Use of substituted 1,4 benzoquinones to treat alpha-synucleinopathies

Abstract

The present disclosure provides methods, compounds, compositions, formulations, or medicaments for treating, preventing, inhibiting, ameliorating, or delaying the onset of a- synucleinopathies (e.g., Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA)) as well as methods for ameliorating, inhibiting, or delaying the onset of signs or symptoms of an a-synucleinopathy in a subject. The disclosed methods, compounds, compositions, formulations, or medicaments are also useful for addressing the related signs and symptoms of a- synucleinopathies. The methods comprise administering to the subject the compounds, mixtures of compounds, or compositions, formulations, or medicaments derived from said compounds or mixtures thereof to thereby produce the aforementioned therapeutically beneficial effect(s).

Description

USE OF SUBSTITUTED 1 ,4 BENZOQUINONES TO TREAT ALPHA-SYNUCLEINOPATHIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 641,682, filed May 2, 2024, the content of which is incorporated herein by reference in its entirety for any and all purposes.TECHNICAL FIELD

[0002] The present application relates generally to methods, compositions / formulations / medicaments and related uses for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy (e.g., Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA)) or its associated signs or symptoms, in a subject in need thereof. The methods, compositions / formulations / medicaments and related uses all relate to the administration of one or more of six compounds specifically identified herein to the subject.INTRODUCTION

[0003] The following description is provided to assist the understanding of the reader. None of the information provided or references cited herein is admitted as being prior art to the compounds, compositions, products, uses and / or methods disclosed herein.

[0004] Alpha-synucleinopathies are characterized as a neurodegenerative disorder displaying an altered a-synuclein (aS) protein in the brain tissue. Alpha-synuclein is a cellular protein that in neurons regulates synaptic vesicle trafficking and subsequent neurotransmitter release. Alpha-synuclein is abundant in the brain but can form dysfunctional aggregates in brain tissue, thereby leading to what is known as an a- synucleinopathy. Alpha-synucleinopathies are considered to be a central nervous system (CNS) injury or disease and include, but are not limited to, Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), and Multiple System Atrophy (MSA). CNS injury or disease can lead to reactive astrogliosis and / or reactive microgliosis. Reactive astrogliosis can contribute to the formation of glial scars, which can inhibit axon regeneration after injury to the CNS. Reactive microgliosis can lead to a cycle of inflammation and repeated neuronal (i.e., CNS) damage.

[0005] Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by unintended or uncontrollable movements such as rhythmic shaking, muscle stiffness and / or difficulty with balance and coordination (e.g., gait). A 2022 study found that nearly 90,000 people are newly diagnosed with Parkinson’s disease annually and it is expected that by 2023, approximately 1.2 million individuals in the United States will be living with Parkinson’s disease (See: www.parkinson.org / ). Because Parkinson’s is a progressive disorder, the signs and symptoms of the disease become more pronounced as the subject ages. Other signs and symptoms of Parkinson’s disease include changes in speech (e.g., speech becomes soft, slurred and / or monotone, sometimes accompanied with hesitation), delays in movement (e.g., bradykinesia) as well as a decrease in reflex movements such as blinking, smiling or arm swinging. Levodopa (a.k.a., L-3,4-dihydroxyphenylalanine), optionally coupled with carbidopa (Lodosyn®) is currently the most popular treatment for subjects with Parkinson’s disease, but this medication addresses its symptoms, not the disease itself, its underlying cause(s), or its rate of progression.

[0006] PD with dementia (PDD) occurs in only a subset of those afflicted with Parkinson’s disease. However, one recent study found that approximately three quarters of people who live with diagnosed Parkinson’s disease for more than 10 years will develop dementia (See: Alzheimer’s Association website: www.alz.org / alzheimers-dementia / what-is-dementia / types- of-dementia / parkinson-s-disease-dementia). Another study estimated that approximately thirty percent of people who live with diagnosed Parkinson’s disease for more than 5 years will develop mild cognitive impairment (MCI). Id. Risk factors for development of PD with dementia include: (i) hallucinations in a person without dementia, (ii) excessive daytime sleepiness, and (iii) postural instability and gait disturbance (e.g., motor function).Commonly reported symptoms of PDD include: (i) changes in memory, concentration, and judgement, (ii) difficulty interpreting speech, (iii) muffled speech, (iv) paranoid delusions, (v) depression and anxiety, and / or (vi) sleep disturbances. Currently available pharmaceuticals directed to treatment of PDD address the symptoms such as sleep disorders and depression; but do not address the PDD per se, its underlying cause(s), or its rate of progression.

[0007] Dementia with Lewy bodies (LBD) is the 2ndmost common type of dementia after Alzheimer’s disease. LBD affects approximately 1.4 million people in the United States and about five percent of dementia cases in older individuals (See: www.lbda.org / about-lbd / #). LBD is associated with abnormal deposits of a-synuclein protein in the brain. Signs andsymptoms of LBD include: (i) hallucinations, (ii) movement disorders such as tremors, rigid muscles, slow movement and gait issues, (iii) poor regulation of autonomic nervous system function such as poor control of blood pressure, heart rate, sweating, and digestion, (iv) cognitive impairment such as confusion, poor attention span, and memory loss, (v) trouble sleeping including rapid eye movement (REM) sleep disorder, drowsiness, and long naps during the day, (vi) depression, and (vii) apathy. LBD is a progressive disease often causing: (i) severe dementia, (ii) aggressive behavior, (iii) depression, (iv) increased risk of falling, and (v) worsening of tremors. Death often occurs within about 7-8 years after first symptoms appear. Like other a-synucleinopathies, currently available pharmaceuticals are directed to treatment of the symptoms of LBD; but do not address the disease itself, its underlying cause(s), or its rate of progression.

[0008] Multiple System Atrophy (MSA) is a progressive, fatal neurodegenerative disorder characterized by a combination of symptoms affecting both the central and autonomic nervous systems. Symptoms of MSA, which reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord, include: (i) slowness of movement, tremor, or stiffness; (ii) clumsiness or lack of coordination; (iii) croaky, quivering voice; (iv) fainting or lightheadedness; and (v) bladder control problems. Symptoms typically present when a patient is in their 50s and advance rapidly over the course of five to ten years. Patients with MSA will develop increased difficulty with movement, eventually become bedridden, and often develop swallowing problems that can lead to pneumonia in the later stages of the disease. No treatments exist to stop or slow the progression of MSA, and there is no known cure. Currently available pharmaceuticals are directed to the management of symptoms; however, these do not address the disease itself, its underlying causes(s), or its rate of progression.

[0009] Vatiquinone (also known as EPI743) has been tested in a phase 2 clinical trial as a possible treatment for Parkinson’s disease, but despite completion of that trial in 2016, no results of that trial appear to have yet been published. Vatiquinone is believed to target ferroptosis in treated subjects (See: Kahn-Kirby et al, Targeting ferroptosis: A novel therapeutic strategy for treatment of mitochondrial disease-related epilepsy).

[0010] As noted, available treatments of a-synucleinopathies (e.g., Parkinson’s disease(PD), PD with dementia, dementia with Lewy bodies (LBD), and Multiple System Atrophy(MSA)) are generally directed to treating signs, and / or symptoms of the disease(s). Better treatments are needed to address a-synucleinopathies, including pharmaceuticals that address the root causes of the disease as well as delaying the onset of and / or arrest the progression of the disease.SUMMARY

[0011] In one aspect, the present technology provides a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound 6, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or a mixture of any two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6;wherein Compound 3 is:wherein Compound 4 is:wherein Compound 5 is:

[0012] In some embodiments, the subject has been diagnosed as having an a- synucleinopathy. In some embodiments, the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

[0013] In some embodiments, the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0014] In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

[0015] In some embodiments, the Compound, or mixture of Compounds, is / are administered daily for 6 weeks or more. In some embodiments, the Compound, or mixture of Compounds, is / are administered daily for 24 weeks or more. In some embodiments, the Compound, or mixture of Compounds, is / are administered daily for 48 weeks or more. In some embodiments, the Compound or mixture of Compounds, is / are administered daily for 52 weeks or more.

[0016] In some embodiments, the Compound, or mixture of Compounds, is / are administered orally or subcutaneously. In some embodiments, the Compound, or mixture of Compounds, is / are administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0017] In some embodiments, the method further comprises separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent(s) comprises levodopa, optionally in combination with carbidopa (LODOSYN®). In some embodiments, the combination of the Compound, or mixture of Compounds, and an additional therapeutic agent(s) has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

[0018] In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), prolongs survival of the subject as compared with an untreated subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0019] In another aspect, the present technology provides for use of Compound, or mixture of Compounds, in the preparation of a composition or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, wherein the Compound, or the Compounds present in the mixture of Compounds, is / are selected from the group consisting of Compound 6, Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5, or a pharmaceutically acceptable salt,stereoisomer, tautomer, hydrate, and / or solvate of any one or more of the selected Compounds 1 to 6,

[0020] In some embodiments of the use, the subject has been diagnosed as having an a- synucleinopathy. In some embodiments of the use, the a-synucleinopathy is Parkinson’sdisease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

[0021] In some embodiments of the use, the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0022] In some embodiments of the use, the subject is a mammal. In some embodiments of the use, the subject is human.

[0023] In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 6 weeks or more. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 24 weeks or more. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 48 weeks or more. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 52 weeks or more.

[0024] In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is formulated for administration orally or subcutaneously. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0025] In some embodiments of the use, administration of the composition or medicament further comprises separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject. In some embodiments of the use, the additional therapeutic agent comprises levodopa, optionally in combination with carbidopa (LODOSYN®). In some embodiments of the use, the combination of the composition or medicament comprising the Compound, or mixture of Compounds, and the additionaltherapeutic agent(s) has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

[0026] In some embodiments of the use, administration of the composition or medicament comprising the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), prolongs survival of the subject, as compared with an untreated subject or an untreated control group of subjects. In some embodiments of the use, administration of the composition or medicament comprising the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the composition or medicament comprising the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the composition or medicament comprising the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the composition or medicament comprising the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0027] In another aspect, the present technology provides for a Compound, mixture of Compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate of any one or more of Compounds 6, 1, 2, 3, 4, or 5, for use in treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, wherein the Compound or Compounds present in the mixture of Compounds is / are selected from the group consisting of Compound 6, Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5,p

[0028] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the subject has been diagnosed as having an a-synucleinopathy. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

[0029] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a- synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0030] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the subject is a mammal. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the subject is human.

[0031] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the Compound, or mixture of Compounds, is / are administered daily for 6 weeks or more. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the Compound, or mixture of Compounds, is / are administered daily for 24 weeks or more. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the Compound, or mixture of Compounds, is / are administered daily for 48 weeks or more. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the Compound, or mixture of Compounds, is / are administered daily for 52 weeks or more.

[0032] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the Compound, or mixture of Compounds, is formulated for administration orally or subcutaneously. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the Compound, or mixture of Compounds, is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0033] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, administration of the Compound or mixture of Compounds further comprises separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the additional therapeutic agent(s) comprises levodopa, optionally in combination with carbidopa (LODOSYN®). In some embodiments of the foregoing Compound, or mixture of Compounds, for use, the combination of the Compound or mixture of Compounds and anadditional therapeutic agent(s) has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

[0034] In some embodiments of the foregoing Compound, or mixture of Compounds, for use, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), prolongs survival of the subject, as compared with an untreated subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, for use, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Fig. 1 is a graphic illustration of data obtained for an in vitro titration assay designed to examine and quantify (i.e., by determining an ECso) the ability of Compound 2 to impact Complex I by-pass activity in an exemplary line of PD fibroblasts (PD38528). Each line represents one run.

[0036] Fig. 2 is a graphic illustration of data obtained for an in vitro titration assay designed to examine and quantify (i.e., by determining an ECso) the ability of Compound 3 to impactComplex I by-pass activity in an exemplary line of PD fibroblasts (PD38528). Each line represents one run.

[0037] Fig. 3 is a graphic illustration of data obtained for an in vitro assay designed to examine, compare and quantify the effect of the titration of Compounds 1-6 and vati quinone to ameliorate the detrimental effect of an RSL3 insult on an exemplary line of PD fibroblasts (cell line PD409906- SNCA fibroblasts).

[0038] Fig. 4 is a graphic illustration of data obtained for an in vitro assay designed to examine, compare and quantify the effect of the titration of Compounds 1-6 and vati quinone to ameliorate the detrimental effect of an RSL3 insult on an exemplary line of PD fibroblasts (cell line PD38528 - Idiopathic PD).

[0039] Fig. 5 is a graphic illustration of data obtained for an in vitro assay designed to examine, compare and quantify the effect of the titration of Compounds 1-6 and vati quinone to ameliorate the detrimental effect of an RSL3 insult on an exemplary line of PD fibroblasts (cell line PD32974 - Iron Accumulation).

[0040] Fig. 6 is a is a graphic illustration of comparative data obtained in a rat pharmacokinetic (PK) profile study for plasma following administration of a single oral (PO) dose of 10 mg / kg of Compound 1. Comparative data is included for vati quinone and idebenone - two compounds that have been investigated for their potential to be useful for treating Parkinson’s disease.

[0041] Fig. 7 is a graphic illustration of comparative data obtained in a rat pharmacokinetic (PK) profile study for plasma following administration of a single oral (PO) dose of each of the compounds identified (ie., vati quinone and its S-enantiomer (S-Vati quinone), Compound 2 and its R-enantiomer (R-Compound 2) and Compound 3 and its R-enantiomer (R- Compound 3)).

[0042] Fig. 8 is a bar graph of comparative data obtained in a rat pharmacokinetic (PK) profile study for brain tissue taken from rats following administration of a single oral (PO) dose of each of the compounds identified (z.e., vati quinone and its S-enantiomer (S- Vatiquinone), Compound 2 and its R-enantiomer (R-Compound 2), and Compound 3 and its R-enantiomer (R-Compound 3)).

[0043] Fig. 9 is a graphic illustration of comparative data obtained in a rat pharmacokinetic (PK) profile study for plasma following administration of a single oral (PO) dose of Compound 4. Comparative data is included for vatiquinone - a compound that has been investigated for its potential to be useful for treating Parkinson’s disease.

[0044] Fig. 10 is a graphic illustration of comparative data obtained in a mouse pharmacokinetic (PK) profile study for plasma where Compound 5 was studied at 20 mg / kg and 60 mg / kg subcutaneous (SC) dosing and Compound 6 was studied at 60 mg / kg SC dosing.

[0045] Fig. 11 is a graphic illustration of comparative data obtained in a PK profile study for plasma where Compound 5 was studied at 20 mg / kg SC dosing in mouse and 10 mg / kg SC dosing in rat (effectively 60 mg / m2irrespective of species examined).

[0046] Fig. 12 is a graphic illustration of comparative data obtained in a PK profile study examining uptake of drug in mouse heart tissue resulting from subcutaneous (SC) administration of Compound 5 at 20 mg / kg and 60 mg / kg dosing and Compound 6 at 60 mg / kg dosing.

[0047] Fig. 13 is a graphic illustration of comparative data obtained in a PK profile study examining uptake of drug in mouse brain tissue resulting from subcutaneous (SC) administration of Compound 5 at 20 mg / kg and 60 mg / kg dosing and Compound 6 at 60 mg / kg dosing.

[0048] Fig. 14 is a graphic illustration of data obtained for the neuroprotective effect of Compound 6 (Comp.6; Cpd 6) on dopamine neurons in an adeno-associated virus (AAV)- mediated mouse model of an a-synucleinopathy. Statistical test: Simple one-way ANOVA with Fisher LSD post-hoc test. * (P< 0.05), *** (P<0.001).DETAILED DESCRIPTION

[0049] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the present disclosure are described below in various levels of detail in order to provide a substantial understanding of the present technology. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this present technology belongs.

[0050] In practicing the present technology, many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology and recombinant DNA are used. These techniques are well-known and are explained in, e.g., Current Protocols in Molecular Biology, Vols. I-III, Ausubel, Ed. (1997); Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989); DNA Cloning: A Practical Approach, Vols. I and II, Glover, Ed. (1985); Oligonucleotide Synthesis, Gait, Ed. (1984); Nucleic Acid Hybridization, Hames & Higgins, Eds. (1985); Transcription and Translation, Hames & Higgins, Eds. (1984); Animal Cell Culture, Freshney, Ed. (1986); Immobilized Cells and Enzymes (IRE Press, 1986); Perbal, A Practical Guide to Molecular Cloning,' the series, Meth. Enzymol., (Academic Press, Inc., 1984); Gene Transfer Vectors for Mammalian Cells, Miller & Calos, Eds. (Cold Spring Harbor Laboratory, N Y, 1987); an Meth. Enzymol., Vols. 154 and 155, Wu & Grossman, and Wu, Eds., respectively.I. Definitions

[0051] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh Ed., inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0052] It is to be appreciated that certain aspects, modes, embodiments, variations and features of the technology are described below in various levels of detail in order to provide a substantial understanding of the present disclosure. The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs.

[0053] As used in this specification and the appended embodiments, the singular forms “a,” “an” and “the” include plural references unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like.

[0054] As used herein, “administering” or the “administration” of an agent (z.e., a therapeutic agent) or compound / drug product (including a composition (z.e., a formulation or medicament)) to a subject includes any route of introducing or delivering to a subject a compound / drug product to perform its intended function. Administration may be carried out by any suitable route, such as oral administration. Administration can be carried out subcutaneously. Administration can be carried out intravenously. Administration can be carried out intraocularly. Administration can be carried out systemically. Alternatively, administration may be carried out topically, intranasally, intraperitoneally, intradermally, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly. Administration includes self-administration, the administration by another or administration by use of a device (e.g., an infusion pump).

[0055] As used herein, to “ameliorate” or “ameliorating” a disease, disorder or condition refers to results that, in a statistical sample or specific subject, make the occurrence of the disease, disorder or condition (or a sign, symptom or condition thereof) better or more tolerable in a sample or subject administered a therapeutic agent relative to a control sample, control subject or group of control subjects.

[0056] As used herein the terms “carrier” or “pharmaceutically acceptable carrier” refer to a diluent, adjuvant, excipient, or vehicle with which a compound / drug product / composition (including a formulation or medicament) is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, oils and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, silica particles (nanoparticles or microparticles) urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington ’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.

[0057] As used herein, the phrase “delaying the onset of’ refers to, in a statistical sample, postponing, hindering the occurrence of a disease, disorder or condition, or causing one or more signs or symptoms of a disease, disorder or condition to occur more slowly thannormal, in a sample or subject administered a therapeutic agent or agents relative to a control sample, control subject or group of control subjects.

[0058] As used herein, the term “effective amount” refers to a quantity of a compound / composition / drug product sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., an amount that treats, prevents, inhibits, ameliorates, or delays the onset of the disease, disorder or condition, or the physiological signs or symptoms of the disease, disorder or condition. In the context of therapeutic or prophylactic applications, in some embodiments, the amount of a compound / composition / drug product administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. In some embodiments, it will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compounds / compositions / drug products can also be administered in combination with one or more additional therapeutic compounds / agents (a so called “co-administration” where, for example, the additional or other therapeutic agent(s) could be administered simultaneously, sequentially or by separate administration).

[0059] As used herein, the term "hydrate" refers to a compound which is associated (e.g., complexed) with water. The number of the water molecules contained in a hydrate of a compound may be (or may not be) in a definite ratio to the number of the compound molecules in the hydrate.

[0060] As used herein, “inhibit” or “inhibiting” refers to the reduction in a sign, symptom, or condition (e.g., risk factor) associated with a disease or disorder associated with a- synucleinopathies. In one embodiment, inhibit or inhibiting refers to the reduction by at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction by at least 5 percent compared to control (or control subject). In various individual embodiments, inhibit or inhibiting refers to a reduction by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent compared to a control sample, or control subject or group of control subjects.

[0061] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a therapeutic compound that can be prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compoundscontain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salt, or a similar salt. When compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine (NEts), trimethylamine, tripropylamine, tromethamine and the like, such as where the salt includes the protonated form of the organic base (e.g., [HNEts]+). Salts derived from pharmaceutically acceptable inorganic acids include salts of boric, carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids (e.g., acetic, butyric, formic, propionic and trifluoroacetic acids), amino acids (e.g., aspartic and glutamic acids), aromatic carboxylic acids (e.g., benzoic, p- chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenylacetic acids), aromatic hydroxyl acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic, 1 -hydroxynaphthal ene-2- carboxylic and 3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylic acids (e.g., fumaric, maleic, oxalic and succinic acids), glucuronic, mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids (e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic, isethionic, methanesulfonic, naphthalenesulfonic, naphthalene- 1,5-disulfonic, naphthalene-2,6-disulfonic, p-toluenesulfonic acids (PTSA)), xinafoic acid, and the like. In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride,chlorotheophyllinate, citrate, ethanedi sulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methyl sulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. In some embodiments, the salt is a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt, a maleate salt, a trifluoroacetate salt, a hydrochloride salt, or a tosylate salt. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts or exist in zwitterionic form. These salts may be prepared by methods known to those skilled in the art. Any other pharmaceutically acceptable carriers known to those of skill in the art are suitable for use with the present technology.

[0062] As used herein, “prevention” or “preventing” of a disease, disorder, or condition refers to results that, in a statistical sample, exhibit a reduction in the occurrence of the disease, disorder, or condition in a sample or subject administered a therapeutic agent or agents relative to a control sample or subject. Such prevention is sometimes referred to as a prophylactic treatment.

[0063] As used herein, the term “separate” therapeutic use refers to an administration of at least two active ingredients (e.g., therapeutic agents) at the same time or at substantially the same time by different routes.

[0064] As used herein, the term “sequential” therapeutic use refers to administration of at least two active ingredients (e.g., therapeutic agents) at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients (e.g., therapeutic agents) before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this definition.

[0065] As used herein, the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients (e.g., therapeutic agents) by the same route and at the same time or at substantially the same time.

[0066] As used herein, the term "solvate" refers to forms of the compound that are associated with a solvent, possibly by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane(s), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like.

[0067] As used herein, a “subject” refers to a living animal. In various embodiments, a subject is a mammal. In various embodiments, a subject is a non-human mammal, including, without limitation, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, minipig, horse, cow, or non-human primate. In certain embodiments, the subject is a human.

[0068] It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described herein, in some embodiments, are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

[0069] As used herein, a “synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of the agents.

[0070] As used herein, the term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0071] As used herein, the terms “treating” or “treatment” refer to therapeutic treatment, wherein the object is to reduce, alleviate or slow down (lessen) a pre-existing disease, disorder or condition, or its related signs, or symptoms. By way of example, but not by way of limitation, a subject is successfully “treated” for a disease if, after receiving an effectiveamount of the compound / composition / drug product or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, the subject shows observable and / or measurable reduction in or absence of one or more signs, or symptoms associated with the disease, disorder or condition. It is also to be appreciated that the various modes of treatment of medical conditions as described are intended to mean “substantial,” which includes total alleviation of conditions, signs or symptoms of the disease, disorder or condition, as well as “partial,” where some biologically or medically relevant result is achieved.II. Pharmaceutical Compositions, Routes of Administration, and Dosing

[0072] The methods, uses, and compositions / formulations / medicaments of the present application utilize a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of any two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of any one or more of the foregoing Compounds 1-6, wherein Compounds 1 to 6 have the following structures:Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of any one or more of the foregoing Compounds 1-6 can be formulated into a drug product suitable for administration to a subject in need thereof. Such a drug product can be referred to as a composition, formulation, or medicament depending on its usage. Any mixture prepared by mixing any one or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of any one or more of the foregoing Compounds 1-6 with a solvent and / or other compound(s) is a composition or formulation and may or may not be intended for administration to a subject. A medicament is generally considered a composition or formulation specifically prepared for administration to a subject to address a disease, disorder, or condition (e.g., an a-synucleinopathy). In some embodiments, one or more of the hydrogen atoms of any one of Compounds 1 to 6, as used in a method, use, medicament, or formulation as disclosed herein, can be substituted with a deuterium atom without any significant deviation from its efficacy or therapeutic profile.

[0073] For purposes of brevity, whenever there is a reference to Compound 1, herein, this reference is intended to encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compound 1, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in the Compound. For purposes of brevity, whenever there is a reference to Compound 2, herein, this reference is intended to encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compound 2, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in the Compound. For purposes of brevity, whenever there is a reference toCompound 3, herein, this reference is intended to encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compound 3, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in the Compound. For purposes of brevity, whenever there is a reference to Compound 4, herein, this reference is intended to encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compound 4, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in the Compound. For purposes of brevity, whenever there is a reference to Compound 5, herein, this reference is intended to encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compound 5, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in the Compound. For purposes of brevity, whenever there is a reference to Compound 6, herein, this reference is intended to encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of Compound 6, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in the Compound. For purposes of brevity, whenever there is a reference to “Compounds 1 to 6 or mixtures of two more of Compounds 1 to 6” herein, this reference is intended to implicitly encompass any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of any of Compounds 1 to 6, individually or within the mixtures, as well as any modifications associated with substitution of a deuterium atom for a hydrogen atom in any one or more of Compounds 1-6.

[0074] Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 disclosed herein can be used, alone or in combination, with one or more other therapeutic agent(s) to address the needs of subjects suffering from a-synucleinopathies. In order to be administered to a subject in need thereof, Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 will generally need to be formulated (for individual administration or in a combined formulation) for the intended route of administration. In some embodiments, the same route of administration can be used to deliver Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6. In some embodiments, two or more of Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 can be administered by different routes. The formulated product(s) can be considered a composition or medicamentcomprising Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and optionally one or more other (i.e., additional) therapeutic agents.

[0075] In some embodiments, the therapeutic agent(s) can be formulated with little or no excipient or carrier. In some embodiments, the therapeutic agent(s) can be formulated such that the majority of the formulation is excipient or carrier. In brief, one of skill in the art will tailor the composition / formulation / medicament to have a suitable amount of excipient or carrier based on the needs / condition of the subject, the kind and extent of the disease to be treated; the properties of the therapeutic agent or agents to be delivered and the selected mode of administration of the particular therapeutic agent or agents.

[0076] In certain embodiments, a pharmaceutical composition (e.g., a medicament) may further comprise at least one additional therapeutic agent (other than Compounds 1 to 6), or a mixture of any two or more of Compounds 1 to 6 (e.g. another (or additional) therapeutic agent for use in combination with the Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6). The at least one other / additional therapeutic agent can be an agent useful in the treatment of a-synucleinopathies or could, for example, be administered to ameliorate the side effect of the administration of Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 (e.g., to address a side reaction or because the combination therapy is preferred for the treatment of a-synucleinopathies). Thus, in some embodiments, pharmaceutical compositions can be prepared, for example, by combining Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, with a pharmaceutically acceptable carrier and, optionally, one or more additional therapeutical agents or otherwise merely administering the other / additional therapeutic agent(s) in combination with the administration of Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6.

[0077] Pharmaceutical compositions may contain an effective amount of one or more of the therapeutic agents as described herein and may optionally be disbursed (e.g. dissolved, suspended or otherwise) in a pharmaceutically acceptable carrier. The components of the pharmaceutical composition(s) may also be capable of being commingled with the Compounds of the present application, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical efficiency or therapeutic profile.

[0078] As stated above, an “effective amount” refers to any amount of a particular therapeutic agent that is sufficient to achieve a desired biological effect. Combined with theteachings provided herein, by choosing among the various therapeutic compound(s) and weighing factors such as potency, relative bioavailability, patient body weight, target tissue uptake, severity of adverse side-effects and mode of administration, an effective prophylactic (z.e. preventative) or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to address the particular condition, disorder or disease of a particular subject in a therapeutic way. The effective amount of a therapeutic agent for any particular indication can vary depending on such factors as the disease, disorder, or condition being treated, the particular compound or compounds being administered, the size of the subject, the age of the subject, the overall health of the subject and / or the severity of the disease, disorder or condition. The effective amount may be determined during pre-clinical trials and / or clinical trials by methods familiar to physicians and clinicians. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated 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. A dose may be administered by oneself, by another or by way of a device (e.g., a pump).

[0079] For any therapeutic compound described herein the therapeutically effective amount can, for example, 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.

[0080] Therapeutic compounds (alone or as formulated in a pharmaceutical composition / medicament) for use in therapy or prevention can be tested in suitable animal model systems. Suitable animal model systems include, but are not limited to, rats, mice, chicken, cows, monkeys, rabbits, pigs, minipigs and the like, prior to testing in human subjects. In vivo testing of any animal model system known in the art can be used prior toadministration to human subjects. In some embodiments, dosing can be tested directly in humans.

[0081] Dosage, toxicity and therapeutic efficacy of any therapeutic agents or compositions (e.g., formulations or medicaments comprising Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6), other / additional therapeutic agents, or mixtures thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. While compounds that exhibit toxic side effects may be used, in such cases it may be prudent to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0082] An exemplary treatment regime can, for example, entail administration once per day, twice per day, thrice per day, once a week, or once a month. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is delayed, reduced or terminated, or until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regimen.

[0083] For use in therapy, an effective amount of the therapeutic compound (alone or as formulated) can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmical, intrathecal, intracerebroventricular, iontophoretical, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by another and administration by a device (e.g, a pump).

[0084] A therapeutic compound / agent disclosed herein (e.g., Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, optionally with one or more additional therapeutic agents) can be delivered to the subject in a formulation or medicament (i.e., a pharmaceutical composition). Formulations and medicaments can be prepared by, for example, dissolving or suspending a therapeutic compound / agent disclosed herein (e.g.,Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6) in water, a solvent, a pharmaceutically acceptable carrier, salt, (e.g, NaCl or sodium phosphate), buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutically acceptable ingredients.

[0085] The pharmaceutical compositions (e.g. a formulation or medicament) can include a carrier (e.g., a pharmaceutically acceptable carrier), which can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation. In many cases, it will be advantageous to include isotonic agents, for example, sugars (e.g., trehalose), polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0086] Solutions or suspensions (e.g, a formulation or medicament) used for parenteral, intradermal, subcutaneous, or intraocular application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. For convenience of the patient or treating physician, the dosing formulation can be provided alone or in a kit containing all necessary equipment (e.g, vials of drug, vials of diluent, syringes and needles) for a treatment course (e.g., 1, 2, 3, 4, 5, 6, 7 days or more of treatment).

[0087] The therapeutic compounds / agents or pharmaceutical compositions, when it is desirable to deliver them systemically, may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion (for example by IV injection or via a pump to meter the administration over a defined time). Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. Pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Additionally, suspensions of the therapeutic compounds (e.g., Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, optionally with one or more additional therapeutic agents) may 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 may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0088] 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.

[0089] For intravenous and other parenteral routes of administration, a compound (e.g., Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, optionally with one or more additional therapeutic agents) can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or lipid-encapsulated therapeutic compound(s), 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] Pharmaceutical compositions (e.g., a formulation or medicament) suitable for injection can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). A composition for administration by injection will generally be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufactureand storage and may be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0091] Sterile injectable solutions (e.g., a formulation or medicament) can be prepared by incorporating the therapeutic compound(s) (e.g., Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, optionally with one or more additional therapeutic agents) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound(s) into a sterile vehicle, that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, typical methods of preparation include vacuum drying and freeze drying, which can yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0092] For oral administration, the compounds can be formulated readily by combining the therapeutic compound(s) (e.g., Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, optionally with one or more additional therapeutic agents) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the therapeutic compound(s) 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. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel®, or corn starch; a lubricant such as magnesium stearate or sterates; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0093] Pharmaceutical preparations for oral use can be obtained as 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 are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or 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 polyvinylpyrrolidone (PVP). If desired, disintegrating agentsmay be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[0094] Also specifically contemplated are oral dosage forms of the above that may 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 therapeutic agent(s), ingredient(s), and / or excipient(s), 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 therapeutic agent(s), ingredient(s), and / or excipient(s) 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, polyvinyl pyrrolidone 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 Biochem 4:185-9 (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 (PEG) moieties of various molecular weights are suitable.

[0095] For the formulation of the therapeutic agent(s), ingredient(s), and / or excipient(s), the location of release may be the stomach, the small intestine (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. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of a therapeutic compound / agent or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0096] 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 may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may 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.

[0097] The therapeutic compound(s) / agent(s) (which term “therapeutic compound(s) / agent(s)” as used herein is intended to refer to Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and any other active pharmaceutical ingredient (e.g., other therapeutic agent) that can be administered in a combination with Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6. The formulation can comprise fine multi-particulates in the form of granules or pellets of particle size about 1-2 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic compound(s) / agent(s) or pharmaceutical composition(s) could be prepared by compression.

[0098] Colorants and flavoring agents may all be included. For example, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be formulated and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0099] One may dilute or increase the volume of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) with an inert material. These diluents could include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress® and Avicel®.

[0100] Disintegrants may be included in the formulation of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) 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 disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, karaya gum or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0101] Binders may be used to hold the therapeutic agent(s) together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin.Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic agent(s).

[0102] An anti -frictional agent may be included in the formulation of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic 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 may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (PEG) of various molecular weights, Carbowax™ 4000 and 6000.

[0103] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0104] To aid dissolution of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) into the aqueous environment, a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation or medicament 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 or medicament disclosed herein or derivative either alone or as a mixture in different ratios.

[0105] Pharmaceutical compositions 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 therapeutic compound(s) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been welldefined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0106] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0107] For topical administration, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well-known in the art. Solutions, gels, ointments, creams, or suspensions may be administered topically. The compounds may 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.

[0108] For administration by inhalation, therapeutic compound(s) / agent(s) or pharmaceutical composition(s) for use according to the present application may 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, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. Such methods include those described in U.S. Pat. No. 6,468,798. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic compound / agent and a suitable powder base such as lactose or starch. Alternatively, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0109] Nasal delivery of a therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is also contemplated. Nasal delivery allows the passage of therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to the blood stream directly after administering the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) 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] For nasal administration, one type of useful device is a small, hard bottle to which a metered dose sprayer is attached. In some embodiments, the metered dose is delivered by drawing a pharmaceutical composition (in solution form) into a chamber of defined volume,which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the therapeutic compound(s) / agent(s) or pharmaceutical composition(s). In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0111] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed can be used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s).

[0112] Also contemplated herein is pulmonary delivery of the compounds disclosed herein. The therapeutic compound(s) / agent(s) or pharmaceutical composition(s)is / are 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 Car diovasc Pharmacol 13(suppl. 5): 143-146 (1989) (endothelin-1); Hubbard et al., Anna! Int Med 3 :206-212 (1989) (al -antitrypsin); Smith et al., 1989, JClin lnvest 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 human 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. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995, to Wong et al.

[0113] Contemplated for use in the practice of this technology 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.

[0114] Some specific examples of commercially available devices suitable for the practice of this technology are the Ultravent™ nebulizer, manufactured by Mallinckrodt, Inc., St.Louis, Mo.; the Acorn II® nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin® metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler® powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0115] All such devices require the use of formulations suitable for the dispensing of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s). Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes, or other types of carriers is contemplated.

[0116] Formulations suitable for use with a nebulizer, either jet or ultrasonic, can, for example, comprise therapeutic compound(s) / agent(s) or pharmaceutical composition(s) dissolved in water at a concentration of about 0.01 to 50 mg of biologically active compound per mL of solution. The formulation may also include a buffer and optionally a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) disclosed herein caused by atomization of the solution in forming the aerosol.

[0117] Formulations for use with a metered-dose inhaler device may generally comprise a finely divided powder comprising the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) disclosed herein suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, di chlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[0118] Formulations for dispensing from a powder inhaler device may comprise a finely divided dry powder containing the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound(s) / therapeutic agent(s) / pharmaceutical composition(s) can advantageously be prepared in particulate or nanoparticulate form with anaverage particle size of less than 10 micrometers (pm), most preferably 0.5 to 5 pm, for most effective delivery to the deep lung.

[0119] For ophthalmic or intraocular indications, any suitable mode of delivering the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) to the eye or regions near the eye can be used. For ophthalmic formulations generally, see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N.Y. (1993) and also Havener, W. H., Ocular Pharmacology, C.V. Mosby Co., St. Louis (1983). Nonlimiting examples of pharmaceutical compositions suitable for administration in or near the eye include, but are not limited to, ocular inserts, minitablets, and topical formulations such as eye drops, ointments, and in situ gels. In one embodiment, a contact lens is coated with a pharmaceutical composition (or contains a pharmaceutical composition encapsulated therein) comprising a therapeutic compound / agent. In some embodiments, a single dose can comprise from between 0.1 ng to 5000 pg, 1 ng to 500 pg, or 10 ng to 100 pg of the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) administered to the eye.

[0120] Eye drops can comprise a sterile liquid formulation that can be administered directly to the eye. In some embodiments, eye drops comprise at least one therapeutic agent (and possibly several) and may further comprise one or more preservatives. In some embodiments, the optimum pH for eye drops equals that of tear fluid and is about 7.4, the pH may be within any range that is not harmful to the eye of the subject. For eye drops, the therapeutic compound(s) / agent(s) can be present in the drop solution from about 0.1% to about 5% (w / v or v / v depending on the physical nature (i.e. solid or liquid) of the active ingredient). In some embodiments, the therapeutic compound / agent can be present in the drop solution from about 1% to about 3% (w / v or v / v, as appropriate). In some embodiments, the therapeutic compound / agent can be present in the drop solution from about 0.2% to about 1.5% (w / v or v / v, as appropriate). In some embodiments, the therapeutic compound / agent can be present in the drop solution from about 0.1% to about 1.0% (w / v or v / v, as appropriate).

[0121] In situ gels are viscous liquids, showing the ability to undergo sol-to-gel transitions when influenced by external factors, such as appropriate pH, temperature, pressure and / or the presence of electrolytes. This property causes slowing of drug drainage from the eyeball surface and increase of the active ingredient bioavailability. Polymers commonly used in in situ gel formulations include, but are not limited to, gellan gum, poloxamer, siliconecontaining formulations, silica-based formulations, and cellulose acetate phthalate. In some embodiments, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is / are formulated into an in-situ gel (as the formulation / medicament).

[0122] For topical ophthalmic administration, therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is / are may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Ointments are semisolid dosage forms for external use such as topical use for the eye or skin. In some embodiments, ointments comprise a solid or semisolid hydrocarbon base of melting or softening point close to human core temperature. In some embodiments, an ointment applied to the eye decomposes into small drops, which stay for a longer time period in conjunctival sac, thus increasing bioavailability.

[0123] Ocular inserts are solid or semisolid dosage forms without disadvantages of traditional ophthalmic drug forms. They are less susceptible to defense mechanisms like outflow through nasolacrimal duct, show the ability to stay in conjunctival sac for a longer period, and can be more stable than conventional dosage forms. They also offer advantages such as accurate dosing of one or more therapeutic compound(s) / agent(s) or pharmaceutical composition(s), slow release of one or more therapeutic compound(s) / agent(s) with constant speed and limiting of one or more therapeutic compounds’ / agents’ systemic absorption. In some embodiments, an ocular insert comprises one or more therapeutic compound(s) / agent(s) and one or more polymeric materials. The polymeric materials can include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the aforementioned polymers. An ocular insert can comprise silica. An ocular insert can comprise liposomes, nanoparticles or microparticles of degradable or biodegradable polymer (as described in more detail below).

[0124] Minitablets are biodegradable, solid drug forms, that transit into gels after application to the conjunctival sac, thereby extending the period of contact between active ingredient (i.e., the therapeutic compound(s) / agent(s)) and the eyeball surface, which in turn increases a therapeutic compounds’ / agents’ bioavailability. The advantages of minitablets include easy application to conjunctival sac, resistance to defense mechanisms like tearing or outflow through nasolacrimal duct, longer contact with the cornea caused by presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation inthe place of application due to the swelling of the outer carrier layers. Minitablets can comprise one or more therapeutic compound(s) / agent(s) and one or more polymers. Nonlimiting examples of polymers suitable for use in in a minitablet formulation include cellulose derivatives, like hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), Carbopol® or carbomer, chitosan, and starch (e.g., drum-dried waxy maize starch). In some embodiments, minitablets further comprise one or more excipients. Nonlimiting examples of excipients include mannitol and magnesium stearate.

[0125] The ophthalmic or intraocular formulations and medicaments may contain non-toxic auxiliary substances such as antibacterial components which are generally non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenyl ethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid (EDTA), and the like.

[0126] In some embodiments, the viscosity of the ocular formulation comprising one or more therapeutic compound(s) / agent(s) is increased to improve contact with the cornea and bioavailability in the eye. Viscosity can be increased by the addition of hydrophilic polymers of high molecular weight which do not diffuse through biological membranes and which form three-dimensional networks in the water. Nonlimiting examples of such polymers include polyvinyl alcohol, poloxamers, hyaluronic acid, carbomers, and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.

[0127] In addition to the formulations described above, therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may also be formulated as a depot preparation. Such long acting formulations may be formulated with 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.

[0128] In some embodiments, the therapeutic compound(s) / agent(s) or pharmaceutical composition(s) is / are administered as a depot formulation wherein the active therapeutic agent(s) is / are encapsulated by, or disposed within, silica-based microparticles. Such a formulation may be a controlled-release, delayed-release or extended release formulation(terms are defined below). Such controlled-release, delayed release or extended release formulation may comprise particles, such as microparticles or nanoparticles.

[0129] The pharmaceutical compositions also may 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, silica / silicone and polymers such as polyethylene glycols.

[0130] Suitable liquid or solid pharmaceutical preparation forms (e.g., a formulation or medicament) can, for example, be aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions / formulations may also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of therapeutic compound(s), 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 can be suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527-33 (1990).

[0131] The therapeutic compound(s) / agent(s) or pharmaceutical composition(s) may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the therapeutic compound(s) / agent(s) as described herein. The particles may contain the therapeutic compound(s) / agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic compound(s) / agent(s) also may be dispersed throughout the particles. The therapeutic compound(s) / agent(s) also may be adsorbed into the particles. The particles may 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 may include, in addition to any therapeutic compound(s) / agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, non-erodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsuleswhich contain the therapeutic compound(s) / agent(s) in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0132] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic compound(s) / agent(s). Such polymers may be natural or synthetic polymers. The polymer can be selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, polyethylene glycols (PEGs), polyvinylalcohols (PVAs), poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly-lactic acid (PLA), poly(lactic -co- glycolic) acid (PLGA), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly(£-caprolactone) or mixtures of two or more of the foregoing. The biodegradable polymeric materials may be substantially pure single polymer or mixes of two or more polymers wherein the materials comprise mixtures of single monomers, block co-polymers or a mixture thereof.

[0133] Therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be formulated in a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome, a phospholipid bilayer vehicle. In one embodiment, therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be encapsulated in a liposome while maintaining integrity of the therapeutic compound(s) / agent(s). One skilled in the art would appreciate that there are a variety of methods to prepare liposomes. (See Lichtenberg, et al.. Methods Biochem. Anal., 33:337-462 (1988); Anselem, etal., Liposome Technology, CRC Press (1993)). Liposomal formulations can delay clearance and increase cellular uptake (See Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). For example, a therapeutic agent can also be loaded into a particle prepared from pharmaceutically acceptable ingredients including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres,biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.

[0134] The carrier can also be a polymer, e.g., a biodegradable, biocompatible polymer matrix. In one embodiment, the therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be embedded in the polymer matrix, while maintaining integrity of the composition. The polymer can be a microparticle or nanoparticle that encapsulates therapeutic compound(s) / agent(s). The polymer may be natural, such as polypeptides, proteins or polysaccharides, or synthetic, such as poly a-hydroxy acids. Examples include carriers made of, e.g., collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharide, fibrin, gelatin, and combinations thereof. In some embodiments, the polymer is poly-lactic acid (PLA), poly lactic / glycolic acid (PLGA) or a mixture thereof. The polymeric matrices can be prepared and isolated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can lead to prolonged duration of therapeutic effect. (See Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). A polymer formulation for human growth hormone (hGH) has been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0135] Examples of polymer microsphere sustained release formulations are described in PCT publication WO 99 / 15154 (Tracy, et al.), U.S. Pat. Nos. 5,674,534 and 5,716,644 (both to Zale, et al.), PCT publication WO 96 / 40073 (Zale, et al.), and PCT publication WO 00 / 38651 (Shah, et al.). U.S. Pat. Nos. 5,674,534 and 5,716,644 and PCT publication WO 96 / 40073 describe a polymeric matrix containing particles of erythropoietin that are stabilized against aggregation with a salt.

[0136] In some embodiments, the nanoparticles or microparticles can be silica-based or silane-based (See for example: W02002 / 080977 entitled: “Biodegradable carrier and method for preparation thereof’).

[0137] In some embodiments, the therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) can be prepared with carriers that will protect the therapeutic compound(s) / agent(s) or other therapeutic agent(s) or mixtures thereof against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using knowntechniques. The materials can also be obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to specific cells with monoclonal antibodies to cell-specific antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0138] The therapeutic compound(s) / agent(s) or mixtures of two or more therapeutic compound(s) / agent(s) may be contained in controlled release systems. The term “controlled-release” is intended to refer 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-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”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed-release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom to thereby make it available to the subject. “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.”

[0139] Use of a long-term controlled-release or sustained-release implant or depot formulation may be particularly suitable for treatment of chronic conditions. The term “implant” and “depot formulation” is intended to include a single composition (such as a mesh) or composition comprising multiple components (e.g., a fibrous mesh constructed from several individual pieces of mesh material) or a plurality of individual compositions where the plurality remains localized and provides the long-term sustained-release of active pharmaceutical ingredient(s) occurring from the aggregate of the one or plurality of compositions. “Long-term” release, as used herein, means that the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 2 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 7 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levelsof the active pharmaceutical ingredient(s) for at least 14 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient for at least 90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least 180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for at least one year. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 15-30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 30-60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 60-90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 90-120 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for 120-180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active pharmaceutical ingredient(s) for up to one year. In some embodiments, the long-term sustained-release implants or depot formulation are well-known to those of ordinary skill in the art and include some of the release systems described above. In some embodiments, such implants or depot formulation can be administered surgically. In some embodiments, such implants or depot formulation can be administered topically or by injection.III. Formulations and Medicaments

[0140] Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6, can be used alone or in combination with one or more other therapeutic agents to address the needs of subjects suffering from a-synucleinopathies. In order to be administered to a subject inneed thereof, Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s) will generally need to be formulated for the suitable route of administration. For example, if Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s) is / are to be administered to the subject by injection, it / they will typically be formulated into an injectable liquid or liquid suspension. For example, this could be accomplished by dissolving or suspending the therapeutic agent(s) in a suitable diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier as described previously herein (See the section above entitled: Pharmaceutical Compositions, Routes of Administration, and Dosing). In some embodiments, the diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier can be water, saline or a buffered aqueous solution. In some embodiments, the diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier can comprise an oil such as sesame oil or other lipophilic excipient. Suitable methods, reagents and compositions for formulating Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s) into a suitable medicament are discussed above.

[0141] Similarly, if Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s), can be to be administered to the subject in oral form, the selected active ingredient(s) can be formulated into a pill, tablet, capsule or other vehicle for such administration as discussed above in the section entitled: “Pharmaceutical Compositions, Routes of Administration, and Dosing” or as otherwise known to those of ordinary skill in the art. Suitable methods, reagents and compositions for formulating Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s), into a suitable orally administrable medicament are discussed above.

[0142] Similarly, Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s), can be formulated for ocular administration, buccal administration, topical administration, nasal administration or any other of the modes of administration previously discussed herein or that are known to those of ordinary skill in the art. Suitable methods, reagents and compositions for formulating Compounds 1 to 6, or a mixture of any two or more of Compounds 1 to 6 and / or other therapeutic agent(s) into a suitable ocular, buccal, topical, or nasal administrable medicament are discussed above.

[0143] In brief, any of the formulations (which can also be referred to as a medicament or composition when formulated for administration to a subject having a certain affliction ormedical condition that requires medical attention) described in the section above entitled: “Pharmaceutical Compositions, Routes of Administration, and Dosing” can be applied to produce a composition (z.e. a formulation or medicament) suitable for administration to a subject in need thereof. Thus, in some embodiments, this application is directed to compositions, formulations and medicaments suitable for administration to a subject suffering from, or believed to be suffering from, a-synucleinopathies.

[0144] In some embodiments, the composition, formulation, or medicament is administered subcutaneously. In some embodiments, the composition, formulation, or medicament is administered orally. In some embodiments, the composition, formulation, or medicament is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0145] In some embodiments, Compounds 1 to 6, and / or other therapeutic agent(s) can be administered in formulations prepared using a pharmaceutically acceptable salt form. In some embodiments, Compounds 1 to 6, and / or other therapeutic agent(s) can be administered in formulations prepared using a hydrate form. In some embodiments, Compounds 1 to 6, and / or other therapeutic agent(s) can be administered in formulations prepared using a solvated form. In some embodiments, Compounds 1 to 6, and / or other therapeutic agent(s) can be administered in formulations prepared using a tautomeric form. In some embodiments, Compounds 1 to 6, and / or other therapeutic agent(s) can be administered in formulations prepared using a stereoisomer of Compounds 1 to 6, and / or the other therapeutic agent(s). In some embodiments of the composition, formulation or medicament, Compounds 1 to 6 can comprise one or more deuterium atoms substituted for one or more hydrogen atoms in one or more of the Compounds 1-6 used in the composition, formulation, or medicament.IV. Therapeutic Methods and Related Uses of the Disclosed Compounds in Addressing a-synucleinopathies

[0146] In one aspect, the present disclosure provides a method for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts,stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 1 is:wherein Compound 6 is:

[0147] In some embodiments, the present disclosure provides a method for treating, an a- synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 1 is:In some embodiments, the present disclosure provides a method for preventing an a-synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 1 is:In some embodiments, the present disclosure provides a method for inhibiting an a-synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 1 is:In some embodiments, the present disclosure provides a method for ameliorating an a-synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 1 is:wherein Compound 2 is:In some embodiments, the present disclosure provides a method for delaying the onset of an a-synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 1 is:

[0148] In some embodiments of the method, administration of the Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, optionally in combination with one or more additional therapeutic agents, affects or relieves one or more of the signs or symptoms of a-synucleinopathies including rhythmic shaking, muscle stiffness and / or difficulty with balance and coordination, dementia, hallucinations, aggressive behavior, confusion, poor attention span, memory loss, instability and gait disturbance (e.g., motor function), excessive daytime sleepiness and other sleep disorders, difficulty interpreting speech, muffled speech, depression, anxiety, apathy, gastrointestinal dysfunction (e.g., constipation), urinary and sexual dysfunction, and cardiovascular autonomic symptoms such as orthostatic hypotension, supine hypertension, and reduced heart rate variability.

[0149] In some embodiments, the subject has been diagnosed as having an a- synucleinopathy. In some embodiments, the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

[0150] In some embodiments, the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0151] In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

[0152] In some embodiments, the Compound, or mixture of Compounds, is / are administered daily for 6 weeks or more. In some embodiments, the Compound, or mixture of Compounds, is / are administered daily for 24 weeks or more. In some embodiments, the Compound, or mixture of Compounds is / are administered daily for 48 weeks or more. In some embodiments, the Compound or mixture of Compounds is / are administered daily for 52 weeks or more.

[0153] In some embodiments, the Compound, or mixture of Compounds, is / are administered orally. In some embodiments, the Compound, or mixture of Compounds, is / are administered subcutaneously. In some embodiments, the Compound or mixture ofCompounds, is / are administered topically. In some embodiments, the Compound or mixture of Compounds, is / are administered intranasally. In some embodiments, the Compound or mixture of Compounds, is / are administered systemically. In some embodiments, the Compound or mixture of Compounds, is / are administered intravenously. In some embodiments, the Compound or mixture of Compounds, is / are administered intraperitoneally. In some embodiments, the Compound or mixture of Compounds, is / are administered intradermally. In some embodiments, the Compound or mixture of Compounds, is / are administered intraocularly. In some embodiments, the Compound or mixture of Compounds, is / are administered ophthalmically. In some embodiments, the Compound or mixture of Compounds, is / are administered intrathecally. In some embodiments, the Compound or mixture of Compounds, is / are administered intracerebroventricularly. In some embodiments, the Compound or mixture of Compounds, is / are administered iontophoretically. In some embodiments, the Compound or mixture of Compounds, is / are administered transmucosally. In some embodiments, the Compound or mixture of Compounds, is / are administered intravitreally. In some embodiments, the Compound or mixture of Compounds, is / are administered intramuscularly.

[0154] In some embodiments, the method further comprises separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent comprises levodopa, optionally in combination with carbidopa (LODOSYN®). In some embodiments, the combination of the Compound, or mixture of Compounds, and the at least one additional therapeutic agent has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a- synucleinopathy.

[0155] In some embodiments, administration of the Compound or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, prolongs survival of the subject, as compared with an untreated subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g.,reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments, administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0156] In another aspect, present disclosure provides for use of a Compound, or mixture of Compounds, in the preparation of a composition or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, wherein the Compound or the Compounds present in the mixture of Compounds is / are selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate of any one or more of the selectedCompounds 1 to 6, wherein Compound 1 is:pwherein Compound 4 is:

[0157] In some embodiments of the use, administration of the composition or medicament to a subject, optionally in combination with one or more additional therapeutic agents, affects or relieves one or more of the signs or symptoms of a-synucleinopathies including rhythmic shaking, muscle stiffness and / or difficulty with balance and coordination, dementia, hallucinations, aggressive behavior, confusion, poor attention span, memory loss, instability and gait disturbance (e.g., motor function), excessive daytime sleepiness and other sleep disorders, difficulty interpreting speech, muffled speech, depression, anxiety, apathy, gastrointestinal dysfunction (e.g., constipation), urinary and sexual dysfunction, and cardiovascular autonomic symptoms such as orthostatic hypotension, supine hypertension, and reduced heart rate variability.

[0158] In some embodiments of the use, the subject has been diagnosed as having an a- synucleinopathy. In some embodiments of the use, the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

[0159] In some embodiments of the use, the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0160] In some embodiments of the use, the subject is a mammal. In some embodiments of the use, the subject is human.

[0161] In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 6 weeks or more. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 24 weeks or more. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 48 weeks or more. In some embodiments of the use, the composition or medicament comprising the Compound, or mixture of Compounds, is / are administered daily for 52 weeks or more.

[0162] In some embodiments of the use, the composition or medicament comprising the Compound or mixture of Compounds is formulated for administration orally. In some embodiments of the use, the composition or medicament comprising the Compound or mixture of Compounds is formulated for administration subcutaneously. In some embodiments of the use, the composition or medicament comprising the Compound or mixture of Compounds is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0163] In some embodiments of the use, administration of the composition or medicament further comprises separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject. In some embodiments of the use, the additional therapeutic agent comprises levodopa, optionally in combination with carbidopa (LODOSYN®). In some embodiments of the use, the combination of the composition or medicament comprising the Compound, or mixture of Compounds, and the at least one additional therapeutic has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

[0164] In some embodiments of the use, administration of the composition or medicament comprising the Compound, or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, prolongs survival of the subject, as compared with an untreated subject or an untreated control group of subjects. In some embodiments of the use, administration of the composition or medicament comprising the Compound, ormixture of Compounds, optionally including administration of the at least one additional therapeutic agent, improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the use, administration of the composition or medicament comprising the Compound, or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the use, administration of the composition or medicament comprising the Compound, or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the use, administration of the composition or medicament comprising the Compound, or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0165] In another aspect, present disclosure provides a Compound, or a mixture of Compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate of any one or more of Compounds 1 to 6, for use in treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, wherein the Compound or Compounds present in the mixture of Compounds is / are selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, wherein Compound 1 is:

[0166] In some embodiments of the foregoing Compound, or mixture of Compounds, administration of the Compound or mixture of Compounds to a subject, optionally in combination with one or more additional therapeutic agents, affects or relieves one or more of the signs or symptoms of a-synucleinopathies including rhythmic shaking, muscle stiffness and / or difficulty with balance and coordination, dementia, hallucinations, aggressive behavior, confusion, poor attention span, memory loss, instability and gait disturbance (e.g., motor function), excessive daytime sleepiness and other sleep disorders, difficulty interpreting speech, muffled speech, depression, anxiety, apathy, gastrointestinal dysfunction (e.g., constipation), urinary and sexual dysfunction, and cardiovascular autonomic symptoms such as orthostatic hypotension, supine hypertension, and reduced heart rate variability.

[0167] In some embodiments of the foregoing Compound or mixture of Compounds, the subject has been diagnosed as having an a-synucleinopathy. In some embodiments of the foregoing Compound or mixture of Compounds, the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

[0168] In some embodiments of the foregoing Compound or mixture of Compounds, the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

[0169] In some embodiments of the foregoing Compound or mixture of Compounds, the subject is a mammal. In some embodiments of the foregoing Compound or mixture of Compounds, the subject is human.

[0170] In some embodiments, the foregoing Compound or mixture of Compounds, is / are administered daily for 6 weeks or more. In some embodiments, the foregoing Compound or mixture of Compounds, is / are administered daily for 24 weeks or more. In some embodiments, the foregoing Compound, or mixture of Compounds, is / are administered daily for 48 weeks or more. In some embodiments, the foregoing Compound, or mixture of Compounds, is / are administered daily for 52 weeks or more.

[0171] In some embodiments of the foregoing Compound or mixture of Compounds, the Compound or mixture of Compounds is formulated for administration orally or subcutaneously. In some embodiments of the foregoing Compound or mixture of Compounds, the Compound or mixture of Compounds is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0172] In some embodiments of the foregoing Compound or mixture of Compounds, administration of the Compound or mixture of Compounds further comprises separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject. In some embodiments of the foregoing Compound or mixture of Compounds, the additional therapeutic agent(s) comprises levodopa optionally in combination with carbidopa (LODOSYN®). In some embodiments of the foregoing Compound, or mixture of Compounds, the combination of the Compound or mixture of Compounds and an additional therapeutic has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

[0173] In some embodiments of the foregoing Compound, or mixture of Compounds, administration of the Compound or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, prolongs survival of thesubject, as compared with an untreated subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, administration of the Compound or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, administration of the Compound or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, administration of the Compound or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects. In some embodiments of the foregoing Compound, or mixture of Compounds, administration of the Compound or mixture of Compounds, optionally including administration of the at least one additional therapeutic agent, attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.EXAMPLES

[0174] The present technology is further illustrated by the following examples, which should not be construed as limiting in any way.Example 1: In Vitro AssaysI. Materials & Methods

[0175] Cell Lines:

[0176] Patient fibroblasts were acquired from the National Institute of Neurological Disorders (NINDS). The PD409906 cell line possesses a mutation in the a-synuclein (SNCA) gene. The PD38528 cell line is of idiopathic (spontaneous / unknown) origin. The PD32974 cell line is from a patient with atypical neurodegeneration that showed signs of iron accumulation in the brain. Cells were cultured at 37 °C at 5% CO2 in complete Dulbecco’s Modified Eagle Medium (DMEM, Gibco), which was supplemented with Earle's salts andnon-essential amino acids, 10% qualified fetal bovine serum, and 1% penicillin / streptomycin (lOOU / lOOg).

[0177] Structure of vatiquinone is provided for reference purposes:The structures ofCompounds 1-6 are disclosed above.

[0178] a. Complex I bypass Assay Using High-Resolution Respirometry:

[0179] High-resolution respirometry (HRR) experiments were conducted using the O2k- Fluorespirometer (Oroboros, Innsbruck, AT). The 02k was calibrated daily using the air calibration protocol on DatLab 7.4. Initial data analysis was performed using DatLab 7.4.

[0180] Complex I-bypass (Ci-bypass) activity was assessed using HRR to measure O2 consumption. Briefly, Idiopathic PD (PD38528) fibroblasts were harvested with trypsin, pelleted at 300 x g centrifugation, and resuspended in prewarmed, complete DMEM. Cells were added to each chamber via buffer replacement at a concentration of 1-2 million per mL. The chambers were closed to initiate measurement of O2 consumption, which is calculated by DatLab and expressed as picomoles per second per number of cells. The slope negative signal or O2 flux was allowed to stabilize over the course of several minutes. Using a Hamilton syringe, rotenone was added to the closed chamber through the central capillary of the stopper to allow for continuous measurement of O2 consumption at a final concentration of 0.5 pM. The slope negative signal was stabilized for several minutes. Compound 2 or 3 was added at increasing concentrations, allowing for several minutes of stabilization of the slope negative signal between titrations. Concentrations on the x-axis reflect the total concentration of Compound in the chamber. Marks were set at signal plateaus in between titrations. Each experiment was performed twice. Values were exported and analyzed using GraphPad Prism 9.

[0181] Defects in Complex I (CI) are prevalent in the substantia nigra of PD patients and are thought to play a role in Parkinson’s disease pathogenesis. Chemical inhibition with rotenone, which binds to Complex I and prevents electron flow down the complex and ETC, was used to test the ability of the Compounds of the present technology to overcome perturbation in CI activity that was inflicted by addition of rotenone. It was found that both Compound 2 and Compound 3 were able to restore oxygen consumption rates and overcome deficiencies in CI.

[0182] Statistical Analysis:

[0183] Statistical analysis was performed using GraphPad Prism 9. Complex I-bypass data were fit using nonlinear sigmoidal 4P fit. Effective concentration (EC) 50 values were calculated to rank compounds with respect to their performance. A lower EC=50 value is indicative of more potent effects in this specific experimental context.

[0184] Results:

[0185] Results are illustrated graphically in Fig. 1 (Compound 2) and Fig. 2 (Compound 3). Compounds 2 and 3 were able to bypass the chemically inhibited complex I defect of the electron transport chain in a dose-dependent manner.

[0186] b. RSL3 Cytoprotection Assay:

[0187] To initiate a RSL3 cytoprotection assay, PD fibroblasts (PD409906, PD38528, or PD32974) were resuspended in Complete Dulbecco’s Modified Eagle Medium (Complete DMEM). Cells were seeded at 10,000 cells per well in a clear, tissue cultured-treated, 96- well plate and incubated at 37°C overnight. Following the incubation, supernatant was manually aspirated, taking care not to disrupt cells. Fibroblasts were co-treated in a final volume of 100 pL with 1 pM (15,3A)-Methyl 2-(2-chloroacetyl)-2,3,4,9-tetrahydro-l-[4- (m ethoxy carbonyl)phenyl]-17 / -pyrido[3,4-Z>]indole-3 -carboxylate (RSL3) and a titration of Compounds 1 to 6, vatiquinone (Caymen Chemicals) or DMSO control. Cells were incubated for 4 hours at 37°C. Cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Kit (ProMega) per Manufacturer’s instructions. Luminescence units were quantified by GEN5 software on a BioTek SYNERGY neo2 plate reader (LUM filter).

[0188] With reference to Figs. 3-5, this assay was performed on cell fibroblasts obtained from patients with various forms of a-synucleinopathies (See: cell line discussion above). The test articles were Compounds 1 to 6 and vatiquinone. Each of Compounds 1 to 6 and vatiquinone produced a titratable protective effect on the cells, thereby suggesting that each of Compounds 1 to 6 and vatiquinone possesses protective properties against the various forms of Parkinson’s disease tested.

[0189] More specifically with respect to Figs. 3-5, Compounds 1-6, and vatiquinone were able to restore cell viability in a dose-dependent manner in PD fibroblasts injured with RSL3, irrespective of the cell type tested. This assay is representative of Parkinson’s disease pathology because RSL3 depletes glutathione in cells and in PD patients, glutathione levels are lower in the brain (substantia nigra).

[0190] Accordingly, these results demonstrate that compositions comprising a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, may be effective in methods for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a- synucleinopathy in a subject in need thereof.Example 2: In Vivo Assessment of Compound 1, Vatiquinone and Idebenone by OralAdministration, in Plasma of RatI. ASSESSMENT OF THE PHARMACOKINETICS OF COMPOUND 1, AND COMPARATOR COMPOUNDS, FOLLOWING A SINGLE ORAL ADMINISTRAHON TOMALE SPRAGUE DAWLEY RATS

[0191] Structure of idebenone is provided for reference purposes:The structure of Compound 1 and vatiquinone are disclosed elsewhere herein.

[0192] a) Dosing Protocol:• Animals: Rat / Sprague Dawley / Male were received from an approved vendor.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• Idebenone and vatiquinone were dissolved in sesame oil. Compound 1 was dissolved in MIGLYOL® 812 N. All test articles were administered perorally (PO) at a dose of 10 mg / kg.• Formulations for dosing the animals were prepared according to Table 1, below.• This was a single dose, serial blood collection study.• There were 3 animals per test article. Blood samples were collected from the animals post dosing at 0.33 hours, 1 hours, 2 hours, 4 hours, 6 hours and 10 hours.TABLE 1 - Formulations for Dosing Animals

[0193] b) Sample collection - Post Dosing:• Blood was collected in EDTA microvette from the tail vein• Blood was centrifuged for 3 minutes at 10000g, plasma collected in low-binding microtube (Nerbe plus). Plasma (95 pl) was added to 5 pl of 2% formic acid to obtain 100 pl plasma solution with formic acid to an end concentration of 0.1%.• Plasma was frozen in liquid nitrogen and stored frozen until analysed.

[0194] c) Sample processing for analysis:• To 100 pL of a previously frozen rat plasma sample was add 4pL of dimethylsulfoxide (DMSO) and then vortex mix• 400pL of deproteinization solution, 1% formic acid in MeOH with internal standard (reserpinel5 ng / mL) was added• The samples were vortexed for 10 seconds at 2800rpm• The samples were put on an orbital shaker for 10 minutes at 200rpm• The samples were vortexed for 10 seconds at 2800rpm• The samples were centrifuged at 12000 rpm for 30 minutes in 5°C• The supernatants were transfer to vials for analysis• The samples were analyzed by LC / MS / MS and the results are presented in Fig. 6.

[0195] d) Results:• For this Example, the oral bioavailability of Compound 1 was compared with idebenone and vatiquinone - two compounds that have been tested as treatments for Parkinson’s disease.• With reference to Fig. 6, the concentration of Compound 1 increased in the blood plasma up to 4 hours post oral administration and then reached essentially a steady state for most of the remainder of the 10 hour study. Though not as orally bioavailable as was vatiquinone, Compound 1 was significantly more bioavailable than idebenone.• Because the study was terminated at 10 hours post administration of the test articles and the blood plasma concentration of Compound 1 had yet to significantly decrease, it is unknown how long the blood concentration of Compound 1 would remain above 10 ng / mL (a potentially efficacious blood level). The data suggests that Compound 1 possesses sufficient oral bioavailability for efficacious oral dosing in view of the comparative results with idebenone and vatiquinone.Example 3: In Vivo Assessment of Compound 2 and its R-enantiomer, Compound 3 and its R-Enantiomer, and Vatiquinone and its S-enantiomer by Oral Administration, in Plasma & Brain Tissue Homogenate of RatI. ASSESSMENT OF THE PHARMACOKINETICS OF VARIOUS COMPOUNDSAND THEIR ENANTIOMERS FOLLOWING A SINGLE ORAL ADMINISTRAHON TOMALE SPRAGUE DAWLEY RATS

[0196] a) Dosing Protocol:• Animals: Rat / Sprague Dawley / Male were received from an approved vendor.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• All test articles were dissolved in sesame oil for administration.• All test articles were administered perorally (PO) at a dose of 10 mg / kg.• Formulations for dosing the animals were prepared according to Table 2, below.• This was a single dose, serial blood collection study.• Animals were sacrificed immediately after the final blood draw and brain tissues were collected.• There were 4 animals per test article. Blood samples were collected from the animals post dosing at 0.33 hours, 1 hours, 2 hours, 4 hours, 6 hours and 10 hours.• Brain tissue was collected post euthanasia.TABLE 2 - Formulations for Dosing Animals

[0197] b) Blood Sample Collection - Post Dosing:• Blood was collected in EDTA microvette from the tail vein.• Blood was centrifuged within 30 minutes of sampling and plasma was collected in low-binding microtubes. Plasma (95 pl) was added to 5 pl of 2% formic acid to obtain 100 pl plasma solution with formic acid to an end concentration of 0.1%.• Plasma was frozen in liquid nitrogen and stored frozen until analysed.

[0198] c) Brain Tissue Sample Collection - Post Euthanasia:• After the chest was opened (post euthanasia) and blood drawn from heart. Transcardial perfusion was performed using 1 x phosphate buffered saline (PBS, pH=7.4). Afterwards brain tissues were collected and snap frozen.• Brain tissue samples were weighed in low protein binding 2 mL micro centrifuge tubes with screw cap, Sarstedt, Germany)• Four times the tissue weight purified deionized water with 0.1 % formic acid (v / w) was then added to each tube.• Two metal beads were placed in each micro centrifuge tube (Metal Bead Lysing Matrix Bulk, MP, USA)• Brain tissues were homogenized using Bead Ruptor (Omni International, USA) for 60 seconds using speed 4 ms per cycle.• Homogenates (96 pL) were transferred to 1.5 mL micro centrifuge tubes.• Homogenates were frozen and kept at -80°C until used for LC / MS / MS analysis.

[0199] d) Plasma and Brain Tissue Sample Processing for Analysis:• To 96 pL of a previously frozen rat plasma sample or brain tissue sample was add 4pL of dimethylsulfoxide (DMSO) and then vortex mixed.• 400pL of deproteinization solution, 1% formic acid in MeOH with internal standard (reserpinel5 ng / mL) was added.• The samples were vortexed for 10 seconds at 2800rpm• The samples were put on an orbital shaker for 10 minutes at 200rpm• The samples were vortexed for 10 seconds at 2800rpm• The samples were centrifuged at 12000 rpm for 30 minutes in 5°C• The supernatants were transfer to vials for analysis• The samples were analyzed by LC / MS / MS and the results of the plasma analysis are presented graphically in Fig. 7 and the results of the analysis of the brain tissue samples are presented graphically in Fig. 8.

[0200] e) Plasma Sample Results:• With reference to Fig. 7, vatiquinone, and its S-enantiomer, exhibited good apparent bioavailability with oral dosing. There was essentially no difference in exposure observed between vatiquinone and its S-enantiomer. In both cases, the exposure in the plasma was essentially undetectable at 10 hours post administration.• With reference to Fig. 7, Compound 2, and its R-enantiomer, exhibited apparent bioavailability with oral dosing. There was essentially no difference in exposure observed between Compound 2, and its R-enantiomer. In both cases, the exposure of each compound in the plasma was essentially undetectable at 10 hours post administration.• With reference to Fig. 7, Compound 3 and its R-enantiomer also exhibited apparent bioavailability with oral dosing. There was essentially no difference in exposure observed between Compound 3, and its R-enantiomer.

[0201] f) Brain Tissue Sample Results:• With reference to Fig. 8, vatiquinone exhibited reasonably good penetration of the brain tissue. Curiously, penetration of the S-enantiomer of vatiquinone was approximately one-half of that of vatiquinone under identical conditions.• With reference to Fig. 8, Compound 2, and its R-enantiomer, exhibited substantially equivalent brain tissue exposure as compared with vatiquinone, despite exhibiting much lower oral bioavailability (about one fifth that exposure level) of vatiquinone based on the plasma sample results. There was essentially no difference in brain tissue exposure observed between Compound 2 and its R- enantiomer. This brain tissue penetration suggests that Compound 2 and its R- enantiomer can achieve efficacious levels in the brain with oral dosing.With reference to Fig. 8, Compound 3, and its S-enantiomer, exhibited no observable brain tissue exposure under these conditions.Example 4: In Vivo Assessment of Compound 4, Delivered by Various Modes of Administration, in Plasma of RatI. ASSESSMENT OF THE PHARMACOKINETICS OF COMPOUND 4 FOLLOWING A SINGLE INTRAVENOUS, SUBCUTANEOUS, OR ORAL ADMINISTRAHON TOMALE SPRAGUE DAWLEY RATS

[0202] a) Dosing Protocol:• Animals: Rat / Sprague Dawley / Male / Naive 225-250 grams were received from an approved vendor.• Animals were fasted overnight prior to dose administration. Food was returned following the 2 hour sample collection.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• This was a single dose, serial blood collection study with tissues collected for possible future analysis.• Doses were administered in accordance with test facility standard operating procedures. Post-dose flushes were administered as applicable.• All dose syringes were weighed prior to and following dosing to gravimetrically determine the amount of formulation administered.• All animals were observed at dosing and each scheduled collection. Any abnormalities were recorded.• Pre-formulated Compound 4 and vatiquinone were provided in ready to be administered form in accordance with the Study Design set forth in Table 3, below.TABLE 3 - Study DesignIV = Intravenous, SC = subcutaneous, PO = oral, N / A = Not Applicable

[0203] b) Sample collection - Post Dosing:• Blood samples were collected via jugular vein catheter (JVC) and transferred to tubes with appropriate anticoagulant. The tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5 °C for 10 minutes) within 20 minutes of collection. Sample aliquots of 100 pL were transferred into individual uniquely labeled matrix tubes containing 10 pL of 5% (v / v) formic acid aqueous solution and stored at nominal -80 °C until analyzed by LC / MS / MS.• Immediately following final serial blood collection (24 hours, JVC), animals were sacrificed and perfused with cold PBS. The following tissues were collected: heart and brain (stored for possible future analysis), in accordance with Table 4.• Plasma and tissue samples were processed for analysis by LC / MS / MS to determine the amounts / concentrations.TABLE 4 - Sample Collection Design

[0204] c) Results:• Compound 4 was effectively administered. Similar plasma exposure levels were seen irrespective of the mode of administration.• For the plasma samples where the animals were dosed at 10 mg / kg (PO or SC), detectable levels of Compound 4 were still observed at 24 hours (SC; data not shown). With reference to Fig. 9, for the animals administered test articles orally, the plasma exposure was comparable for Compound 4 and vatiquinone.• For the blood plasma samples where the animals were dosed at 1 mg / kg intravenous (IV), Compound 4 was detectable for up to 8 hours (data not shown).• Therefore, the data suggests that an efficacious dose can be delivered to the subject without regard to the mode of administration (z.e., intravenous, subcutaneous, or oral administration).• Brain tissue analysis was performed only on the PO administered rats and the result was below the lowest level of quantification for 2 of 3 samples tested. Accordingly, all that can be said is that Compound 4 was detected in one of the three brain samples tested but further investigation is warranted. For the one result that was positive, the amount of Compound 4 in the brain tissue was commensurate with the amount seen for other of the Compounds described herein.• Irrespective of the mode of administration, Compound 4 was well tolerated at the dosing levels examined in this study.Example 5: In Vivo Plasma & Tissue Uptake Assays In Mouse and Rat (Compounds 5 & 61I. ASSESSMENT OF THE PHARMACOKINETICS OF COMPOUND 5 ANDCOMPOUND 6 FOLLOWING FIVE DAILY SUBCUTANEOUS DOSES TO MALE C57BL / 6MICE

[0205] a) Dosing Protocol:• Animals: Male / C57Bl / 6 mice / - 18-25 grams were received from an approved vendor.• Fasting was not required for this study.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• This was a multiple dose terminal study dosed once per day over 5 days. Mice were taken down following their 5thand final dose.• Doses were administered in accordance with test facility standard operating procedures. Post-dose flushes were administered as applicable.• All dose syringes were weighed prior to and following dosing to gravimetrically determine the amount of formulation administered.• All animals were observed at dosing and each scheduled collection. Any abnormalities were recorded.• Pre-formulated Compound 5 and Compound 6 were provided in a ready to be administered form for each day in accordance with the Study Design set forth in Table 5, below.TABLE 5 - Study DesignSC = subcutaneous

[0206] b) Sample collection - Post Dosing:• Terminal blood samples were collected via cardiac puncture following inhalation of anesthesia in accordance with test facility standard operating procedures.• Blood samples were collected into tubes with appropriate anticoagulant. The tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5 °C for 10 minutes) within 20 minutes of collection. Sample aliquots of 100 pL were transferred into individual uniquely labeled matrix tubes and stored at nominal -80 °C until transferred to analytical chemistry for analysis by LC / MS / MS.• Immediately following each terminal blood collection for all groups, animals were sacrificed and perfused with cold PBS. The following tissues were collected: heart and brain in accordance with Table 6.• Plasma and tissue samples were processed for analysis by LC / MS / MS to determine the amounts / concentrations reported in the Figs. 10-13.TABLE 6 - Sample Collection Design

[0207] c) Results: Results are discussed below and presented graphically in Figs. 10-13. It is also worth noting that administration of Compound 5 and Compound 6 was well- tolerated under the concentrations and conditions employed.II. AN ASSESSMENT OF THE PHARMACOKINETICS OF COMPOUND 5FOLLOWING REPEATED (5 DAYS) SUBCUTANEOUS DOSE ADMINISTRAHON TO MALE SPRAGUE DA WLEY RATS

[0208] a) Dosing Protocol:• Animals: Rat / Sprague Dawley / Male / Naive 225-250 grams were received from an approved vendor.• Fasting was not required for this study.• Body weights were recorded prior to dose administration. The volume of each dose delivered (mL / kg) was based on each individual animal's body weight.• This was a multiple dose terminal study dosed once per day over 5 days. Rats were taken down following their 5thand final dose.• Doses were administered in accordance with test facility standard operating procedures. Post-dose flushes were administered as applicable.• All dose syringes were weighed prior to and following dosing to gravimetrically determine the amount of formulation administered.• All animals were observed at dosing and each scheduled collection. Any abnormalities were recorded.• Pre-formulated Compound 5 was provided by Study sponsor ready to be dosed for each day in accordance with the Study Design set forth in Table 7, below.TABLE 7 - Study DesignSC = subcutaneous

[0209] b) Sample collection - Post Dosing:• Terminal blood samples were collected via cardiac puncture following inhalation anesthesia in accordance with test facility standard operating procedures.• Blood samples were collected into tubes with appropriate anticoagulant. Tubes were stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5°C for 10 minutes) within 20 minutes of collection. Sample aliquots of 100 pL were transferred into individual uniquely labeled matrix tubes and stored at nominal -80 °C until transferred to analytical chemistry for analysis.• Immediately following each terminal blood collection for all groups, animals were sacrificed and perfused with cold PBS. The following tissues were collected: heart and brain, in accordance with Table 8.• Plasma and tissue samples were processed for analysis by LC / MS / MS to determine the amounts / concentrations reported in the Figures.TABLE 8 - Sample Collection Design

[0210] c) Results: Are discussed below in Section III and presented graphically in Fig. 11. It is also worth noting that administration of Compound 5 was well -tolerated under the concentrations and conditions employed.III. RELEVANT RESULTS OF THE MOUSE AND RAT PK EXPERIMENTS

[0211] With reference to Fig. 10, the plasma concentrations of Compound 5 (dosed both at 20 mg / kg and 60 mg / kg dosing) and Compound 6 (dosed only 60 mg / kg dosing) are plotted from 30 minutes to 24 hours post-administration. Because the route of administration is subcutaneous injection (SC), the drug (i.e., each of Compounds 5 and 6) needs to migrate to be taken up into the blood stream to provide for potentially efficacious tissue dosing. The data demonstrates that both Compound 5 and Compound 6 migrate into the blood stream of the mouse plasma and that higher dosing elicits an approximately proportional increase in plasma concentrations. Furthermore, the plasma concentrations drop off over time as would be expected as they are cleared from the subject.

[0212] In Fig. 11, the data obtained with Compound 5 for plasma concentrations for the 20 mg / kg dose in mouse is graphically compared with the data obtained at 10 mg / kg dosing (also Compound 5) in rats over the period of 30 minutes to 24 hours post administration. Because the comparison is between species (i.e., mouse and rat), these doses are approximately equal if you base them on mg / m2of body area (i.e., in this case 60 mg / m2) of each species. With reference to Fig. 11, the data suggests that uptake of Compound 5 to plasma resulting from SC dosing, as well as half-life, across the two species of mammal is essentially equivalent over the period tested.

[0213] Delivery of a drug to the heart can be difficult (See: Sahoo et al., Targeted Delivery of Therapeutic Agents to the Heart, Nat. Rev Cardiol., (2021) 18(6): 389-399). With reference to Fig. 12, the concentrations of Compound 5 (dosed both at 20 mg / kg and 60 mg / kg dosing) and Compound 6 (dosed only 60 mg / kg dosing) in heart tissue are plotted from 30 minutes to 24 hours post-administration. The data demonstrate that up to microgram quantities of drug per gram of heart tissue were found at up to 2 hours post (after 5 days of) drug administration and that clearance of the drugs from the tissues proceeded over time as expected. These data suggest that efficacious quantities of Compound 5 and Compound 6 can be delivered to heart tissue of mice under these dosing conditions.

[0214] Delivery of a drug to the brain can be difficult because the blood-brain barrier or BBB protects the brain (and other central nervous system (CNS) tissues) against the penetration of certain types of molecules. With reference to Fig. 13, the concentrations of Compound 5 (dosed both at 20 mg / kg and 60 mg / kg dosing) and Compound 6 (dosed only 60 mg / kg dosing) in brain tissue are plotted from 30 minutes to 24 hours post-administration. The data demonstrate that up to microgram quantities of drug per gram of brain tissue were found up to 2 hours post (after 5 days of) drug administration and that clearance of the drugs from the tissues proceeded over time as expected. These data suggests that efficacious quantities of Compound 5 and Compound 6 can be delivered to brain tissue of mice under these dosing conditions. d) Summary / Discussion of Results:• Both Compound 5 and Compound 6 were well-tolerated at dose levels up to 60 mg / kg in mouse (administered by SC injection).• Compound 5 dose scales well by allometry in rodents (20 mg / kg in mouse ~ 10 mg / kg in rat).• Compound 5 plasma exposure is approximately proportional to dose (compare data for 20 mg / kg and 60 mg / kg in mouse).• Concentrations achieved in the plasma and heart and brain tissues represent amounts expected to be efficacious for purposes of treatment, prevention, inhibition, amelioration, and / or delay in the onset of a-synucleinopathies or the signs or symptoms of a-synucleinopathies and neurodevel opmental and neurodegenerative aspects of the disease.Example 6: In Vivo Assessment of the Neuroprotective Effects of Compound 6 in a Mouse Model of a-synucleinopathy

[0215] This Example was designed to evaluate the potential neuroprotective effects of Compound 6 on dopaminergic neurons in a mouse model of an a-synucleinopathy.Purpose and Experimental Design:

[0216] This Example utilized a mouse model characterized by the overexpression of human a- synuclein associated with the A53T mutation (A53TaSYN). This mouse model exhibits a- synuclein accumulation and aggregation, resulting in the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the animal’s brain. To generate this model, stereotaxic microinjections of the adeno-associated virus (AAV) vector expressing A53TaSYN (a AAV-A53TaSYN conjugate) were injected directly into the SNpc of 9-week- old male C57bl / 6 mice. Specifically, IpL of the AAV-A53TaSYN conjugate was bilaterally injected into the SNpc to generate the disease affected mice. Treatment began one week later by once daily subcutaneous injection of Compound 6 (at either 20 mg / kg or 60 mg / kg, Compound 6 to body weight of the mice) and continued for 8 weeks (9 weeks post AAV injection) until the day of sacrifice of the mice. Mice with adeno-associated virus (AAV) vector conjugated to nano luciferase (AAV-Nluc) injected into the SNpc were used as a negative control (z.e., these mice should not develop the a-synuclein accumulation and aggregation expected to be seen in the disease-affected mice). Nine weeks after injection of AAV vector dosing (eight weeks after the commencement of administration of Compound 6), animals were sacrificed for endpoint analysis. On the last day of the in-life portion of the study, Compound 6 was administered at the requisite dose one hour prior to euthanasia, and terminal blood collection was conducted, post sacrifice, through cardiac puncture to collect samples for drug exposure levels and exploratory biomarkers. The collected blood wasprocessed into plasma and brains were collected for analysis. Endpoint analysis of the brains included histological examination of the anatomically relevant brain sections as described below. The experimental groups of mice and their treatment can be found in Table 9.

[0217] Brains were harvested after cardiac perfusion of the euthanized mice (regulated CO2) with cold phosphate buffered solution and 4% paraformaldehyde fixative. Fixed, whole brains were coronally sectioned and brain sections around the substantia nigra regions were chosen for immunohistochemical staining. Primary staining with the antibody for tyrosine hydroxylase (a well validated marker for dopamine neurons) was performed (Staining with Abeam anti-tyrosine hydroxylase antibody: PN ab76442). Post staining, individual labelled cells were counted in the substantia nigra pars compacta region only, using stereological method (Neuro-Lucida). Cell count analysis from successfully stained animal brains is illustrated graphically in Fig. 14.TABLE 9 - Experimental GroupsResults'.

[0218] With reference to Fig- 14, there was a statistically significant drop in dopamine neuron count between animals treated with vehicle and the AAV-control (AAV-Nluc) and those treated with vehicle and the disease inducing vector conjugate (AAV-A53TaSYN). This data suggests that the disease inducing vector was active in the mice and the control vector was not. By comparison, there was a statistically significant increase in dopamine neuron count when Compound 6 was administered to the disease infected animals daily at 20 mg / kg dosing (P<0.05) and a larger statistically significant increase in dopamine neuron count when Compound 6 was administered to the disease infected animals daily at 60 mg / kg dosing (P<0.001). This data suggests a dose response. It is noteworthy that daily administration of the 60 mg / kg dose may have nearly or completely reversed the biological effect of the disease inducing vector conjugate (AAV-A53TaSYN) in at least some of the mice studied. Accordingly, this data demonstrates that administration of Compound 6 iscapable of treating, preventing, ameliorating, inhibiting or delaying the onset of an a- synucleinopathy in subjects in need thereof.EQUIVALENTS

[0219] The present technology is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present technology is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this present technology is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0220] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0221] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

[0222] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0223] Other embodiments are set forth within the following claims.

Claims

CLAIMSWhat is claimed is:

1. A method for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 6, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or a mixture of two or more of Compounds 1 to 6, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates of any one or more of Compounds 1 to 6, wherein Compound 6 is:wherein Compound 3 is:wherein Compound 4 is:wherein Compound 5 is:

2. The method of claim 1, wherein the subject has been diagnosed as having an a- synucleinopathy.

3. The method of claim 1 or claim 2, wherein the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

4. The method of any one of claims 1 to 3, wherein the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

5. The method of any one of claims 1 to 4, wherein the subject is a mammal.

6. The method of claim 5, wherein the mammalian subject is a human.

7. The method of any one of claims 1 to 6, wherein the Compound, or mixture ofCompounds, is administered orally or subcutaneously.

8. The method of any one of claims 1 to 6, wherein the Compound, or mixture of Compounds, is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

9. The method of any one of claims 1 to 8, further comprising separately, sequentially, or simultaneously administering at least one additional therapeutic agent to the subject.

10. The method of claim 9, wherein the additional therapeutic agent(s) comprises levodopa, optionally in combination with carbidopa (LODOSYN®).

11. The method of claim 9 or claim 10, wherein the combination of the Compound, or mixture of Compounds, and the at least one additional therapeutic agent has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

12. The method of any one of claims 1 to 11, wherein administration of the Compound or mixture of Compounds to the subject, optionally including administration of the at least one additional therapeutic agent(s), prolongs survival of the subject as compared with an untreated subject or an untreated control group of subjects.

13. The method of any one of claims 1 to 11, wherein administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects.

14. The method of any one of claims 1 to 11, wherein administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) the a- synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects.

15. The method of claim 14, wherein administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects.

16. The method of claim 14, wherein administration of the Compound, or mixture of Compounds, to the subject, optionally including administration of the at least one additional therapeutic agent(s), attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

7. Use of a Compound, or mixture of Compounds, in the preparation of a composition or medicament for treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, wherein the Compound, or the Compounds present in the mixture of Compounds, is / are selected from the group consisting of Compound 6, Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate of any one or more of the selected Compounds 1 to 6, wherein Compound 6 is:wherein Compound 1 is:wherein Compound 4 is:wherein Compound 5 is:

18. The use of claim 17, wherein the subject has been diagnosed as having an a- synucleinopathy.

19. The use of claim 17 or claim 18, wherein the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), Multiple System Atrophy (MSA).

20. The use of any one of claims 17 to 19, wherein the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

21. The use of any one of claims 17 to 20, wherein the subject is a mammal.

22. The use of claim 21, wherein the mammalian subject is a human.

23. The use of any one of claims 17 to 22, wherein the composition or medicament is formulated for administration orally or subcutaneously.

24. The use of any one of claims 17 to 22, wherein the composition or medicament is formulated for administration, topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

25. The use of any one of claims 17 to 24, further comprising separately, sequentially, or simultaneously administering an additional therapeutic agent to the subject.

26. The use of claim 25, wherein the additional therapeutic agent(s) comprises levodopa, optionally in combination with carbidopa (LODOSYN®).

27. The use of claim 25 or claim 26, wherein the combination of the composition or medicament and the at least one additional therapeutic agent(s) has a synergistic effect on treating, preventing, inhibiting, ameliorating, or delaying the onset of the a- synucleinopathy.

28. The use of any one of claims 17 to 27, wherein administration of the composition or medicament to the subject prolongs survival of the subject, as compared with an untreated subject or an untreated control group of subjects.

29. The use of any one of claims 17 to 27, wherein administration of the composition or medicament to the subject improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects30. The use of any one of claims 17 to 27, wherein administration of the composition or medicament to the subject attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects.

31. The use of claim 30, wherein administration of the composition or medicament to the subject attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects.

32. The use of claim 30, wherein administration of the composition or medicament to the subject attenuates (e.g, reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

33. A Compound or a mixture of Compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate of any one or more of Compounds 6, 1, 2, 3, 4, or 5, for use in treating, preventing, inhibiting, ameliorating, or delaying the onset of an a-synucleinopathy in a subject in need thereof, wherein the Compound, or Compounds present in the mixture of Compounds, is / are selected from the group consisting of Compound 6, Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5, wherein Compound 6 is:wherein Compound 3 is:wherein Compound 4 is:wherein Compound 5 is:

34. The Compound, or mixture of Compounds, for the use according to claim 33, wherein the subject has been diagnosed as having an a-synucleinopathy.

35. The Compound, or mixture of Compounds, for the use according to claim 33 or claim 34, wherein the a-synucleinopathy is Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA).

36. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 35, wherein the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy comprises attenuating (e.g., reducing) the loss of dopaminergic neurons in the subject as compared to an untreated control subject or an untreated control group of subjects.

37. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 36, wherein the subject is a mammal.

38. The Compound, or mixture of Compounds, for the use according to claim 37, wherein the mammalian subject is a human.

39. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 38, wherein the compound is formulated for administration orally or subcutaneously.

40. The Compound, or mixture of Compounds, for the use according to any one of 33 to 38, wherein the compound is formulated for administration topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

41. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 40, wherein the Compound or mixture of Compounds is separately, sequentially, or simultaneously used with at least one additional therapeutic agent.

42. The Compound, or mixture of Compounds, for the use according to claim 41, wherein the additional therapeutic agent comprises levodopa, optionally in combination with carbidopa (LODOSYN®).

43. The Compound, or mixture of Compounds, for the use according to claim 41 or claim 42, wherein the combination of the Compound(s) and the at least one additionaltherapeutic agent has a synergistic effect in the treating, preventing, inhibiting, ameliorating, or delaying the onset of the a-synucleinopathy.

44. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 43, wherein administration of the Compound(s) to the subject, optionally including administration of the additional therapeutic agent(s), prolongs survival of the subject, as compared with an untreated subject or an untreated control group of subjects.

45. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 43, wherein administration of the Compound(s) to the subject, optionally including administration of the additional therapeutic agent(s), improves the motor function (e.g., gait) of the subject as compared to an untreated control subject or an untreated control group of subjects.

46. The Compound, or mixture of Compounds, for the use according to any one of claims 33 to 43, wherein administration of the Compound(s) to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) the a-synucleinopathy pathology in the substantia nigra of the subject as compared to an untreated control subject or an untreated control group of subjects.

47. The Compound, or mixture of Compounds, for the use according to claim 46, wherein administration of the Compound(s) to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) reactive astrogliosis and / or glial scar formation in the subject as compared to an untreated control subject or an untreated control group of subjects.

48. The Compound, or mixture of Compounds, for the use according to claim 46, wherein administration of the Compound(s) to the subject, optionally including administration of the additional therapeutic agent(s), attenuates (e.g., reduces) reactive microgliosis in the subject as compared to an untreated control subject or an untreated control group of subjects.

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