-linking reaction was initiated by the addition of 2 µL of 300 µM Ru(BPY)3 and 2 µL of 6 mM ammonium persulfate. Then, samples were irradiated immediately using a light exposure of a 1 second duration for ^-syn and 120 seconds duration for 2N4R tau, with a 53 W (120 V) incandescent lamp installed in a homemade dark-box. After ^^^ irradiation, 8.3 µL of Laemmli loading buffer containing 15% β-mercaptoethanol was immediately added to the solution, followed by incubation at 95°C for 10 min. The cross-linked samples were separated on a 16% SDS-PAGE gel and visualized by Coomassie blue staining.

[0228] Amyloidogenic oligomers of ^-syn and tau are believed to be the culprits of neurodegeneration in PD and tauopathies, respectively.42–45However, assessment of the ^^^ neurotoxic oligomers is very challenging due to the metastable nature of these protein assemblies.46,47Unlike traditional techniques such as electrophoresis and dynamic light scattering, the photo-induced cross-linking of unmodified proteins (PICUP) assay was successfully applied to investigate the size distribution of soluble oligomer and protofibrils. The photo-oxidation of tris-bipyridyl Ru(II) complex using visible light irradiation generates ^^^ radicals within the polypeptide which in turn generate intermolecular cross-linked oligomers.37,40Compounds 5k, 5l and 5r showed the highest inhibitory activity against the ^- syn oligomeric band between 35-40 kDa (Figs.2A-2C). On the other hand, 4c and 4d exhibited a negligible inhibition on the ^-syn oligomers. To further evaluate the anti-oligomer activity, the dose-response oligomer inhibitions at varying compound concentrations (50, 100, and 200 ^^^ µM) were monitored. As stated earlier, compound 3b served as a negative control in the study. Intriguingly, increasing the concentration of 5r to 100 µM stroked the reduction in the ^-syn oligomer formation to 86%. Further increasing in compound concentration to 200 µM slightly increased the inhibitory effect to 91% (Fig.2C). Regarding 2N4R tau, 5l showed a remarkable decrease in the tau oligomers at 100 µM, while upon increasing the compound concentration ^^^ to 400 µM, the formation of tau oligomers unexpectedly occurred again (Fig. 2D). This behaviour could be interpreted as the compound at a certain high concentration, might enhance the stability of the protein oligomers or exhibit poor solubility. On the other hand, 5r showed ^70836-02^ a significant decrease in the 2N4R oligomers in a dose-dependent manner (Fig. 2E). These findings confirmed the utility of 5l and 5r as powerful candidates in suppressing oligomer formation of both ^-syn and 2N4R tau. ^^ Example 4 Optical Properties

[0229] The photophysical properties of 5l and 5r were evaluated (Figs. 3A-3C). The excitation and emission wavelengths were 450 and 510 nm, respectively, for 5l whereas 5r displayed slightly higher wavelength values of 460 and 540 nm for the excitation and emission, respectively (Fig. 3A). The fluorescence profile was characterized with 5l in the presence of ^^^ ^-syn and 2N4R tau mature fibrils (Fig.3B). When in contact with fibrils, 5r exhibited a very weak flat signal (Fig. 3C). An expected bell-shaped pattern was obtained with 5l, but not 5r. The inhibitor showed a slight decrease in the fluorescence intensity with a hypsochromic shift of 10 nm when bound to ^-syn aggregates after 1 hour incubation. Importantly, 5l quenched the fluorescence to half its value upon binding to 2N4R aggregates. These results underscored ^^^ the remarkably higher binding behaviour of 5l towards 2N4R aggregates than that with ^-syn fibrils.

[0230] A probe prototype 5l (Figs. 4A-4D) was selected to identify probes that bind IAPP fibrils. Our first step toward developing probes that bind IAPP will be to generate small molecules with a rhodanine and indole scaffold for their ability to bind IAPP fibrils. Our choice ^^^ of scaffold is justified because of our data with rhodamine and our previous work on IAPP and indoles. Our findings presented in Figs.4A-4D show fluorescence enhancement of 5l in contact with feline IAPP and human IAPP fibrils but not ^-syn and tau fibrils. Competition dialysis validate the binding of 5l with feline IAPP and human IAPP fibrils but not ^-syn. This indicate that rhodanine indole scaffold can be used as a backbone to generate probes capable of binding ^^^ specifically to IAPP fibrils. The increase in fluorescence intensity only and not shift ("turn-on" fluorescence) was observed when IAPP fibrils were treated with 5l. This increase in intensity often suggests binding results in restriction of rotation and vibrations, which leads to stronger fluorescence. ^^^ Example 5 In vitro Transmission Electron Microscope (TEM) Analysis

[0231] The proteins (6 µM of ^-syn or 12 µM of 2N4R tau) were incubated with 5 mM DTT, 0.92 µg / mL arachidonic acid, and 0.15 mM heparin, and 100 µM compound. The samples were incubated for 3 days and 5 days for ^-syn and 2N4R tau, respectively, at 37° C. For any samples prepared, a volume of 10 µL was applied on a 400-mesh Formvar-carbon-coated copper grid. ^70836-02^ The grids were incubated for 1 minute and washed three times with distilled water. They were carefully air-dried and incubated for 1 minute in a fresh solution of 1% uranyl acetate. Pictures were obtained at accelerating voltage of 100 kV and magnification of 40k.

[0232] The transmission electron microscope (TEM) was used to evaluate the anti-fibril ^^ ability of the top compounds that showed the highest reduction in ThT fluorescence against both ^-syn and 2N4R tau aggregates. Dense mature fibrils were observed with the control vehicle (DMSO 0.25%) while compound 3b was set as a negative control (Figs. 5A-5B and 5I-5J). TEM analyses of both proteins demonstrated that both 5l significantly decreased the aggregation of ^-syn and 2N4R fibrils (Figs. 5C-5D and Figs. 5E-5F, respectively). On the ^^^ other hand, 5j showed moderate effect on the reduction of both protein fibrils (Figs. 5E-5F). In addition, compounds 4c and 4d were powerful inhibitors of ^-syn aggregates, which aligned with the fluorescence ThT assay results. The TEM analyses of the anti-fibril activity of 4c and 4d (100 µM) toward ^-syn (2 µM) are shown in Fig. 8. Incubation time was 3 days at 37° C. Scale bars: 200 nm, magnification: 40K. ^^^ Example 6 Ex vivo A^-Plaque Disaggregation

[0233] Purified amyloid-^ plaques from human AD brains were examined with a polarized and scanning electron microscope using Congo Red and thioflavin-S staining. A volume of 20 µL of extracted plaques was incubated with 1.5% DMSO (control vehicle) or compounds 5l or ^^^ 5r (50 µM each) in 10 mM PBS buffer (pH 7.4) for 120 h at 37 C prior to visualization by TEM. Each aliquot of amyloid-^ plaques was solubilized in 60 ^L of 10 mM PBS buffer (pH 7.4). Experiments were repeated twice with two different extractions, and the best representative images were selected. One extraction consisted of 0.37 mg / mL of protein, as measured with a NanoDrop (A260 / 280 nm). ^^^

[0234] The disaggregation effects of 5l (and soon 136) were monitored using A^-plaques isolated from AD brains (Fig. 6). A^-plaque samples were incubated with 1.5% DMSO (control) or compounds 5l and 5r (50 ^M) to analyses by transmission electron microscopy. In contrast to the control (1.5% DMSO), disaggregation experiments showed less plaques were present in the samples treated with 5l and 5r. In addition, 5l reduced the density of the plaques ^^^ (Fig.6). Example 7 ^-Synuclein Inclusion-Forming Neuroblastoma Cell Experiment ^70836-02^

[0235] Dox-inducible neuroblastoma cells M17D-TR / ^S-3K::YFP have been used as previously published. This assay utilized a 96-well plate with cellular density of 30,000 cells per well. Compounds were added after 24 hours, and ^S-3K::YFP transgene expression was induced 48 hours later. Induction of inclusions was achieved by adding 1 µg per mL (final ^^ concentration) dox to culture media. Cell incubation was done using the Incucyte Zoom 2000 platform (Essen Biosciences) and images (green, bright field) were acquired at various times. Endpoint analysis of inclusion formation or growth was assessed 48 hours after induction (96 hours after plating). The Incucyte processing definition ‘Inclusions’ is defined by the following: Parameters, Fixed Threshold, Threshold (GCU) 50; Edge Split On, Edge Sensitivity ^^^ 100; Cleanup, Hole Fill (µm2): 10, Adjust Size (pixels): 0; Filters, Area (µm2): max 50, Mean Intensity: min 60, Integrated Intensity: min 2000. Cell confluences were determined by the processing definition ‘Cells’ by the following: Parameters, Segmentation Adjustment 0.7; Cleanup, all parameters set to 0; Filters, Area (µm2): min 345.00.

[0236] The dox-inducible neuroblastoma M17D-TR / ^S3K::YFP assay was performed to ^^^ assess the activity of the most active inhibitors towards the inclusion of ^-syn in a cell-based model.48–50Unexpectedly, both 5l and 5r showed no inhibitory activity towards the cell inclusion while compound 5j revealed a strong reduction in the protein inclusion at a low micromolar concentration (5 µM) with undetected cytotoxicity (Figs. 7A-7C). By contrast, compound 3b did not cause any changes in the prevention of ^-syn inclusion at similar ^^^ concentrations. Fortunately, the cell confluence has not been affected by all compounds. Example 8 Ex vivo A^-plaques disaggregation

[0237] The anti-aggregation effect of compounds 5l and 5r was explored further using amyloid beta (A^) 1–40. A ThT assay was performed using 21 ^M of A^ 1–40. The A^ 1–40 ^^^ was treated for several hours with HFIP prior to ThT assay; however, some aggregates remained as the kinetics started at about 40 %. Compounds III, 3b, 5l, and 5r were tested at 100 ^M. Compounds 5l and 5r resulted in better anti-aggregation activity in comparison to compound 3b and our previously published compound III (Figs. 9A-9B). Both compounds 5l and 5r disintegrated the aggregates initially present in solution as the kinetics start at a ^^^ percentage of fluorescence intensity inferior to 10 %.

[0238] The disaggregation effects of 5l and 5r were monitored using A^- plaques isolated from AD brains in order to expand the applications of these compounds as a therapeutic one, i.e. disintegration of existing mature fibrils from diseased patients (Figs.10A-10C). A^-plaque samples were incubated with 0.125 % DMSO (control) or compounds 5l and 5r (50 ^M) for ^70836-02^ analyses by transmission electron microscopy. In contrast to the control (0.125 % DMSO), disaggregation experiments demonstrated that less plaques were present in the samples treated with 5l and 5r. In addition, 5l reduced the density of the plaques. ^^ Example 9 Desing and synthesis of esters and amides

[0239] The targeted ethyl ester and piperidyl amide indole-rhodanine or indole-2,4- thiazolidinedione or indole-methyl hydantoin hybrids were synthesized using their corresponding carboxylic acids as indicated in Scheme 3. To prepare the acetic acid tail of 2,4- thiazolidinedione (5c) and N-methyl hydantoin (5e), alkylation of the free NH groups was ^^^ performed using iodoacetic acid in the presence of potassium carbonate as a base to produce 6c and 6e, respectively. Then, equimolar amounts of crude products and indole-3-carbaldehyde were coupled using Knoevenagel condensation in the presence of a sodium acetate / acetic acid buffer solution to give 1c and 1e, respectively, in relatively low yields (15% and 21%, respectively). The desired ethyl ester compounds (2a- 2e) were easily prepared by esterifying ^^^ their corresponding carboxylic acids (1a- 1e) in ethanol and a catalytic amount of sulfuric acid. On the other hand, the 1-piperidyl amides (3a- 3e) were straightforwardly achieved by reacting their corresponding carboxylic acids with piperidine. The final candidates were obtained in moderate to high yields. ^70836-02^

[0240] In Scheme 2 the reagents and conditions: (a) iodoacetic acid, K2CO3, acetonitrile, reflux, 6-8 h, 88-97%; (b) indole-3-carbaldehyde, Na acetate, acetic acid, reflux, 3-4 h, 58- 63%; (c) H2SO4, ethanol, reflux, 4-5 h, 58-63%; (d) piperidine, ethanol, reflux, 4-6 h, 58-63%. ^^

[0241] To prepare the indole hybrids with free NH functionality, various reaction conditions were employed to obtain the desired products (Scheme 4). While sodium acetate / acetic acid mixture was applied to prepare DM-4a and DM-4e from the starting rhodanine and isorhodanine, respectively, the piperidine / ethanol was effectively used to synthesise the remaining hybrids (DM-4b to DM-4d) in excellent yields. ^70836-02^^^

[0242] In Scheme 4 reagents and conditions: (a) Na acetate, acetic acid, reflux, 4 h, 72% and 62%, for DM-4a and DM-4e, respectively; piperidine, ethanol, reflux, 4-6 h, 78-89% for DM- 4b to DM-4d. ^^^ General procedure for synthesizing the 1-piperidyl amide of the indole hybrids (DM-3a to DM-f).

[0243] Piperidine (2 equiv.) was added to a stirred solution of indole-3-carbaldhyde (1 equiv.) in ethanol under a nitrogen atmosphere. The reaction mixture was refluxed for 4-6 h. The precipitated solid was then filtered and washed with ethanol (2 x 10 mL), and diethyl ether ^^^ (10 mL), affording the targeted compounds in good yields.

[0244] Ethyl (Z,E)-2-(5-((1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3- yl)acetate (DM-2a). Yield: 63%, orange solid, m.p.: 206.8 – 208.5°C.;1H NMR (500 MHz, DMSO) ? 8.15 (s, 1H), 7.97 (m, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.25 (ddd, J = 15.5, 7.8, 1.2 Hz, 2H), 4.81 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, ^^^ DMSO) ? 192.7, 166.7, 166.5, 137.0, 131.6, 127.8, 127.3, 124.0, 122.2, 119.1, 114.2, 113.1, 111.6, 62.0, 45.4, 14.5.

[0245] Ethyl (Z,E)-3-(5-((1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3- yl)propanoate (DM-2b). Yield: 68%, orange solid, m.p.: 207.6 – 209.5°C.;1H NMR (500 MHz, DMSO) ? 12.34 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.52 – 7.47 ^^^ (m, 1H), 7.28 – 7.18 (m, 2H), 4.26 (t, J = 7.6 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, DMSO) ? 192.7, 170.7, 166.9, 136.9, 131.2, 127.2, 126.8, 123.9, 122.1, 119.0, 114.8, 113.1, 111.6, 60.9, 39.5, 31.5, 14.4.

[0246] Ethyl (Z,E)-2-(5-((1H-indol-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)acetate (DM-2c). Yield: 29%, canary yellow solid, m.p.: 215.2 – 216.5°C.;1H NMR (500 MHz, ^^^ DMSO) ? 12.25 (s, 1H), 8.23 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.85 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29 – 7.18 (m, 2H), 4.46 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). ^70836-02^

[0247] Ethyl (Z,E)-3-(5-((1H-indol-3-yl)methylene)-2,4-dioxothiazolidin-3- yl)propanoate (DM-2d). Yield: 59%, yellow solid, m.p.: 168.3 – 170.5°C.;1H NMR (500 MHz, DMSO) ? 12.17 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.27 – 7.16 (m, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.87 (t, J = 7.1 Hz, 2H), 2.65 (t, J ^^ = 7.1 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H).13C NMR (126 MHz, DMSO) ? 170.6, 167.1, 165.5, 136.4, 129.3, 127.0, 125.9, 123.4, 121.4, 118.6, 113.8, 112.7, 110.6, 60.5, 37.4, 32.0, 14.1.

[0248] Ethyl (Z,E)-2-(4-((1H-indol-3-yl)methylene)-3-methyl-2,5-dioxoimidazolidin-1- yl)acetate (DM-2e). Yield: 62%, yellow solid, m.p.: 193.3 – 195.7°C.;1H NMR (500 MHz, DMSO) ? 11.73 (s, 1H), 8.79 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.21 ^^^ – 7.12 (m, 2H), 6.87 (s, 1H), 4.33 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.27 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, DMSO) ? 167.8, 161.4, 152.0, 135.9, 129.1, 127.9, 123.9, 122.4, 120.2, 118.4, 112.2, 109.8, 108.7, 61.5, 39.2, 26.5, 14.2.

[0249] Ethyl (Z,E)-3-(4-((1H-indol-3-yl)methylene)-3-methyl-2,5-dioxoimidazolidin-1- yl) propanoate (DM-2f). Yield: 58%, yellow solid, m.p.: 180.8 – 182.4°C.;1H NMR (500 ^^^ MHz, DMSO) ? 11.69 (s, 1H), 8.81 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.19 – 7.11 (m, 2H), 6.78 (s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.77 (t, J = 7.1 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, DMSO) ? 170.7, 161.7, 152.4, 135.9, 128.9, 127.9, 124.3, 122.3, 120.1, 118.4, 112.2, 108.8, 108.7, 60.4, 34.4, 32.5, 26.4, 14.1. ^^^

[0250] (Z,E)-5-((1H-indol-3-yl)methylene)-3-(2-oxo-2-(piperidin-1-yl)ethyl)-2- thioxothiazolidin-4-one (DM-3a). Yield: 75%, orange solid, m.p.: 266.4 – 267.7°C.;1H NMR (500 MHz, DMSO) ? 10.41 (brs, 1H), 8.01 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.29 – 7.13 (m, 2H), 4.40 (s, 2H), 2.93 – 2.90 (m, 4H), 1.63 – 1.58 (m, 4H), 1.53 – 1.48 (m, 2H).13C NMR (126 MHz, DMSO) ? 192.7, 167.8, 166.9, 136.9, 130.9, ^^^ 127.3, 126.4, 123.8, 122.0, 119.0, 115.3, 113.1, 111.6, 47.4, 44.0, 22.7, 22.3.

[0251] (Z,E)-5-((1H-indol-3-yl)methylene)-3-(3-oxo-3-(piperidin-1-yl)propyl)-2- thioxothiazolidin-4-one (DM-3b). Yield: 64%, orange solid, m.p.: 218.2 – 220.6°C.;1H NMR (500 MHz, DMSO) ? 8.06 (s, 1H), 7.98 – 7.89 (m, 1H), 7.87 (s, 1H), 7.54 – 7.46 (m, 1H), 7.29 – 7.16 (m, 2H), 4.20 – 4.13 (m, 2H), 2.87 – 2.85 (m, 4H), 2.39 – 2.33 (m, 2H), 1.61 – 1.38 (m, ^^^ 6H).13C NMR (126 MHz, DMSO) ? 192.5, 173.3, 167.0, 137.0, 131.1, 127.3, 126.5, 123.8, 122.0, 119.0, 115.0, 113.1, 111.6, 44.3, 41.8, 33.4, 23.4, 22.8.

[0252] (Z,E)-5-((1H-indol-3-yl)methylene)-3-(2-oxo-2-(piperidin-1- yl)ethyl)thiazolidine-2,4-dione (DM-3c). Yield: 46%, yellow solid,1H NMR (500 MHz, DMSO) ? 8.11 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.26 – ^70836-02^ 7.15 (m, 2H), 3.93 (s, 2H), 2.92 – 2.90 (m, 4H), 1.64 – 1.46 (m, 6H).13C NMR (126 MHz, DMSO) ? 168.3, 167.2, 165.8, 136.4, 128.9, 127.0, 125.0, 123.2, 121.2, 118.6, 114.8, 112.6, 110.7, 45.4, 43.8, 22.7, 22.2.

[0253] (Z,E)-5-((1H-indol-3-yl)methylene)-3-(3-oxo-3-(piperidin-1- ^^ yl)propyl)thiazolidine-2,4-dione (DM-3d). Yield: 71%, orange solid, m.p.: 218.7 – 220.4°C; 1H NMR (500 MHz, DMSO) ? 8.14 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.26 – 7.14 (m, 2H), 3.79 (t, J = 8.0 Hz, 2H), 2.89 – 2.85 (m, 4H), 2.36 (t, J = 8.0 Hz, 2H), 1.62 – 1.45 (m, 6H).13C NMR (126 MHz, DMSO) ? 173.2, 167.1, 165.7, 136.5, 129.1, 127.0, 125.6, 123.3, 121.3, 118.6, 118.5, 114.1, 112.7, 44.0, 42.4, 34.2, 23.2, 22.6.^^^

[0254] (Z,E)-5-((1H-indol-3-yl)methylene)-1-methyl-3-(2-oxo-2-(piperidin-1- yl)ethyl)imidazolidine-2,4-dione (DM-3e). Yield: 68%, yellow solid, m.p.: 266.5 – 269.4°C.; 1H NMR (500 MHz, DMSO) ? 11.92 (s, 1H), 8.78 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.22 – 7.04 (m, 2H), 6.60 (s, 1H), 3.85 (s, 2H), 3.09 (s, 3H), 2.92 – 2.90 (m, 4H), 1.63 – 1.55 (m, 4H), 1.54 – 1.45 (m, 2H).13C NMR (126 MHz, DMSO) ? 170.3, 162.2, ^^^ 153.3, 136.1, 129.1, 128.2, 125.0, 122.3, 120.2, 118.5, 112.4, 109.0, 108.0, 43.8, 42.4, 26.4, 22.8, 22.4. (Z,E)-5-((1H-indol-3-yl)methylene)-1-methyl-3-(3-oxo-3-(piperidin-1- yl)propyl)imidazolidine-2,4-dione (DM-3f). Yield: 63%, canary yellow solid, m.p.: 264.5 – 267.8°C.;1H NMR (500 MHz, DMSO) ? 11.75 (s, 1H), 8.83 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), ^^^ 7.44 (d, J = 7.8 Hz, 1H), 7.20 – 7.10 (m, 2H), 6.74 (s, 1H), 3.70 – 3.65 (m, 2H), 3.21 (s, 3H), 2.83 – 2.81 (m, 4H), 2.37 – 2.30 (m, 2H), 1.65 – 1.35 (m, 6H).13C NMR (126 MHz, DMSO) ? 173.6, 161.8, 152.7, 135.9, 128.9, 127.9, 124.6, 122.2, 120.0, 118.4, 112.2, 108.7, 108.3, 44.3, 35.7, 35.2, 26.4, 23.7, 23.0.

[0255] (Z,E)-5-((1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (DM-4a). Yield: ^^^ 59%, dark brown solid, m.p.: 285.6 – 287.1°C.;1H NMR (500 MHz, DMSO) ? 12.20 (s, 1H), 7.91 – 7.87 (m, 1H), 7.83 (s, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.26 – 7.21 (m, 1H), 7.20 – 7.16 (m, 1H).13C NMR (126 MHz, DMSO) ? 196.3, 172.1, 136.8, 133.9, 129.9, 127.2, 123.6, 123.5, 121.7, 118.9, 112.9, 111.6.

[0256] (Z,E)-5-((1H-indol-3-yl)methylene)thiazolidine-2,4-dione (DM-4b). Yield: 87%, ^^^ canary yellow solid, m.p.: > 300°C.;1H NMR (500 MHz, DMSO) ? 12.28 (s, 1H), 12.11 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.20 – 7.14 (m, 1H).13C NMR (126 MHz, DMSO) ? 168.2, 167.8, 136.7, 129.1, 127.3, 125.0, 123.5, 121.5, 118.8, 116.7, 112.9, 110.9. ^70836-02^

[0257] (Z,E)-5-((1H-indol-3-yl)methylene)-1-methylimidazolidine-2,4-dione (DM-4c). Yield: 81%, yellow solid, m.p.: > 300°C;1H NMR (500 MHz, DMSO) ? 11.59 (s, 1H), 11.17 (s, 1H), 8.78 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.21 – 7.09 (m, 2H), 6.66 (s, 1H), 3.17 (s, 3H).13C NMR (126 MHz, DMSO) ? 163.8, 153.5, 136.1, 129.0, 128.1, ^^ 126.1, 122.5, 120.3, 118.6, 112.4, 109.0, 107.9, 26.2.

[0258] (Z,E)-5-((1H-indol-3-yl)methylene)-1-methyl-2-thioxoimidazolidin-4-one (DM- 4d). Yield: 77%, yellow solid, m.p.: 270.3 – 272.0°C.;1H NMR (500 MHz, DMSO) ? 12.23 (s, 1H), 11.88 (s, 1H), 9.01 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.24 – 7.14 (m, 2H), 7.05 (s, 1H), 3.58 (s, 3H).13C NMR (126 MHz, DMSO) ? 173.4, 163.5, 136.3, ^^^ 131.0, 128.3, 125.9, 123.0, 120.9, 118.9, 113.0, 112.7, 109.3, 30.2.

[0259] (Z,E)-5-((1H-indol-3-yl)methylene)-4-thioxothiazolidin-2-one (DM-4e). Yield: 62%, dark red solid, m.p.: 282.4 – 284.7°C.;1H NMR (500 MHz, DMSO) ? 12.40 (s, 1H), 8.42 (s, 1H), 7.90 (d, J = 3.1 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29 – 7.20 (m, 2H).13C NMR (126 MHz, DMSO) ? 193.5, 170.6, 136.9, 130.9, 129.6, 127.6, 124.1, 123.7, ^^^ 122.2, 118.7, 113.2, 112.5. Example 10 Biological evaluation of esters and amides Thioflavin-T (ThT) Fluorescence Assay

[0260] The thioflavin-T (ThT) fluorescence assay is one of the most employed in vitro proof-^^^ of-concept kinetic tools for tracking the development of misfolded protein aggregates in a time- course manner. The ThT dye displayed a substantial increase in the fluorescence quantum yield with a new excitation maximum after binding to the quaternary ^-sheet structures of the amyloid-like fibrils.Click or tap here to enter text. Therefore, the anti-fibrillar activity of the probe could be assessed by its ability to decrease the fluorescence of the ThT dye. Concomitant ^^^ diagnostic and therapeutic characteristics in a single compound make it serve as a theragnostic agent. Ideally, probes 5l and rhodanine amides, DM-3a, and DM-3b, significantly blocked the aggregation of hIAPP and fIAPP (Figs.11A-11B). These theragnostics showed a sharp decline in the ThT fluorescence below 2%. All probes with the ethyl ester group showed poor inhibitory activity against both fibrils (Table 4). Conversely, the amide-containing probes with^^^ either thiazolidinediones or methyl hydantoin moieties showed a relatively moderate anti- fibrillar activity (ThT% was below 20%). Regarding the non-alkylated free NH probes, the rhodanine- and isorhodanine-based probes, DM-4a and DM-4e, respectively, showed a drastic fall in ThT fluorescence, whereas the other probes displayed moderate to weak fluorescence responses. ^70836-02^ Table 4. In vitro ThT assay of all synthesized probes against 7 M of hIAPP and fIAPP.^70836-02^^70836-02^ DM-3e O N-CH3 O III-60 13.5 ± 12.7 ± 0.4 0.616.7 ± 21.5 ± 0.8 1.2 DM-3f O N-CH3O III-151 13.3 ± 4.9 ±1.3 0.2 16.5 ± 10.5 ± 0.7 0.3 DM-4aHS S OIII-33 8.4 ± 2.4 ± 2.4 0.1 7.7 ± 4.0 ± 0.4 0.5 DM-4bHO S OIII-18 50.3 ± 36.6 ± 4.0 0.7 45.4 ± 48.4 ± 2.2 2.8 DM-4cHO N-CH3OIII-55 70.6 ± 61.7 ± 1.1 2.3 67.1 ± 71.2 ± 7.1 2.5 DM-4dHS N-CH3OIII-56 47.7 ± 34.2 ± 1.3 1.3 44.3 ± 35.5 ± 0.3 0.8 DM-4eHO S SIII-47 -1.4 ± -1.3 ± 0.0 0.0 -0.7 ± -1.6 ± 0.0 0.0 ^70836-02^ In vitro Transmission Electron Microscope (TEM) analysis

[0261] To validate the anti-aggregation activity of our probes, the transmission electron microscope (TEM) was employed to further corroborate the ThT fluorescence results toward ^^ hIAPP and fIAPP fibrils. Compared to the control vehicle, which showed tightly packed filaments (Figs. 12A-12B), DM-3a and DM-3b demonstrated a significant reduction in both the length and density of the mature fibrils (Figs. 12E-12H). Probe 5l showed a lower anti- fibrillar effect on both protein aggregates (Figs. 12B-12C). The TEM analyses perfectly aligned with the ThT assay measurements and highlighted the promising theragnostic ^^^ characteristics of the rhodanine amide probes.

[0262] Rhodanine-based compounds were designed and synthesized to tackle the fibrils and oligomers of ^-syn and 2N4R tau proteins. Thioflavin fluorescence assays were performed to evaluate the anti-aggregation activity of the prepared compounds. The most promising anti- ^^^ fibrillar derivatives, depicted by the highest reduction in ThT fluorescence, were then subjected to PICUP assay to assess their anti-oligomer activity. The indole-containing derivatives, compounds 5l and 5r, displayed almost the same reduction in ThT fluorescence (~ 1.9 %) with powerful inhibition against the oligomers of both ^-syn and 2N4R tau in a dose-dependent manner. In addition, incubating 5l with the 2N4R tau fibrils reduced the fluorescence by half ^^^ at an emission wavelength of 510 nm demonstrating a significant binding interaction between the inhibitor and the fibrils. TEM analyses confirmed the high anti-aggregation activity of compounds 5l and 5r against both protein fibrils. 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[0263] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference. ^^^

[0264] The invention illustratively described herein may be suitably practiced in the absence of any element(s) or limitation(s), which is / are not specifically disclosed herein. Thus, for example, each instance herein of any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. Likewise, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates ^^^ otherwise. Thus, for example, references to "the method" includes one or more methods and / or steps of the type, which are described herein and / or which will become apparent to those ordinarily skilled in the art upon reading the disclosure.

[0265] The term “about,” when referring to a number or a numerical value or range (including, for example, whole numbers, fractions, and percentages), means that the number or ^^^ numerical range referred to is an approximation within experimental variability (or within statistical experimental error) and thus the numerical value or range can vary between 1% and 15% of the stated number or numerical range (e.g., + / - 5 % to 15% of the recited value) provided that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). The term “substantially” can allow for a degree of ^^^ variability in a value or range, for example, within 90%, within 95%, or within 99% of a stated value or of a stated limit of a range.

[0266] The terms and expressions, which have been employed, are used as terms of description and not of limitation. In this regard, where certain terms are defined under ^70836-02^ "Definitions" and are otherwise defined, described, or discussed elsewhere in the "Detailed Description," all such definitions, descriptions, and discussions are intended to be attributed to such terms. There also is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. Furthermore, while ^^ subheadings, e.g., "Definitions," are used in the "Detailed Description," such use is solely for ease of reference and is not intended to limit any disclosure made in one section to that section only; rather, any disclosure made under one subheading is intended to constitute a disclosure under each and every other subheading.

[0267] It is recognized that various modifications are possible within the scope of the ^^^ claimed invention. Thus, although the present invention has been specifically disclosed in the context of preferred embodiments and optional features, those skilled in the art may resort to modifications and variations of the concepts disclosed herein. Such modifications and variations are considered within the scope of the invention as claimed herein. ^^^ ^

Claims

70836-02^ WHAT IS CLAIMED IS:

1. A compound of formula (I):or a pharmaceutically acceptable salt or hydrate thereof, wherein:

2. The compound of claim 1, wherein:.

3. The compound of claim 1, wherein:

4. The compound of claim 1, wherein:^70836-02^ or a pharmaceutically acceptable salt or hydrate thereof, wherein:n = 1 or 2.

6. The compound of claim 5, wherein:

7. The compound of claim 5, wherein8. A compound of the formula:^ or a pharmaceutically acceptable salt or hydrate thereof, wherein: R3is 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) substituted with (R5)n; n is 0, 1, 2 or 3; R4is carboxy-6- to 10-membered aryl substituted with (R5)n, carboxy alkyl substituted with (R5)n, -C1-C6alkyl-C(O)O-alkyl or -C1-C6alkyl-C(O)NR7R8, wherein R7and R8are each independently, H or C1-C6 alkyl or R7 and R8, together with the nitrogen atom to which they are attached, form a 5- to 10-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S); and R5 in each instance is independently OH, halo, S(O)xR6 (wherein R5 is H, C1-C6 alkyl or 6- to 10-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S) and x is 0, 1 or 2), -SCN, -NCS, C1-C6-alkyl, C1- C6-alkoxy, C1-C6-haloalkyl, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 5- to 10- membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, ^70836-02^ O, and S), or two R4 groups, together with carbon atoms to which they are attached, form a 5- to 6-membered heterocycloalkyl (wherein 1 or 2 heterocycloalkyl members are independently selected from N, O, and S).

9. The compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3is selected from:of which is substituted with (R5)n.

10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3is selected from:each of which is substituted with (R5)n.

11. The compound of claim 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from:each of which is substituted with (R5)n. ^70836-02^ 12. The compound of claim 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from:each of which is substituted with (R5)n.

13. The compound of claim 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3is selected from:each of which is substituted with (R5)n.

14. The compound of claim 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3is selected from:^70836-02^ 15. The compound of claim 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3 is selected from:

16. The compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is carboxy alkyl substituted with (R5)n.

17. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is carboxy C1-C6 alkyl substituted with (R5)n.

18. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4is -(CH2)pCO2H, -(CH2)pCO2C1-C6-alkyl or -(CH2)pCONR7R8, wherein p is 1, 2, 3, 4, 5, 6 or from 1 to 6, 1 to 3, 1 to 4, 1 to 2, 2 to 3, 3 to 6 or 2 to 5; and R7and R8, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl.

19. The compound of any of claims 8-15, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is carboxy-6- to 10-membered aryl substituted with (^^)n.

20. The compound of claim 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is:

21. The compound of claim 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is selected from: ^70836-02^22. The compound of claim 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is selected from:

23. The compound of claim 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 is selected from:substituted with (R5)n.

24. A pharmaceutical composition comprising a compound of claim 1 or 8, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

25. A method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 1 or 8, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. ^70836-02^ 26. A method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 2, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

27. The method of claim 25, wherein the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB).

28. The method of claim 27, wherein the compound is a compound of claim 4 in which R2 is, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, and the compound also inhibits ^-syn oligomers.

29. A method of inhibiting alpha-synuclein (^-syn) protein fibril formation in a subject having, or at risk for, ^-syn protein fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 6 or 7, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

30. The method of claim 29, wherein the subject has, or is at risk for, Parkinson’s disease or dementia with Lewy bodies (DLB).

31. The method of claim 29, wherein the compound is the compound of claim 7, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier, and the compound also inhibits ^-syn oligomers. ^70836-02^ 32. A method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 4 in which R2is, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

33. A method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 7, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

34. A method of decreasing A^-plaques or their density in a subject having, or at risk for, A^-plaque formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 4 in which R2 is, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

35. A method of decreasing A^-plaques in a subject having, or at risk for, A^-plaque formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 7, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

36. A method of inhibiting islet amyloid polypeptide (IAPP) fibril formation in a subject having, or at risk for, IAPP fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of formula (I): ^70836-02^or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is selected fromor (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

37. The method of claim 36, wherein the subject is a human.

38. The method of claim 36, wherein the subject is a feline.

39. A method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation, which method comprises (i) administering to the subject an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt or hydrate thereof, wherein:(ii) detecting fluorescence, whereupon IAPP fibrils in a subject are detected. ^70836-02^ 40. The method of claim 39, wherein the subject is a diabetic human and the presence of IAPP fibrils indicates the diabetic human has pancreatic amyloidosis.

41. The method of claim 39, wherein the subject is a diabetic feline and the presence of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis.

42. A method of inhibiting tau 2N4R oligomer formation in a subject having, or at risk for, 2N4R oligomer formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

43. A method of decreasing A^-plaques in a subject having, or at risk for, A^-plaque formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof, or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

44. A method of inhibiting islet amyloid polypeptide (IAPP) fibril formation in a subject having, or at risk for, IAPP fibril formation, which method comprises administering to the subject an effective amount of (i) a compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof; or (ii) a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

45. The method of claim 44, wherein the subject is a human.

46. The method of claim 44, wherein the subject is a feline.

47. A method of detecting islet amyloid polypeptide (IAPP) fibrils in a subject having, or at risk for IAPP fibril formation which method comprises administering to the subject an effective amount of (i) a compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof; or (ii) a pharmaceutical composition comprising the compound, or a ^70836-02^ pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier; and detecting fluorescence, whereupon IAPP fibrils in a subject are detected.

48. The method of claim 47, wherein the subject is a diabetic human and the presence of IAPP fibrils indicates the diabetic human has pancreatic amyloidosis.

49. The method of claim 47, wherein the subject is a diabetic feline and the presence of IAPP fibrils indicates the diabetic feline has pancreatic amyloidosis. ^

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