Bodipy for reducing the progression of Parkinson's disease

Abstract

The present disclosure relates to the c-Abl inhibitor, bodovatinib, or a pharmaceutically acceptable salt thereof, for use in the treatment, delay, inhibition, or suppression of progression of neurodegenerative diseases, preferably early Parkinson's disease, in a subject.

Description

Technical Field

[0001] This application claims the benefit of Indian Provisional Patent Application No. 202221025575, filed on May 2, 2022, and Indian Provisional Patent Application No. 202221062155, filed on November 1, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a method for treating and / or reducing the progression of neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), synucleinopathy, Lewy body dementia (LBD), rapid eye movement (REM), sleep behavior disorder, multiple system atrophy (MSA), early Parkinson's disease, early Alzheimer's disease, early synucleinopathy, early Lewy body dementia, early rapid eye movement, early sleep behavior disorder, and early multiple system atrophy in a subject (e.g., a human subject in need thereof) by administering a c-Abl inhibitor (e.g., bodevatinib, or a pharmaceutically acceptable salt thereof) to the subject.

Background Art

[0003] Neurodegenerative diseases (NDs) occur when nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. Although these diseases cannot be completely cured, there are some drugs that are used to alleviate some of the symptoms associated with the diseases (Fernando et al. Pharmaceuticals. 2018, 11, 44).

[0004] For patients with progressive neurodegenerative diseases, some surgical procedures are options, but these procedures are risky for the elderly population (the population most frequently affected by the progressive stages of neurodegenerative diseases) and do not stop the progression of the disease.

[0005] Nilotinib has been tested for the treatment of Parkinson's disease in three randomized clinical trials (see, for example, Pagan et al., JAMA Neurol., 2020;77(3):309-317; Simuni et al., medRxiv preprint, May 12, 2020. See also Turner et al., Annals Neurology 88(1):183-194, 2020). Nilotinib showed improvement in some cerebrospinal fluid (CSF) biomarker levels, but was shown to have no clinical benefit as its effectiveness against motor outcomes was insufficient (Xie et al., Front Aging Neurosci. 2022, 14:996217).

[0006] Nilotinib has also been shown to fail to slow the progression of Parkinson's disease (PD) (Simuni et al. JAMA Neurol., 2021;78(3):312-320). The concentration of nilotinib in cerebrospinal fluid (CSF) was found to be 7-fold lower than that of c-Abl IC 50 Therefore, the failure of nilotinib at the maximum tolerated dose of 300 mg was due to insufficient brain penetration. Simuni specifically states that low CSF exposure, lack of biomarker effect, and the trend of negative efficacy data indicate that nilotinib should not be further tested in Parkinson's disease.

[0007] Bodovatinib (N'-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide), a c-Abl inhibitor, is represented by formula I (hereinafter referred to interchangeably as bodovatinib or a compound of formula I). [Chemical formula]

[0008] International Publication Numbers WO2017 / 208267A1, WO2020 / 250133A1, and WO2022 / 024072A1, which are incorporated herein by reference, disclose respective methods of using compounds of Formula I for the treatment of Parkinson's disease, synucleinopathy, and Alzheimer's disease (AD).

[0009] There is a continuing need for effective and safe methods for the treatment and delaying the progression of neurodegenerative diseases, including early-stage diseases.

[0010] Objectives of the Invention One objective of the present invention is a method for the treatment and delaying the progression of neurodegenerative diseases (including early neurodegenerative diseases) in a human subject in need thereof, and more specifically, a method for the treatment and / or delaying the progression of Parkinson's disease (such as early Parkinson's disease), Alzheimer's disease, and other synucleinopathies associated with c-Abl. Further, an objective of the present invention is to provide a very effective and safe method for the treatment of neurodegenerative diseases in a human subject, preferably for the treatment of Parkinson's disease, more preferably for the treatment of early Parkinson's disease. Another objective of the present invention is to provide a method for reducing the rate of progression of early Parkinson's disease. Another objective of the present invention is to provide a method for reducing the rate of progression of movement disorders caused by Parkinson's disease. Another objective of the present invention is to provide a method for regulating or maintaining autonomic function in a subject (e.g., human) having early Parkinson's disease. Another objective of the present invention is to provide a method for reducing a decrease in autonomic function in a subject (e.g., human) having early Parkinson's disease.

[0011] Another objective of the present invention is a method for treating or delaying or inhibiting or suppressing the progression of a neurodegenerative disease (e.g., Parkinson's disease) in a subject. An objective of the present invention is to provide a method for treating a neurodegenerative disease, or delaying or inhibiting or suppressing the progression of a neurodegenerative disease, wherein the subject is diagnosed at an early stage of the disease.

[0012] Yet another object of the present invention is a method for retarding the progression of Parkinson's disease in a subject. Another specific object of the present invention is a method for reducing the rate of progression of Parkinson's disease in a subject, wherein the subject is diagnosed at an early stage of the disease.

[0013] Yet another object is a method for eliminating symptoms associated with a neurodegenerative disease in a subject in need thereof. In particular, the object is to provide a method for eliminating symptoms associated with a neurodegenerative disease or an early neurodegenerative disease in a subject, wherein the subject is at an early stage of the disease. More specifically, the object is to provide a method for eliminating symptoms associated with Parkinson's disease in a subject, wherein the subject is at an early stage of the disease.

[0014] Yet another object of the present invention is the use of a c-Abl inhibitor for any of the objects and / or methods described herein.

[0015] Yet another object of the present invention is a compound of formula I,

Chemical formula

[0016] Another object of the present invention is to provide a c-Abl inhibitor that is effective and safe for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject in need thereof. Accordingly, an object of the present invention is to provide a c-Abl inhibitor for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, which delays the progression of the neurodegenerative disease, reduces the rate of progression of the disease, or eliminates symptoms associated with the neurodegenerative disease in a subject at an early stage of the disease.

[0017] Another object of the present invention is a pharmaceutical composition for treating or delaying the progression of a neurodegenerative disease in a subject in need thereof, which is an effective and safe pharmaceutical composition. Preferably, the composition effectively reduces the rate of progression of the disease or eliminates symptoms associated with the neurodegenerative disease in a subject in the early stages of the disease.

[0018] Yet another object of the present invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for any of the objects and / or methods described herein.

Summary of the Invention

[0019] The inventors have surprisingly found that in a subject (e.g., a human subject), bodovatinib delays (or reduces the rate of progression of) the progression of a neurodegenerative disease, particularly early Parkinson's disease.

[0020] One aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting, or suppressing its progression in a subject (e.g., a human subject) in need thereof by administering (e.g., an effective amount of) a c-Abl inhibitor to the subject.

[0021] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) or delaying, inhibiting, or suppressing its progression in a subject (e.g., a human subject) in need thereof, the method comprising administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits a disease severity according to a modified Hoehn and Yahr severity of ≤2.

[0022] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) or delaying, inhibiting, or suppressing its progression in a subject (e.g., a human subject) in need thereof, the method comprising administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits at least a 25 Montreal Cognitive Assessment score.

[0023] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing its progression, in a subject (e.g., a human subject) in need thereof, the method comprising administering to the subject a c-Abl inhibitor (e.g., an effective amount), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0024] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing its progression, in a subject (e.g., a human subject) in need thereof, the method comprising administering to the subject a c-Abl inhibitor (e.g., an effective amount), wherein the subject has received treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0025] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing its progression, in a subject (e.g., a human subject) in need thereof, the method comprising administering to the subject a c-Abl inhibitor (e.g., an effective amount), wherein the subject is not using a symptomatic treatment drug for Parkinson's disease in combination.

[0026] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing its progression, in a subject (e.g., a human subject) in need thereof, the method comprising administering to the subject a c-Abl inhibitor (e.g., an effective amount), wherein the subject i) has a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), iii) has abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 and has a body mass index. v) Initial diagnosis of neurodegenerative diseases (such as Parkinson's disease or early Parkinson's disease), vi) The subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) The subject is not using symptomatic therapy drugs for neurodegenerative diseases (such as Parkinson's disease or early Parkinson's disease) in combination, viii) The subject has not received dopamine agonist therapy for at least 30 days before administration, ix) The subject is diagnosed as having "clinically likely neurodegenerative disease" (such as "clinically likely Parkinson's disease" or "clinically likely early Parkinson's disease") according to the MDS clinical diagnostic criteria, and x) The subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0027] Another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) or delaying, inhibiting, or suppressing its progression in a subject (such as a human subject) in need thereof, the method comprising administering to the subject a compound of formula I (for example, an effective amount), and the subject i) Disease severity ≦ 2 according to the modified Hoehn and Yahr severity, ii) Dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), iii) Abnormal alpha-synuclein deposition determined by skin biopsy, iv) The subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and has a body mass index, v) Initial diagnosis of neurodegenerative diseases (such as Parkinson's disease or early Parkinson's disease), vi) The subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic drug for a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as having "clinically probable neurodegenerative disease" (such as "clinically probable Parkinson's disease" or "clinically probable early Parkinson's disease") according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0028] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) or delaying, inhibiting, or suppressing its progression in a subject (such as a human subject) in need thereof, the method comprising administering to the subject a c-Abl inhibitor (such as an effective amount), and the subject i) has a disease severity of ≤2 according to the modified Hoehn and Yahr severity, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≥18.5 kg / m 2 and ≤45 kg / m 2 and has a body mass index, v) has an initial diagnosis of Parkinson's disease, vi) the subject has received treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic drug for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as having "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0029] In a preferred embodiment, the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0030] For a compound to be effective in the treatment of a neurodegenerative disease, it needs to be present in the brain in an effective amount. Although some c-Abl inhibitors have been shown to be present in the brain, they have not shown much effect in the treatment of neurodegenerative diseases. For example, nilotinib is not effective in patients with Parkinson's disease at the administered doses (150 and 300 mg), and one reason for its failure is thought to be the lack of sufficient CSF exposure [see Simuni et al. JAMA Neurol., 2021;78(3):312-320]. Higher doses are limited because they may cause cardiovascular toxicity.

[0031] Surprisingly, the inventors have found that the compounds of formula I exhibit higher CSF exposure when administered at a therapeutically effective amount compared to other c-Abl inhibitors.

[0032] Furthermore, the inventors unexpectedly found that when the compound of formula I is administered to a subject at a therapeutically effective amount, the ratio of the concentration of the compound of formula I or a pharmaceutically acceptable salt thereof in the CSF to the IC 50 of c-Abl inhibition is greater than or equal to 1. This is particularly surprising because this ratio is approximately 0.2 when nilotinib is administered at the highest dose, which is much lower than the ratio when the lowest therapeutically effective amount of the compound of formula I is administered.

[0033] Furthermore, the inventors also observed that when the compound of formula I is administered at a therapeutically effective amount, it results in a plasma concentration that provides CSF exposure that is safe and effective for the treatment, or delay, inhibition, or suppression of the progression of a neurodegenerative disease.

[0034] Accordingly, in one embodiment, the present invention provides a method for treating a neurodegenerative disease or for delaying, inhibiting, or suppressing its progression, the method comprising administering to a subject in need thereof (e.g., orally) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0035] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an average plasma AUC in the range of about 5000 ng*h / mL to about 75000 ng*h / mL 0-24

[0036] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject (e.g., a human) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an average plasma AUC in the range of about 20,000 ng*h / mL to about 60,000 ng*h / mL 0-24

[0037] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15000 ng / mL max

[0038] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a plasma C in the range of about 1800 ng / mL to about 12,000 ng / mL max

[0039] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ​​​​A method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve

[0040] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the cerebrospinal fluid C in the range of about 2.0 ng / mL to about 7.0 ng / mL max A method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve

[0041] In one embodiment of any of the methods and uses described herein, the subject (e.g., a human) has cerebrospinal fluid C within 6 hours from the administration of the compound of formula I or a pharmaceutically acceptable salt thereof max to achieve.

[0042] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a cerebrospinal concentration in the range of about 0.2 ng / mL to about 2.7 ng / mL

[0043] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a cerebrospinal concentration in the range of about 0.6 ng / mL to about 2.7 ng / mL

[0044] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the average cerebrospinal C in the range of about 0.3 ng / mL to about 4.0 ng / mL avg A method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve

[0045] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the average cerebrospinal C in the range of about 2.0 ng / mL to about 3.0 ng / mL avgA method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of brain spinal cord C to IC50.

[0046] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of brain spinal cord C to IC50 for one or more cAbl inhibitions. max A method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of brain spinal cord C to IC50.

[0047] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an average ratio of brain spinal cord C to IC50 for 1 to 14 cAbl inhibitions. max A method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of brain spinal cord C to IC50.

[0048] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of C to IC50 greater than 5. max to IC 50 A method comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio.

[0049] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to pass through the blood-brain barrier.

[0050] In one embodiment of any of the methods and uses described herein, neurodegenerative diseases include, but are not limited to, Parkinson's disease (PD), Alzheimer's disease (AD), synucleinopathy, Lewy body dementia (LBD), rapid eye movement (REM) sleep behavior disorder, multiple system atrophy (MSA), early Parkinson's disease, early Alzheimer's disease, early synucleinopathy, early Lewy body dementia, early rapid eye movement, early sleep behavior disorder, and early multiple system atrophy.

[0051] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has received an initial diagnosis of a neurodegenerative disease. In a preferred embodiment, the subject (e.g., a human) has received an initial diagnosis of Parkinson's disease.

[0052] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has received an initial diagnosis of a neurodegenerative disease within 3 years from the start of treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the progression of a neurodegenerative disease in a subject (e.g., a human).

[0054] In one embodiment of any of the methods and uses described herein, reduction of the progression of a neurodegenerative disease is achieved by increasing the time to progression from part 1 to part 2 score to part 2 to part 3 score in a subject (e.g., a human), as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS - UPDRS).

[0055] Yet another embodiment is a method for reducing the rate of progression of a neurodegenerative disease or reducing the worsening of symptoms of a neurodegenerative disease, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the reduction is achieved by increasing the time to progression from part 1 to part 2 score to part 2 to part 3 score in a subject (e.g., a human), as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS - UPDRS). In a preferred embodiment, the time to progression to part 1 to part 2 score in a subject (e.g., a human) increases by at least 40 weeks. In another embodiment, the time to progression to part 2 to part 3 score in a subject (e.g., a human) increases by at least 40 weeks.

[0056] In one embodiment of any of the methods and uses described herein, the progression time from the score of part 1 to the score of part 2 in a subject (e.g., a human) increases by at least 40 weeks.

[0057] In one embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the rate of progression of a neurodegenerative disease. In another embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the rate of progression of a movement disorder resulting from a neurodegenerative disease in a subject (e.g., a human). In yet another embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof modulates or maintains autonomic function in a human subject having a neurodegenerative disease.

[0058] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has a neurodegenerative disease and the disease severity is ≤2 according to the modified Hoehn and Yahr severity. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has received treatment with a monoamine oxidase B (MAOB) inhibitor. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has not received dopamine treatment other than a monoamine oxidase-B (MAO-B) inhibitor. In another embodiment of any of the methods and uses described herein, a subject (e.g., a human) has not received dopamine agonist therapy for at least 30 days prior to administration. In yet another embodiment of any of the methods and uses described herein, a subject (e.g., a human) exhibits a Montreal Cognitive Assessment score of at least 25. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is not concomitantly using a symptomatic therapy drug for Parkinson's disease. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is diagnosed as "clinically highly likely to have Parkinson's disease" according to the MDS clinical diagnostic criteria. In another embodiment of any of the methods and uses described herein, a subject (e.g., a human) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) exhibits abnormal alpha-synuclein deposition as determined by skin punch biopsy. In one embodiment of any of the methods and uses described herein, the neurodegenerative disease (e.g., Parkinson's disease) is an early neurodegenerative disease (e.g., early Parkinson's disease).

[0059] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has received an initial diagnosis of Parkinson's disease.

[0060] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the progression of Parkinson's disease in a subject (e.g., a human).

[0062] In one embodiment of any of the methods and uses described herein, reduction of the progression of Parkinson's disease is achieved by increasing the time to progression from the score of part 1 to part 2 to the score of part 2 to part 3 in a subject (e.g., a human), as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS - UPDRS).

[0063] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or reducing the worsening of symptoms of Parkinson's disease, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the reduction is achieved by increasing the time to progression from the score of part 1 to part 2 to the score of part 2 to part 3 in a subject (e.g., a human), as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS - UPDRS). In a preferred embodiment, the time to progression to the score of part 1 to part 2 in a subject (e.g., a human) increases by at least 40 weeks. In another embodiment, the time to progression to the score of part 2 to part 3 in a subject (e.g., a human) increases by at least 40 weeks.

[0064] In one embodiment of any of the methods and uses described herein, the time to progression from the score of part 1 to part 2 to the score of part 2 to part 3 in a subject (e.g., a human) increases by at least 40 weeks.

[0065] In one embodiment of any of the methods and uses described herein, Parkinson's disease is early Parkinson's disease. In one embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the rate of progression of early Parkinson's disease. In another embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the rate of progression of movement disorders resulting from Parkinson's disease in a human subject suffering from early Parkinson's disease. In yet another embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof modulates or maintains autonomic function in a human subject having early Parkinson's disease. In another embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof reduces the rate of decline of autonomic function due to early Parkinson's disease.

[0066] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) has early Parkinson's disease and the disease severity by modified Hoehn and Yahr severity ≦ 2.

[0067] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is undergoing treatment with a monoamine oxidase B (MAOB) inhibitor. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is not undergoing dopamine treatment other than a monoamine oxidase-B (MAO-B) inhibitor. In another embodiment of any of the methods and uses described herein, a subject (e.g., a human) has not undergone dopamine agonist therapy for at least 30 days prior to administration. In yet another embodiment of any of the methods and uses described herein, a subject (e.g., a human) exhibits a Montreal Cognitive Assessment score of at least 25. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is not concomitantly using symptomatic therapy drugs for Parkinson's disease. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is diagnosed as "clinically highly likely to have Parkinson's disease" according to the MDS clinical diagnostic criteria. In another embodiment of any of the methods and uses described herein, a subject (e.g., a human) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) exhibits abnormal alpha-synuclein deposition as determined by skin punch biopsy.

[0068] In one embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof prolongs the time to significant worsening of a subject (e.g., a human) in parts II and III of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

[0069] In yet another embodiment of any of the methods and uses described herein, administration of a compound of formula I or a pharmaceutically acceptable salt thereof prolongs the time to significant worsening of a subject (e.g., a human) in parts I, II, and III of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

[0070] In yet another embodiment of any of the methods and uses described herein, administration of the compound of formula I or a pharmaceutically acceptable salt thereof slows the progression of the overall severity of Parkinson's disease in a subject (e.g., a human) as measured by the Clinical Global Impression - Severity (CGIS) scale.

[0071] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state at least 1 hour prior to administration. In yet another embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state at least 2 hours prior to administration.

[0072] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fed state. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered the compound of formula I or a pharmaceutically acceptable salt thereof immediately after completion of a meal, preferably 10 minutes later, more preferably 30 minutes later.

[0073] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is 50 years of age or older. In yet another embodiment of any of the methods and uses described herein, a subject (e.g., a human) is 20 years of age or older.

[0074] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is not concomitantly using a dopamine replacement drug.

[0075] In yet another embodiment of any of the methods and uses described herein, a subject (e.g., a human) is ≧18.5 kg / m2 and ≤ 45 kg / m 2 has a fatness index of

[0076] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered from about 5 mg to about 480 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered from about 48 mg to about 480 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, a subject (e.g., a human) is administered about 48 mg or 96 mg or 144 mg or 192 mg or 240 mg or 288 mg or 336 mg or 384 mg or 432 mg or 480 mg. In a preferred embodiment, a subject (e.g., a human) is administered from about 134 mg to about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, a subject (e.g., a human) is administered about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is administered about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of a solid dosage form.

[0078] In one embodiment of any of the methods and uses described herein, if an adverse event occurs, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is reduced by half.

[0079] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally.

[0080] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily.

[0081] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0082] In one embodiment of any of the methods and uses described herein, a subject (e.g., a human) is (i) at least 50 years old, (ii) has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with the compound of formula I or a pharmaceutically acceptable salt thereof, (iii) has a modified Hoehn and Yahr severity score of 2 or less, and (iv) has not received dopamine treatment other than a monoamine oxidase - B (MAO - B) inhibitor. Yet another aspect is a method for performing it in a subject (e.g., a human subject) in need of treatment of a neurodegenerative disease (such as Parkinson's disease) or delay, inhibition, or suppression of progression, the method comprising administering to the subject the compound of formula I or a pharmaceutically acceptable salt thereof (e.g., an effective amount).

Chemical formula

[0083] Yet another aspect is a method for performing it in a subject (e.g., a human subject) in need of treatment of a neurodegenerative disease (such as Parkinson's disease) or delay, inhibition, or suppression of progression, the method comprising administering to the subject the compound of formula I or a pharmaceutically acceptable salt thereof (e.g., an effective amount),

Chemical formula

[0084] Yet another aspect is a method for performing it in a subject (e.g., a human subject) in need of treatment of a neurodegenerative disease (such as Parkinson's disease) or delay, inhibition, or suppression of progression, the method comprising administering to the subject the compound of formula I or a pharmaceutically acceptable salt thereof (e.g., an effective amount),

Chemical formula

[0085] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing progression thereof, in a subject (e.g., a human subject) in need thereof, comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., an effective amount). [Chemical formula] A method wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0086] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing progression thereof, in a subject (e.g., a human subject) in need thereof, comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., an effective amount). [Chemical formula] A method wherein the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0087] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease), or delaying, inhibiting, or suppressing progression thereof, in a subject (e.g., a human subject) in need thereof, comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., an effective amount). [Chemical formula] A method wherein the subject is not using a symptomatic treatment drug for Parkinson's disease in combination.

[0088] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical formula] to a subject (e.g., a human) in need thereof, in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, preferably about 20,000 ng*h / mL to about 60,000 ng*h / mL, more preferably about 15,000 ng*h / mL to about 55,000 ng*h / mL 0-24 (e.g., orally).

[0089] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical formula] to a subject (e.g., a human) in need thereof, in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity,

[0090] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical formula] to a subject (e.g., a human) in need thereof, in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24administering in an amount sufficient to achieve (e.g., orally), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25, a method.

[0091] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0092] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0093] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0094] Yet another aspect is a method of treating or slowing, inhibiting, or preventing the progression of a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I, or a pharma- ceutical acceptable salt thereof, to a patient of the present invention. [ka] In human subjects in need thereof, a mean plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and administering (e.g., orally) to the subject in an amount sufficient to achieve i) disease severity score ≦2 according to the modified Hoehn-Yahre scale; ii) dopamine transporter single-photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease; iii) abnormal synuclein deposits as determined by skin biopsy; iv) Subjects have a body mass of ≥ 18.5 kg / m 2 And ≦45kg / m 2 having a body mass index of v) early diagnosis of Parkinson's disease; vi) The subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor; vii) The subject is not taking any symptomatic medication for Parkinson's disease. viii) subjects have not received dopamine agonist therapy for at least 30 days prior to dosing; ix) The subject has been diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more of the following: a Montreal Cognitive Assessment score of at least 25 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0095] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0096] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0097] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0098] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0099] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0100] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0101] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chem.

[0102] Yet another aspect is a method of treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof,

Chem.

[0103] Yet another aspect is a method of treating a neurodegenerative disease (e.g., Parkinson's disease), or delaying, inhibiting, or suppressing its progression, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof

Chemical formula

[0104] Yet another aspect is a method of treating a neurodegenerative disease (e.g., Parkinson's disease), or delaying, inhibiting, or suppressing its progression, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof

Chemical formula

[0105] ​​Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical Formula] in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL (e.g., orally), wherein the subject exhibits at least a 25 - Montreal Cognitive Assessment score. In a preferred embodiment, the subject achieves CSF C max within 6 hours of administration of the compound of formula I or a pharmaceutically acceptable salt thereof. max

[0106] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical Formula] in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL (e.g., orally), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In a preferred embodiment, the subject achieves CSF C max within 6 hours of administration of the compound of formula I or a pharmaceutically acceptable salt thereof. max

[0107] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical Formula] ​​administering to a subject in need thereof an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL (e.g., orally), wherein the subject is undergoing treatment with a monoamine oxidase-B (MAO-B) inhibitor. In a preferred embodiment, the subject achieves CSF C within 6 hours of administration of the compound of formula I or a pharmaceutically acceptable salt thereof. max max

[0108] Yet another aspect is a method of treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof

Chemical formula

[0109] Yet another aspect is a method of treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), or delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof

Chemical formula

[0110] In one embodiment of any of the methods and uses described herein, the subject achieves cerebrospinal fluid C within 6 hours from the administration of the compound of formula I or a pharmaceutically acceptable salt thereof max to achieve.

[0111] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof

Chemical formula

[0112] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof [Chemical] A method comprising administering to a subject in need thereof, in an amount sufficient to achieve a CSF concentration of at least about 0.6 ng / mL to about 2.7 ng / mL (e.g., orally).

[0113] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof [Chemical] A method comprising administering to a subject in need thereof, in an amount sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL (e.g., orally), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0114] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof [Chemical] A method comprising administering to a subject in need thereof, in an amount sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL (e.g., orally), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0115] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof [Chemical] Administering to a subject in need thereof, in an amount sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL (e.g., orally), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, is a method.

[0116] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0117] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0118] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0119] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof

Chemical formula

[0120] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0121] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0122] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0123] ​​​Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0124] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0125] Yet another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof,

Chemical formula

[0126] ​​​Another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease (e.g., Parkinson's disease), the method comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, [Chemical Formula] to a subject in need thereof in an amount sufficient to achieve an average CSF C of from about 0.3 ng / mL to about 4.0 ng / mL (e.g., orally), wherein the subject avg has i) a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal alpha-synuclein deposition as determined by a skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 and v) an early diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not receiving concomitant symptomatic medications for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0127] Another aspect of the invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, max wherein the average CSF C of c-Abl inhibition 50Administering to a subject (e.g., a human subject) in need thereof, in an amount sufficient to achieve a ratio of 1 or more, a c-Abl inhibitor (e.g., brivanib or a pharmaceutically acceptable salt thereof) (e.g., orally).

[0128] Another aspect of the invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject (e.g., a human subject) in need thereof, in an amount sufficient to achieve a ratio of average CSF C of c-Abl inhibition max to IC 50 of 1 or more, a c-Abl inhibitor (brivanib or a pharmaceutically acceptable salt thereof) (e.g., orally), wherein the subject exhibits a disease severity of ≦2 according to the modified Hoehn and Yahr severity.

[0129] Another aspect of the invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject (e.g., a human subject) in need thereof, in an amount sufficient to achieve a ratio of average CSF C of c-Abl inhibition max to IC 50 of 1 or more, a c-Abl inhibitor (brivanib or a pharmaceutically acceptable salt thereof) (e.g., orally), wherein the subject exhibits at least 25 Montreal Cognitive Assessment scores.

[0130] Another aspect of the invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject (e.g., a human subject) in need thereof, in an amount sufficient to achieve a ratio of average CSF C of c-Abl inhibition max to IC 50 of 1 or more, a c-Abl inhibitor (brivanib or a pharmaceutically acceptable salt thereof) (e.g., orally), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0131] Another aspect of the invention is a method of treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, comprising administering to a subject (e.g., a human subject) in need thereof a c-Abl inhibitor (bortezomib or a pharmaceutically acceptable salt thereof) (e.g., orally) in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject is undergoing treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0132] Another aspect of the invention is a method of treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, comprising administering to a subject (e.g., a human subject) in need thereof a c-Abl inhibitor (bortezomib or a pharmaceutically acceptable salt thereof) (e.g., orally) in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject is not using a symptomatic therapy drug for Parkinson's disease.

[0133] Yet another aspect of the invention is a method of treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, the method comprising administering to a subject (e.g., a human subject) in need thereof a c-Abl inhibitor (e.g., orally) in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject i) has a disease severity according to the modified Hoehn and Yahr severity of ≦ 2, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and v) has an initial diagnosis of Parkinson's disease, vi) the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic drug for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0134] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject (e.g., a human subject) in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof i) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , or iii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , and a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max (e.g., orally) in an amount sufficient to achieve the same.

[0135] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject (e.g., a human subject) in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof i) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , or iii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24and plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering in an amount sufficient to achieve (e.g., orally), a method in which the subject exhibits a disease severity of disease severity due to the modified Horn - Yard ≤ 2.

[0136] Yet another aspect of the present invention is a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, i) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max or iii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering in an amount sufficient to achieve (e.g., orally), a method in which the subject exhibits at least a 25 - point Montreal Cognitive Assessment score.

[0137] Yet another aspect of the present invention is a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, i) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max or iii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering in an amount sufficient to achieve (e.g., orally), A method wherein the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0138] Yet another aspect of the present invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, i) having an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) having a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , or iii) having an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , and having a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max in an amount sufficient to achieve (e.g., orally), wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0139] Yet another aspect of the present invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, i) having an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) having a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , or iii) having an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , and having a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max in an amount sufficient to achieve (e.g., orally), The method is one in which the subject is not concomitantly using a symptomatic therapeutic drug for Parkinson's disease.

[0140] Another aspect of the invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject (e.g., a human subject) in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof i) at an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , ii) at a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , or iii) at an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , and at a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max in an amount sufficient (e.g., orally) to achieve, wherein the subject i) has a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition as determined by a skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 , v) has an early diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic drug for Parkinson's disease, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0141] Another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor to a subject in need thereof (e.g., a human subject), a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, max achieving, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally),

[0142] Another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor to a subject in need thereof (e.g., a human subject), a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, max achieving, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity,

[0143] Another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor to a subject in need thereof (e.g., a human subject), a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL d) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or e) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), and d), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0144] Yet another aspect of the invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof a) to cross the blood-brain barrier b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL d) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or e) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), and d), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0145] Yet another aspect of the invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof a) to cross the blood-brain barrier b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or e) administering in a sufficient amount (e.g., orally) for any combination of a), b), c), and d), wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor, a method.

[0146] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof, a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or e) administering in a sufficient amount (e.g., orally) for any combination of a), b), c), and d), wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, a method.

[0147] Yet another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, the method comprising administering a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof, a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) the average CSF C of c-Abl inhibition max versus IC 50achieve a ratio of 1 or more, or e) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), and d), wherein the subject i) has a disease severity of ≦ 2 according to the severity of the modified Hoehn and Yahr, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and has a body mass index, v) has an initial diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO - B) inhibitor, vii) the subject is not concomitantly using symptomatic therapy drugs for Parkinson's disease, viii) the subject has not received dopamine agonist therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of having a Montreal Cognitive Assessment score of at least 25.

[0148] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of Formula I or a pharmaceutically acceptable salt thereof, a) passing through the blood - brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, max c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving a ratio of the average CSF C of c - Abl inhibition to IC max of 1 or more, or 50 achieve a ratio of 1 or more, or e) administering orally in an amount sufficient for any combination of a), b), c), and d).

[0149] Yet another aspect of the present invention is a method of treating, delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max and c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0150] Yet another aspect of the present invention is a method of treating, delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max and c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0151] Another aspect of the present invention is a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, which comprises administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to cross the blood-brain barrier (e.g., orally).

[0152] Another aspect of the present invention is a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, which comprises administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally), wherein the subject has received an initial diagnosis of Parkinson's disease.

[0153] Another aspect of the present invention is a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, which comprises administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally), wherein the subject has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with the compound of formula I or a pharmaceutically acceptable salt thereof.

[0154] Another aspect of the present invention is a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, which comprises administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof a) that crosses the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max thereof, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), A method in which the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease.

[0155] Yet another aspect of the present invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, max achieving, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0156] Yet another aspect of the present invention is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) passing through the blood-brain barrier, b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, max achieving, c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) achieving an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), wherein the subject is not concomitantly using a symptomatic therapy drug for Parkinson's disease.

[0157] Another aspect is a method of treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof, a) that crosses the blood-brain barrier, b) that achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, max c) that achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, d) that achieves an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or e) administering in an amount sufficient for any combination of a), b), c), and d) (e.g., orally), wherein the subject i) has a disease severity of ≦ 2 according to the modified Hoehn and Yahr severity, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and, v) has an early diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor,

[0158] vii) the subject is not concomitantly using symptomatic medications for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores. ​

[0159] Another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject in need thereof (e.g., a human subject), a c-Abl inhibitor, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 thereof, b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max thereof, c) passing through the blood-brain barrier, d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max thereof, e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) achieving a ratio of average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) administering in an amount sufficient (e.g., orally) for any combination of a), b), c), d), e), and f).

[0160] Another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject in need thereof (e.g., a human subject), a c-Abl inhibitor, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 thereof, b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max thereof, c) passing through the blood-brain barrier, d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max thereof, e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) achieving a ratio of average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), a method in which the subject exhibits a disease severity of ≦ 2 according to the severity of the modified Hoehn - Yahr.

[0161] Another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, the method comprising administering a c - Abl inhibitor to a subject (e.g., a human subject) in need thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passing through the blood - brain barrier, d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) achieving an average CSF C of c - Abl inhibition max versus IC 50 to a ratio of 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), a method in which the subject exhibits at least a 25 - point Montreal Cognitive Assessment score.

[0162] Another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, the method comprising administering a c - Abl inhibitor to a subject (e.g., a human subject) in need thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passing through the blood - brain barrier, ​​​​​d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; f) achieving an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), wherein the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, a method.

[0163] Another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passing through the blood-brain barrier, d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; f) achieving an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), wherein the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, a method.

[0164] Another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject in need thereof (e.g., a human subject), a c-Abl inhibitor, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passing through the blood-brain barrier d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) administering in an amount sufficient (e.g., orally) for any combination of a), b), c), d), e), and f), wherein the subject is not concurrently using a symptomatic treatment drug for Parkinson's disease.

[0165] Yet another aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject in need thereof (e.g., a human subject), a c-Abl inhibitor, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passing through the blood-brain barrier d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) achieving an average CSF C of c-Abl inhibition max to IC 50achieve a ratio of 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), wherein the subject i) has a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 and v) has an initial diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO - B) inhibitor, vii) the subject is not concomitantly using symptomatic therapy drugs for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of having a Montreal Cognitive Assessment score of at least 25.

[0166] Another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject (e.g., a human subject) in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max and c) passing through the blood - brain barrier, d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mLmax to achieve e) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or g) a method comprising administering to a subject in need thereof (e.g., a human subject), in a sufficient amount for any combination of a), b), c), d), e), and f) (e.g., orally).

[0167] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject), a compound of formula I or a pharmaceutically acceptable salt thereof, a) to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 to achieve b) to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max to achieve c) to cross the blood-brain barrier d) to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve e) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or g) comprising administering in a sufficient amount for any combination of a), b), c), d), e), and f) (e.g., orally), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn-Yahr severity.

[0168] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject), a compound of formula I or a pharmaceutically acceptable salt thereof, a) An average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 is achieved, b) Plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max is achieved, c) Passes through the blood-brain barrier, d) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max is achieved, e) Achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) The ratio of the average CSF C of c-Abl inhibition max to IC 50 is achieved to be 1 or more, or g) Includes administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), wherein the subject exhibits at least a 25-monotrial cognitive assessment score, a method.

[0169] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of Formula I or a pharmaceutically acceptable salt thereof, a) An average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 is achieved, b) Plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max is achieved, c) Passes through the blood-brain barrier, d) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max is achieved, e) Achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) The ratio of the average CSF C of c-Abl inhibition max to IC 50 is achieved to be 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), A method in which a subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0170] Yet another aspect of the present invention is a method of treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of Formula I or a pharmaceutically acceptable salt thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passing through the blood-brain barrier d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) average CSF C of c-Abl inhibition max versus IC 50 achieving a ratio of 1 or more, or g) administering in a sufficient amount (e.g., orally) in any combination of a), b), c), d), e), and f), A method in which a subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0171] Yet another aspect of the present invention is a method of treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of Formula I or a pharmaceutically acceptable salt thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL​​​​max achieving c) passing through the blood-brain barrier d) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max achieving e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) average CSF C of c-Abl inhibition max versus IC 50 achieving a ratio of 1 or more, or g) including administering in a sufficient amount (e.g., orally) for any combination of a), b), c), d), e), and f), wherein the subject is not concurrently using a symptomatic therapeutic agent for Parkinson's disease.

[0172] Yet another aspect of the present invention is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, the method comprising administering to a subject in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 achieving b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max achieving c) passing through the blood-brain barrier d) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max achieving e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) average CSF C of c-Abl inhibition max versus IC 50 achieving a ratio of 1 or more, or g) including administering in a sufficient amount (e.g., orally) for any combination of a), b), c), d), e), and f), wherein the subject i) disease severity ≦ 2 according to the modified Hoehn and Yahr severity ii) Dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) Abnormal synuclein deposition determined by skin biopsy, iv) The subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 and has a body mass index, v) Initial diagnosis of Parkinson's disease, vi) The subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) The subject is not using symptomatic medications for Parkinson's disease, viii) The subject has not received dopaminergic drug therapy for at least 30 days prior to dosing, ix) The subject is diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0173] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and achieves an average plasma AUC, b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max and achieves a plasma C, c) crosses the blood-brain barrier, d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max and achieves a CSF C, e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) achieves a ratio of average CSF C of c-Abl inhibition max to IC 50 of 1 or greater, or g) Use comprising a c-Abl inhibitor in an amount sufficient for any combination of a), b), c), d), e), and f).

[0174] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) achieves a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) comprises a c-Abl inhibitor in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0175] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL​​​​​max to achieve e) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or g) containing a c-Abl inhibitor in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25, for use.

[0176] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 to achieve b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max to achieve c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve e) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or g) containing a c-Abl inhibitor in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, for use.

[0177] Another aspect is the use of a c-Abl inhibitor for the preparation of an agent for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the agent a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) achieves a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) contains the c-Abl inhibitor in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0178] Another aspect is the use of a c-Abl inhibitor for the preparation of an agent for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the agent a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) the average CSF C of c-Abl inhibitionmax for an IC 50 to achieve a ratio of 1 or more, or g) containing a c-Abl inhibitor in a sufficient amount for any combination of a), b), c), d), e), and f), wherein the subject is not using a symptomatic treatment drug for Parkinson's disease, is a use.

[0179] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 to achieve b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max to achieve c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) the average CSF C of c-Abl inhibition max for an IC 50 to achieve a ratio of 1 or more, or g) containing a c-Abl inhibitor in a sufficient amount for any combination of a), b), c), d), e), and f), wherein the subject i) disease severity ≦ 2 according to the severity of modified Hoehn and Yahr, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and has a body mass index, v) an initial diagnosis of Parkinson's disease, vi) the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapy drug for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to dosing, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0180] Yet another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier, d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) achieves a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f).

[0181] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) achieves an average CSF C for c-Abl inhibition max to IC 50 ratio of 1 or more, or g) contains a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity, is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0182] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) the average CSF C of c-Abl inhibition max versus IC 50 achieving a ratio of 1 or more, or g) containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25, which is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0183] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL c) passes through the blood-brain barrier, max d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) the average CSF C of c-Abl inhibition max versus IC achieving a ratio of 1 or more, or f) the average CSF C of c-Abl inhibition max versus IC 50 achieving a ratio of 1 or more, or g) containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, which is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0184] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL f) achieves a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more, or g) contains a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject is undergoing treatment with a monoamine oxidase-B (MAO-B) inhibitor, a compound of formula I or a pharmaceutically acceptable salt thereof.

[0185] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) the average CSF C of c-Abl inhibition max versus IC 50 and achieving a ratio of 1 or more, or g) containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, which is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0186] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the medicament a) achieves an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieves a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passes through the blood-brain barrier, d) achieves a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieves a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, f) the average CSF C of c-Abl inhibition max versus IC 50 and achieving a ratio of 1 or more, or g) containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient for any combination of a), b), c), d), e), and f), wherein the subject i) has a disease severity ≦ 2 according to the modified Hoehn & Yahr severity, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) Abnormal synuclein deposition determined by skin biopsy, iv) The subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and has a body mass index within this range, v) An initial diagnosis of Parkinson's disease, vi) The subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) The subject is not concomitantly using symptomatic therapy drugs for Parkinson's disease, viii) The subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) The subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0187] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of the progression, of a neurodegenerative disease in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves a CSF C max to IC 50 ratio of 1 or more, and comprises administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a CSF C

[0188] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of the progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves a CSF C max to IC 50 ratio of 1 or more.

[0189] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio of 1 or greater, and the subject exhibits a disease severity of ≦2 according to the modified Hoehn and Yahr severity.

[0190] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio of 1 or greater, and the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0191] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio of 1 or greater, and the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0192] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio of 1 or more and the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0193] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio of 1 or more and the subject is not using a symptomatic therapy drug for Parkinson's disease in combination.

[0194] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof safely achieves a CSF C max to IC 50 ratio of 1 or more, and the subject i) has a disease severity of ≤2 according to the modified Hoehn and Yahr severity, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition as determined by a skin biopsy, iv) the subject has a 2 and ≤45 kg / m2 having a body mass index of v) early diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not taking symptomatic medications for Parkinson's disease concomitantly, viii) the subject has not received dopaminergic pharmacotherapy for at least 30 days prior to dosing, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0195] Another aspect of the invention is a method for reducing the rate of progression of early neurodegenerative disease in a subject (e.g., a human subject), the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50 ratio of 1 or more.

[0196] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50 ratio of 1 or more.

[0197] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of to of 1 or more, wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity, a method.

[0198] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), comprising administering to the subject a CSF C of c-Abl inhibition max vs. IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of to of 1 or more, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25, a method.

[0199] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), comprising administering to the subject a CSF C of c-Abl inhibition max vs. IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of to of 1 or more, wherein the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, a method.

[0200] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), comprising administering to the subject a CSF C of c-Abl inhibition max vs. IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of to of 1 or more, wherein the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, a method.

[0201] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), comprising administering to the subject a CSF C of c-Abl inhibitionmax for an IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of for an IC of 1 or more, wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease.

[0202] Yet another aspect of the invention is a method for reducing the rate of progression of an early neurodegenerative disease, preferably early Parkinson's disease, in a subject (e.g., a human subject), the method comprising administering to the subject a CSF C of c-Abl inhibition max for an IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of for an IC of 1 or more, wherein the subject i) disease severity according to modified Hoehn and Yahr severity ≤ 2, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal alpha-synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and has a body mass index, v) an initial diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopamine agonist therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0203] Another aspect of the invention is a method for reducing the rate of progression of an early neurodegenerative disease, preferably early Parkinson's disease, the method comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max The method includes administering in an amount sufficient to achieve the above.

[0204] Another aspect of the invention is a method for reducing the rate of progression of an early neurodegenerative disease, preferably early Parkinson's disease, the method comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max The method includes administering in an amount sufficient to achieve the above, and the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0205] Another aspect of the invention is a method for reducing the rate of progression of an early neurodegenerative disease, preferably early Parkinson's disease, the method comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max The method includes administering in an amount sufficient to achieve the above, and the subject exhibits at least 25 Montreal Cognitive Assessment scores.

[0206] Another aspect of the invention is a method for reducing the rate of progression of an early neurodegenerative disease, preferably early Parkinson's disease, the method comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, a method.

[0207] Another aspect of the invention is a method for reducing the rate of progression of early neurodegenerative diseases, preferably early Parkinson's disease, comprising administering to a subject in need thereof (e.g., a human subject) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, wherein the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, a method.

[0208] Another aspect of the invention is a method for reducing the rate of progression of early neurodegenerative diseases, preferably early Parkinson's disease, comprising administering to a subject in need thereof (e.g., a human subject) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, wherein the subject is not using a symptomatic therapeutic agent for Parkinson's disease in combination, a method.

[0209] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases, preferably Parkinson's disease, more preferably early Parkinson's disease, or the delay, inhibition, or suppression of progression in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has an average plasma AUC in the range of about 30,000 ng*h / mL to about 50,000 ng*h / mL 0-24 and / or a plasma C in the range of about 3,000 ng / mL to about 7,000 ng / mL max is a compound of formula I or a pharmaceutically acceptable salt thereof that achieves.

[0210] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases, preferably Parkinson's disease, more preferably early Parkinson's disease, or the delay, inhibition, or suppression of progression in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has an average plasma AUC in the range of about 40,000 ng*h / mL to about 60,000 ng*h / mL 0-24 and / or a plasma C in the range of about 5,000 ng / mL to about 9,000 ng / mL max is a compound of formula I or a pharmaceutically acceptable salt thereof that achieves.

[0211] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases, preferably Parkinson's disease, more preferably early Parkinson's disease, or the delay, inhibition, or suppression of progression in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has an average plasma AUC in the range of about 15,000 ng*h / mL to about 40,000 ng*h / mL 0-24 and / or a plasma C in the range of about 1,000 ng / mL to about 4,000 ng / mL max is a compound of formula I or a pharmaceutically acceptable salt thereof that achieves.

[0212] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression, of a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject), wherein the compound of formula I or a pharmaceutically acceptable salt thereof has an average plasma AUC in the range of about 25,000 ng*h / mL to about 50,000 ng*h / mL 0-24 and / or a plasma C in the range of about 2,000 ng / mL to about 6,000 ng / mL max is achieved, which is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0213] Yet another aspect of the invention is a method for reducing the rate of progression of an early neurodegenerative disease, preferably early Parkinson's disease, the method comprising administering (e.g., orally) to a subject (e.g., a human subject) in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max wherein the subject has i) a disease severity of ≦2 according to the modified Hoehn and Yahr severity ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease iii) abnormal alpha-synuclein deposition as determined by a skin biopsy iv) the subject has a body mass index of ≧18.5 kg / m and ≦45 kg / m 2 and ≦45 kg / m 2 v) an early diagnosis of Parkinson's disease vi) the subject is not receiving treatment with a monoamine oxidase B (MAO-B) inhibitor vii) the subject is not receiving a symptomatic treatment drug for Parkinson's disease viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration ix) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0214] Another aspect of the invention is a method of reducing the rate of progression of an early neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of Formula I or a pharmaceutically acceptable salt thereof, a) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; c) achieving an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or e) administering in an amount sufficient for any combination of a), b), and c) (e.g., orally).

[0215] Another aspect of the invention is a method of reducing the rate of progression of an early neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of Formula I or a pharmaceutically acceptable salt thereof, a) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; c) achieving an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, or d) including administering in an amount sufficient for any combination of a), b), and c) (e.g., orally), wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0216] Another aspect of the present invention is a method for reducing the rate of progression of early neurodegenerative diseases, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; c) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more; or d) administering in an amount sufficient for any combination of a), b), and c) (e.g., orally), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0217] Another aspect of the present invention is a method for reducing the rate of progression of early neurodegenerative diseases, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; c) achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more; or d) administering in an amount sufficient for any combination of a), b), and c) (e.g., orally), wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0218] Another aspect of the present invention is a method for reducing the rate of progression of early neurodegenerative diseases, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL maxto achieve b) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL c) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or d) administering in a sufficient amount (e.g., orally) for any combination of a), b), and c), wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor, a method.

[0219] Another aspect of the present invention is a method of reducing the rate of progression of an early neurodegenerative disease, comprising administering to a subject in need thereof (e.g., a human subject) a compound of formula I or a pharmaceutically acceptable salt thereof, a) to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve b) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL c) the average CSF C of c-Abl inhibition max versus IC 50 to achieve a ratio of 1 or more, or d) administering in a sufficient amount (e.g., orally) for any combination of a), b), and c), wherein the subject is not concurrently using a symptomatic therapeutic agent for Parkinson's disease, a method.

[0220] Yet another aspect is a method of reducing the rate of progression of an early neurodegenerative disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve b) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) administering in a sufficient amount (e.g., orally) to provide a ratio of the average CSF C of c-Abl inhibition max versus IC 50 of 1 or more, comprising wherein the subject is i) Disease severity ≤ 2 based on the severity of the modified Hoehn and Yahr, ii) Dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) Abnormal synuclein deposition determined by skin biopsy, iv) The subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and, v) Early diagnosis of Parkinson's disease, vi) Has received treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) Is not using symptomatic medications for Parkinson's disease in combination, viii) The subject has not received dopaminergic drug therapy for at least 30 days prior to dosing, ix) Is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) Exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores,

[0221] Another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, the composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, a) An average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) Plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) A CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or greater, The composition is a pharmaceutical composition for use in the treatment of a neurodegenerative disease, or for delaying, inhibiting, or suppressing progression thereof.

[0222] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for treating a neurodegenerative disease, or for delaying, inhibiting, or suppressing progression thereof in a subject, the composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof in a) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) a CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, wherein the subject is i) disease severity ≦ 2 according to the modified Hoehn and Yahr severity, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 , v) an initial diagnosis of Parkinson's disease, vi) receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) A pharmaceutical composition presenting one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0223] According to the present invention, the neurodegenerative diseases (ND) referred to herein include, but are not limited to, synucleinopathies such as Parkinson's disease (PD), Alzheimer's disease (AD), or Lewy body dementia (LBD), rapid eye movement (REM) sleep behavior disorder, and multiple system atrophy (MSA). In a preferred embodiment, the neurodegenerative disease is Parkinson's disease, more preferably early Parkinson's disease. In another embodiment, the neurodegenerative disease includes early stages of synucleinopathies including early Parkinson's disease (PD), early Alzheimer's disease (AD), and early Lewy body dementia (LBD), early rapid eye movement (REM) sleep behavior disorder, and early multiple system atrophy (MSA), but is not limited thereto, including early-stage neurodegenerative diseases.

[0224] Another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL. 0-24 A method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL.

[0225] Yet another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity. 0-24 A method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0226] Yet another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, wherein the subject exhibits at least a 25 - Montreal Cognitive Assessment score. 0-24 and the method is one where the subject is not concurrently using a symptomatic therapy drug for Parkinson's disease.

[0227] Yet another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, 0-24 wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0228] Yet another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, 0-24 wherein the subject is undergoing treatment with a monoamine oxidase B (MAO - B) inhibitor.

[0229] Yet another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, 0-24 wherein the subject is not concurrently using a symptomatic therapy drug for Parkinson's disease.

[0230] Yet another aspect is a method for treating Parkinson's disease (PD) or for doing so in a subject in need of delaying, inhibiting, or suppressing progression thereof, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, wherein the subject 0-24 has i) a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal alpha-synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 , v) an early diagnosis of Parkinson's disease, vi) is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores,

[0231] Another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing progression thereof, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max

[0232] Another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing its progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL, wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity. max

[0233] Another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing its progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL, max wherein the subject exhibits at least a 25 - point Montreal Cognitive Assessment score.

[0234] Another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing its progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL, max wherein the subject exhibits a dopamine transporter single - photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0235] Another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing its progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL, max wherein the subject is receiving treatment with a monoamine oxidase B (MAO - B) inhibitor.

[0236] ​Another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL, wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease. max

[0237] Yet another aspect is a method for treating Parkinson's disease or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL, wherein the subject max i) has a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 , v) has an early diagnosis of Parkinson's disease, vi) has received treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0238] ​​Another aspect is a method for treating Parkinson's disease, or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max This method includes administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve max .

[0239] Another aspect is a method for treating Parkinson's disease, or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve CSF C in the range of about 2 ng / mL to about 7 ng / mL. max This method includes administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve max .

[0240] Another aspect is a method for treating Parkinson's disease, or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, wherein the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity. max This method includes administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve max .

[0241] Another aspect is a method for treating Parkinson's disease, or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, wherein the subject exhibits at least 25 Montreal Cognitive Assessment scores. max This method includes administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve max .

[0242] Another aspect is a method for treating Parkinson's disease, or for doing so in a subject in need of delaying, inhibiting, or suppressing progression, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. maxadministering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, for example, orally, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0243] Another aspect is a method for doing so in a subject in need of treatment of Parkinson's disease or delay, inhibition, or suppression of progression, comprising CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, for example, orally, wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0244] Another aspect is a method for doing so in a subject in need of treatment of Parkinson's disease or delay, inhibition, or suppression of progression, comprising CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, for example, orally, wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease.

[0245] Yet another aspect is a method for doing so in a subject in need of treatment of Parkinson's disease or delay, inhibition, or suppression of progression, comprising CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve, for example, orally, wherein the subject i) disease severity according to modified Hoehn and Yahr severity ≤ 2, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m2 having a body mass index of v) being in the early diagnosis of Parkinson's disease, vi) having received treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) not being concomitantly administered a symptomatic therapeutic agent for Parkinson's disease, viii) the subject not having received dopaminergic drug therapy for at least 30 days prior to administration, ix) being diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) showing at least 25 Montreal Cognitive Assessment scores, one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of which are presented, a method.

[0246] Another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor to a subject in need thereof (e.g., orally) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 or more.

[0247] Yet another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor to a subject in need thereof (e.g., orally) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 or more, wherein the subject shows a disease severity of ≦2 according to the modified Hoehn and Yahr severity.

[0248] Still another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor to a subject in need thereof (e.g., orally) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 or more, wherein the subject shows at least 25 Montreal Cognitive Assessment scores.

[0249] Yet another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor (e.g., orally) to a subject in need thereof in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0250] Yet another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater to a subject in need thereof (e.g., orally), wherein the subject has received treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0251] Yet another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor (e.g., orally) to a subject in need thereof in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject is not using a symptomatic therapy drug for Parkinson's disease.

[0252] Yet another aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, comprising administering a c-Abl inhibitor in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater to a subject in need thereof (e.g., orally), wherein the subject i) disease severity according to the modified Hoehn and Yahr severity ≦ 2, ii) a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) Abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and has a body mass index, v) an initial diagnosis of Parkinson's disease, vi) has received treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not using a symptomatic therapy drug for Parkinson's disease in combination, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of at least 25 Montreal Cognitive Assessment scores, a method.

[0253] One aspect is a method of treating Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof (e.g., orally) a c-Abl inhibitor in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 to 14.

[0254] In a preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a ratio of C max to IC 50 greater than 5.

[0255] One aspect is a method for treating a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof (e.g., a human) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 to 14.

[0256] One aspect is a method for treating or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 to 14.

[0257] One aspect is a method for treating or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient (e.g., orally) to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 to 14, wherein the subject exhibits a disease severity of ≦2 according to the modified Hoehn and Yahr severity.

[0258] One aspect is a method for treating or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient (e.g., orally) to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 of 1 to 14, wherein the subject exhibits at least a Montreal Cognitive Assessment score of 25.

[0259] One aspect is a method for treating a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, which comprises administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 from 1 to 14 (e.g., orally), wherein the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0260] One aspect is a method for treating a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, which comprises administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 from 1 to 14 (e.g., orally), wherein the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0261] One aspect is a method for treating a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, which comprises administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient to achieve a ratio of mean CSF C of c-Abl inhibition max to IC 50 from 1 to 14 (e.g., orally), wherein the subject is not using a symptomatic therapy drug for Parkinson's disease in combination.

[0262] One aspect is a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease, or early Parkinson's disease, the method comprising administering to a subject in need thereof a c-Abl inhibitor (preferably the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof) in an amount sufficient to achieve a ratio of average CSF C max to IC 50 of 1 to 14, wherein the subject has i) a disease severity according to the modified Hoehn and Yahr severity of ≦ 2, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and, v) an initial diagnosis of Parkinson's disease, vi) is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not using a symptomatic therapy drug for Parkinson's disease in combination, viii) the subject has not received dopamine agonist therapy for at least 30 days prior to administration, ix) is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0263] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a ratio of C max to IC 50 greater than 5.

[0264] Yet another aspect is a method for treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression thereof, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a. achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b. achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c. passing through the blood-brain barrier d. achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e. achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f. administering in an amount sufficient to achieve a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more (e.g., orally).

[0265] Yet another aspect is a method for treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression thereof, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a. achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b. achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c. passing through the blood-brain barrier d. achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e. achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f. achieving a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more in an amount sufficient to achieve, and A method wherein the subject exhibits a disease severity of ≤ 2 according to the severity of the modified Hoehn - Yahr.

[0266] Yet another aspect is a method of treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passing through the blood - brain barrier d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f) administering in an amount sufficient to achieve an average CSF C for c - Abl inhibition max to IC 50 ratio of 1 or more (e.g., orally), wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0267] Yet another aspect is a method of treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max c) passing through the blood - brain barrier d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ​​​​​​e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL and / or f) administering (e.g., orally) in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. The method is one in which the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0268] Yet another aspect is a method of treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ; c) passing through the blood-brain barrier d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ; e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL and / or f) administering (e.g., orally) in an amount sufficient to achieve an average CSF C max to IC 50 ratio of 1 or greater, wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor. The method is one in which the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0269] Yet another aspect is a method of treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 ; b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max to achieve c) pass through the blood-brain barrier d) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve e) achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f) the average CSF C of c-Abl inhibition max versus IC 50 administering in an amount sufficient to achieve a ratio of 1 or more (e.g., orally), wherein the subject is not concurrently using a symptomatic therapy drug for Parkinson's disease, a method

[0270] Yet another aspect is a method of treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 to achieve b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max to achieve c) pass through the blood-brain barrier d) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to achieve e) achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f) the average CSF C of c-Abl inhibition max versus IC 50 administering in an amount sufficient to achieve a ratio of 1 or more (e.g., orally), wherein the subject i) disease severity according to the modified Hoehn and Yahr severity ≦ 2 ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease iii) Abnormal synuclein deposition determined by skin biopsy, iv) The subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 and has a body mass index, v) Early diagnosis of Parkinson's disease, vi) Receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) Not using symptomatic medications for Parkinson's disease in combination, viii) The subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) Diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) Exhibiting one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores, is a method.

[0271] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in a) achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and achieving, b) achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max and achieving, c) passing through the blood-brain barrier, d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max and achieving, e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f) containing in an amount sufficient to achieve a ratio of mean CSF C for c-Abl inhibition max to IC 50 of 1 or greater, wherein the medicament is used for the treatment of Parkinson's disease or early Parkinson's disease, or the delay, inhibition, or suppression of progression, is a method.

[0272] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating Parkinson's disease, or early Parkinson's disease, or delaying, inhibiting, or suppressing progression in a subject, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to a) achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 to be achieved, b) achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max to be achieved, c) pass through the blood-brain barrier, d) achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max to be achieved, e) achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or f) contain an amount sufficient to achieve an average CSF C of c-Abl inhibition max versus IC 50 in a ratio of 1 or more, wherein the subject i) has a disease severity of ≤2 according to the modified Hoehn and Yahr severity, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≥18.5 kg / m 2 and ≤45 kg / m 2 and, v) has an initial diagnosis of Parkinson's disease, vi) is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not concomitantly using symptomatic medications for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) A compound of formula I or a pharmaceutically acceptable salt thereof that exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the Montreal Cognitive Assessment scores of at least 25.

[0273] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease, or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression, wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio that safely achieves 1 or more, a compound of formula I or a pharmaceutically acceptable salt thereof.

[0274] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease, or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression, wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a CSF C max to IC 50 ratio that safely achieves 1 or more, and the subject has i) disease severity ≦ 2 according to the modified Hoehn and Yahr severity, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) abnormal alpha-synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and v) an initial diagnosis of Parkinson's disease, vi) has received treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not concomitantly using symptomatic medications for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) Diagnosed as "clinically highly probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) A compound of formula I or a pharmaceutically acceptable salt thereof that exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0275] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50 ratio of 1 or more.

[0276] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50 ratio of 1 or more, wherein the subject exhibits a disease severity of ≦2 according to the modified Hoehn and Yahr severity.

[0277] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50 ratio of 1 or more, wherein the subject exhibits at least 25 Montreal Cognitive Assessment scores.

[0278] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a CSF C max to IC 50administering a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of 1 or more, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0279] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a CSF C of c-Abl inhibition max versus IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of 1 or more, wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0280] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a CSF C of c-Abl inhibition max versus IC 50 administering a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve a ratio of 1 or more, wherein the subject is not using a symptomatic therapy drug for Parkinson's disease.

[0281] Another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment, or delay, inhibition, or suppression of progression of Parkinson's disease or early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof safely achieves a ratio of CSF C of c-Abl inhibition max versus IC 50 of 1 or more, wherein the subject i) disease severity ≦ 2 according to the modified Hoehn and Yahr severity ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease iii) abnormal synuclein deposition determined by skin biopsy iv) the subject has a body mass index of ≧ 18.5 kg / m2 and ≦ 45 kg / m 2 having a degree of obesity index of, v) early diagnosis of Parkinson's disease, vi) receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) not using a symptomatic treatment drug for Parkinson's disease in combination, viii) the subject not having received dopamine agonist therapy for at least 30 days prior to administration, ix) diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) showing a Montreal Cognitive Assessment score of at least 25, one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of which are exhibited by a compound of formula I or a pharmaceutically acceptable salt thereof.

[0282] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max This is a method that includes administration.

[0283] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max This method includes administration, and the subject shows a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0284] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max The subject exhibits at least a 25 - point Montreal Cognitive Assessment score.

[0285] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max The subject exhibits dopamine transporter single - photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0286] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max The subject is undergoing treatment with a monoamine oxidase B (MAO - B) inhibitor.

[0287] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve, wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, a method.

[0288] Another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the average plasma AUC is in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 and / or plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally) in an amount sufficient to achieve, wherein the subject i) disease severity ≦ 2 according to the modified Hoehn and Yahr severity, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) abnormal alpha-synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and has a body mass index, v) early diagnosis of Parkinson's disease, vi) is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) exhibits one or more (2, 3, 4, 5, 6, 7, 8, 9 or 10) of at least 25 Montreal Cognitive Assessment scores, a method.

[0289] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) an average CSF C of c-Abl inhibition max versus IC 50 in an amount sufficient to achieve a ratio of 1 or more, (e.g., orally).

[0290] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) an average CSF C of c-Abl inhibition max versus IC 50 in an amount sufficient to achieve a ratio of 1 or more, and the subject exhibits a disease severity ≦ 2 according to the modified Hoehn and Yahr severity.

[0291] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) an average CSF C of c-Abl inhibition max versus IC 50administering, in an amount sufficient to achieve a ratio of 1 or more, (e.g., orally), a method in which the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0292] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) the average CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, (e.g., orally), a method in which the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0293] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, the method comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) the average CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, (e.g., orally), a method in which the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0294] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) the average CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, (e.g., orally), wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease.

[0295] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, a) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or c) the average CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, (e.g., orally), wherein the subject i) has a disease severity of ≦2 according to the modified Hoehn and Yahr severity, ii) has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 , v) has an initial diagnosis of Parkinson's disease, vi) is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) not concomitantly using symptomatic drugs for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) presenting one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores, a method.

[0296] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for treating Parkinson's disease or early Parkinson's disease, or delaying, inhibiting, or suppressing progression in a subject, the composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, a) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, a pharmaceutical composition.

[0297] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for treating Parkinson's disease or early Parkinson's disease, or delaying, inhibiting, or suppressing progression in a human patient, the composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, a) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mLmax , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max versus IC 50 in an amount sufficient to achieve a ratio of 1 or more, A pharmaceutical composition, wherein the patient exhibits a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity.

[0298] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of Parkinson's disease or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression, in a human patient, wherein the composition comprises the compound of formula I or a pharmaceutically acceptable salt thereof in a) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max versus IC 50 in an amount sufficient to achieve a ratio of 1 or more, A pharmaceutical composition, wherein the patient exhibits a Montreal Cognitive Assessment score of at least 25.

[0299] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of Parkinson's disease or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression, in a human patient, wherein the composition comprises the compound of formula I or a pharmaceutically acceptable salt thereof in a) An average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) Plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) A CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max vs. IC 50 in an amount sufficient to achieve a ratio of 1 or more, A pharmaceutical composition, wherein the patient exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0300] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of Parkinson's disease or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression in a human patient, the composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof a) An average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) Plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) A CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max vs. IC 50 in an amount sufficient to achieve a ratio of 1 or more, A pharmaceutical composition, wherein the patient has received treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0301] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of Parkinson's disease or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression, in a human patient, wherein the composition comprises the compound of formula I or a pharmaceutically acceptable salt thereof, a) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, and the patient is not concomitantly using a symptomatic therapy drug for Parkinson's disease.

[0302] Yet another aspect is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of Parkinson's disease or early Parkinson's disease, or for delaying, inhibiting, or suppressing progression, in a human patient, wherein the composition comprises the compound of formula I, a) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , b) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , c) CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or e) CSF C of c-Abl inhibition max to IC 50 in an amount sufficient to achieve a ratio of 1 or more, and the subject is i) Disease severity ≤ 2 according to the severity of the modified Hoehn and Yahr, ii) Dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease, iii) Abnormal alpha-synuclein deposition determined by skin biopsy, iv) The subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and has a body mass index, v) Initial diagnosis of Parkinson's disease, vi) Receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) Not using symptomatic drugs for Parkinson's disease in combination, viii) The subject has not received dopaminergic drug therapy for at least 30 days before administration, ix) Diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) Exhibiting one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores, is a pharmaceutical composition.

[0303] Another aspect of the invention relates to a method of reducing the progression rate of Parkinson's disease or early Parkinson's disease in a human subject.

[0304] Another aspect of the invention is a method of reducing the progression rate of Parkinson's disease or early Parkinson's disease in a human subject, wherein the subject exhibits a disease severity ≤ 2 according to the severity of the modified Hoehn and Yahr.

[0305] Another aspect of the invention is a method of reducing the progression rate of Parkinson's disease or early Parkinson's disease in a human subject, wherein the subject exhibits at least 25 Montreal Cognitive Assessment scores.

[0306] Another aspect of the invention is a method of reducing the rate of progression of Parkinson's disease or early Parkinson's disease in a human subject, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0307] Another aspect of the invention is a method of reducing the rate of progression of Parkinson's disease or early Parkinson's disease in a human subject, wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0308] Another aspect of the invention is a method of reducing the rate of progression of Parkinson's disease or early Parkinson's disease in a human subject, wherein the subject is not concomitantly using symptomatic therapy drugs for Parkinson's disease.

[0309] Yet another aspect of the invention relates to a method of reducing the rate of progression of Parkinson's disease or early Parkinson's disease in a human subject, wherein the subject i) has a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, ii) exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition as determined by a skin biopsy, iv) the subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and v) has an early diagnosis of Parkinson's disease, vi) the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using symptomatic therapy drugs for Parkinson's disease, viii) the subject has not received dopamine agonist therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0310] Another aspect of the invention is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease in a subject (e.g., a human subject) having a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally). In a preferred embodiment, the subject is human. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0311] Another aspect of the invention is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease in a human subject having a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof once daily (e.g., orally).

[0312] Another aspect of the invention is a method for reducing the rate of progression of motor disorders caused by Parkinson's disease in a human subject suffering from early Parkinson's disease. Another aspect of the invention is a method for reducing the rate of progression of motor disorders caused by Parkinson's disease in a human subject suffering from early-stage Parkinson's disease, wherein the subject exhibits a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity.

[0313] Another aspect of the invention is a method for reducing the rate of progression of motor disorders caused by Parkinson's disease in a human subject suffering from early Parkinson's disease, wherein the subject exhibits at least 25 Montreal Cognitive Assessment scores.

[0314] Another aspect of the present invention is a method for reducing the rate of progression of movement disorders due to Parkinson's disease in a human subject suffering from early Parkinson's disease, wherein the subject exhibits dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0315] Another aspect of the present invention is a method for reducing the rate of progression of movement disorders due to Parkinson's disease in a human subject suffering from early Parkinson's disease, wherein the subject is undergoing treatment with a monoamine oxidase - B (MAO - B) inhibitor.

[0316] Another aspect of the present invention is a method for reducing the rate of progression of movement disorders due to Parkinson's disease in a human subject suffering from early Parkinson's disease, wherein the subject is not using symptomatic therapy drugs for Parkinson's disease in combination.

[0317] Another aspect of the present invention is a method for reducing the rate of progression of movement disorders due to Parkinson's disease in a human subject suffering from early Parkinson's disease, wherein the subject i) disease severity according to the modified Hoehn - Yahr severity ≤ 2, ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) abnormal alpha - synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and, v) early diagnosis of Parkinson's disease, vi) the subject is undergoing treatment with a monoamine oxidase B (MAO - B) inhibitor, vii) the subject is not using symptomatic therapy drugs for Parkinson's disease in combination, viii) the subject has not received dopamine agonist therapy for at least 30 days prior to administration. ix) the subject has been diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0318] Another aspect of the present invention is a method for reducing the progression rate of movement disorders caused by Parkinson's disease in a human subject suffering from early Parkinson's disease and having a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, the method comprising orally administering to the subject, once a day, an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0319] Yet another aspect of the present invention is a method for regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease. In one embodiment, the method comprises orally administering to the subject, for example, once a day, an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Yet another aspect of the present invention is a method for regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease, wherein the subject exhibits a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity.

[0320] Yet another aspect of the present invention is a method for regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease, wherein the subject exhibits at least 25 Montreal Cognitive Assessment scores.

[0321] Yet another aspect of the present invention is a method for regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease.

[0322] Yet another aspect of the present invention is a method of regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease, wherein the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0323] Yet another aspect of the present invention is a method of regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease, wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease.

[0324] Yet another aspect of the present invention is a method of regulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease, wherein the subject i) has a disease severity of ≤2 according to the modified Hoehn and Yahr severity, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal synuclein deposition determined by skin biopsy, iv) the subject has a body mass index of ≥18.5 kg / m 2 and ≤45 kg / m 2 and, v) has an early diagnosis of Parkinson's disease, vi) the subject is undergoing treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0325] In one embodiment, the method comprises orally administering to a subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, for example, once daily.

[0326] Yet another aspect is a method of modulating or maintaining autonomic function in a human subject having Parkinson's disease or early Parkinson's disease and a disease severity of ≦2 according to the modified Hoehn and Yahr severity, the method comprising orally administering to the subject once daily an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0327] Yet another aspect is a method of reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof. In one embodiment, the method comprises orally administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, for example, once daily.

[0328] Yet another aspect is a method of reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof, wherein the subject exhibits a disease severity of ≦2 according to the modified Hoehn and Yahr severity.

[0329] Yet another aspect is a method of reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof, wherein the subject exhibits at least a Montreal Cognitive Assessment score of 25.

[0330] Yet another aspect is a method of reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0331] Yet another aspect is a method of reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof, wherein the subject has received treatment with a monoamine oxidase B (MAO-B) inhibitor.

[0332] Yet another aspect is a method of reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof, wherein the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease.

[0333] Another aspect of the invention is a method of reducing the decline in autonomic function due to Parkinson's disease or early Parkinson's disease in a human subject in need thereof, wherein the subject i) has a disease severity of ≦ 2 according to the modified Hoehn and Yahr severity, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≧ 18.5 kg / m 2 and ≦ 45 kg / m 2 and has a body mass index, v) has an initial diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0334] In one embodiment, the method comprises administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, e.g., orally once daily.

[0335] Yet another aspect is a method for reducing the decline in autonomic function due to Parkinson's disease or early Parkinson's disease in a human subject who requires it and has a disease severity ≤ 2 according to the severity of the modified Hoehn and Yahr, the method comprising orally administering to the subject, once a day, an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. Yet another aspect is a method for treating early Parkinson's disease, wherein the subject i) has a disease severity ≤ 2 according to the severity of the modified Hoehn and Yahr, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition as determined by skin biopsy, iv) the subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and has a body mass index, v) has an initial diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using symptomatic therapeutic agents for Parkinson's disease, viii) the subject has not received dopaminergic drug therapy for at least 30 days prior to administration, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0336] In one embodiment, the method comprises orally administering to the subject, once a day, an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0337] Yet another aspect of the invention is a method of treating Parkinson's disease in a human subject having early Parkinson's disease and disease severity ≦ 2 according to the modified Hoehn and Yahr severity, comprising administering to the subject, once a day (e.g., orally), an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0338] Yet another aspect is a method of treating Parkinson's disease in a human subject, comprising administering to the subject, once a day (e.g., orally), (i) about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension, or (ii) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., about 134 or about 269 mg) in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves in the subject (i) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , or (iii) cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL avg , or is orally administered in an amount sufficient to achieve any combination of (i), (ii), (iii) and (iv). In one embodiment, the human subject has a disease severity ≦ 2 according to the modified Hoehn and Yahr severity. In one embodiment, the human subject exhibits at least a 25 Montreal Cognitive Assessment score. In one embodiment, the human subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In one embodiment, the human subject has received treatment with a monoamine oxidase-B (MAO-B) inhibitor. In one embodiment, the human subject is not using a symptomatic therapeutic agent for Parkinson's disease in combination.

[0339] Yet another aspect of the present invention is a method for reducing the progression rate of Parkinson's disease in a human subject, comprising orally administering to the subject once a day (i) about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension, or (ii) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., about 134 mg or about 269 mg) in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, or (iii) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., about 134 mg or about 269 mg) in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves in the subject (i) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , or (iii) cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL avg , or is orally administered in an amount sufficient to achieve any combination of (i), (ii), (iii), and (iv). In one embodiment, the human subject has a disease severity ≦ 2 according to the modified Hoehn and Yahr severity. In one embodiment, the human subject exhibits at least a 25 Montreal Cognitive Assessment score. In one embodiment, the human subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In one embodiment, the human subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor. In one embodiment, the human subject is not concomitantly using a symptomatic therapeutic agent for Parkinson's disease.

[0340] Yet another aspect of the invention is a method of reducing the rate of progression of movement disorders resulting from Parkinson's disease in a human subject, the method comprising administering to the subject (i) about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension, or (ii) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., about 134 or about 269 mg) in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, once daily orally, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves in the subject (i) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , or (iii) cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL avg , or is orally administered in an amount sufficient to achieve any combination of (i), (ii), (iii) and (iv). In one embodiment, the human subject has a disease severity ≦ 2 according to the modified Hoehn and Yahr severity. In one embodiment, the human subject exhibits at least a 25 Montreal Cognitive Assessment score. In one embodiment, the human subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In one embodiment, the human subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor. In one embodiment, the human subject is not concomitantly using a symptomatic therapy drug for Parkinson's disease.

[0341] Yet another aspect of the present invention is a method for reducing the decline in autonomic function due to Parkinson's disease in a human subject, the method comprising administering to the subject (i) about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension, or (ii) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., about 134 or about 269 mg) in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, once daily orally, wherein the compound of formula I or a pharmaceutically acceptable salt thereof, in the subject, (i) has a plasma C max in the range of about 500 ng / mL to about 15,000 ng / mL, (ii) has an average plasma AUC 0-24 in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL, or (iii) has a cerebrospinal fluid C max in the range of about 0.4 ng / mL to about 7.0 ng / mL, and (iv) has an average cerebrospinal fluid C avg in the range of about 0.3 ng / mL to about 4.0 ng / mL, or is orally administered in an amount sufficient to achieve any combination of (i), (ii), (iii) and (iv). In one embodiment, the human subject has a disease severity ≦2 according to the modified Hoehn and Yahr severity. In one embodiment, the human subject exhibits at least 25 Montreal Cognitive Assessment scores. In one embodiment, the human subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. In one embodiment, the human subject has received treatment with a monoamine oxidase-B (MAO-B) inhibitor. In one embodiment, the human subject is not concurrently using a symptomatic therapeutic agent for Parkinson's disease.

[0342] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a C max to IC 50 ratio greater than about 5, such as about 6, about 7, about 8, about 9, about 10, about 11, about 12, or about 13.

[0343] In one embodiment of any of the methods and uses described herein, the subject is diagnosed as "clinically likely to have Parkinson's disease" according to the MDS clinical diagnostic criteria. See, for example, Pasta et al., Movement Disorders, 30(12), 1591-1599, 2015. Considering multiple uses, the MDS-PD criteria include two different levels of diagnostic certainty.

[0344] 1. Clinically established PD: To maximize specificity, the category is fixed at the goal of having a majority (i.e., at least 90%) with PD. It is presumed that many true PD cases do not meet this level of certainty.

[0345] 2. Clinically probable PD: This category aims to balance sensitivity and specificity while having at least 80% of the patients diagnosed as possibly having PD truly having PD and identifying 80% of the true PD cases.

[0346] In one embodiment of any of the methods and uses described herein, the subject has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. See, for example, Akdemir et al., Turk. J. Med. Sci., 51(2)400-410, 2021.

[0347] In one embodiment of any of the methods and uses described herein, the subject exhibits abnormal alpha-synuclein deposition as determined by skin punch biopsy.

[0348] In one embodiment of any of the methods and uses described herein, administration of the compound of Formula I or a pharmaceutically acceptable salt thereof prolongs the time to significant worsening of the subject in MDS-UPDRS (Unified Parkinson's Disease Rating Scale) Parts II and III.

[0349] In one embodiment of any of the methods and uses described herein, administration of the compound of formula I or a pharmaceutically acceptable salt thereof prolongs the time to significant worsening of the subject in Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS - UPDRS) parts I, II, and III.

[0350] In one embodiment of any of the methods and uses described herein, the c - Abl inhibitor is administered to a human subject in an amount of about 192 mg to about 384 mg. Preferably, the c - Abl inhibitor is administered in the form of an aqueous suspension. More preferably, the c - Abl inhibitor is the compound of formula I or a pharmaceutically acceptable salt thereof.

[0351] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in an amount of about 192 mg to about 384 mg. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in an amount of about 192 mg. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in an amount of about 384 mg. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the form of an aqueous suspension. In yet another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in one or more dosage forms sufficient to achieve the same bioavailability as an aqueous suspension containing about 192 mg or about 384 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0352] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 48 mg to about 480 mg. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 96 mg to about 432 mg. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 148 mg to about 384 mg. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 192 mg to about 336 mg. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 240 mg to about 288 mg. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 288 mg to about 336 mg. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in the range of about 336 mg to about 384 mg. In a preferred embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in an amount of about 192 mg. In a more preferred embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in an amount of about 384 mg.

[0353] In one embodiment of any of the methods described herein, the compound of Formula I or a salt thereof is administered orally to a human subject. In a more preferred embodiment, the compound of Formula I or a salt thereof is administered to a human subject in the form of an aqueous suspension. In yet another embodiment, the compound of Formula I or a salt thereof is administered in one or more dosage forms sufficient to achieve the same bioavailability as an aqueous suspension containing about 192 mg or about 384 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0354] In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a human subject in an amount of about 48 mg, about 96 mg, about 144 mg, about 192 mg, about 240 mg, about 288 mg, about 336 mg, about 384 mg, or about 432 mg per day.

[0355] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a human subject. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily to a human subject. In a preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally.

[0356] In one embodiment of any of the methods and uses described herein for the treatment of a human subject, the human subject i) has a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, ii) has dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease, iii) has abnormal alpha-synuclein deposition as determined by a skin biopsy, iv) the subject has a body mass index of ≥ 18.5 kg / m 2 and ≤ 45 kg / m 2 and, v) has an early diagnosis of Parkinson's disease, vi) the subject is receiving treatment with a monoamine oxidase B (MAO-B) inhibitor, vii) the subject is not concomitantly using symptomatic therapy drugs for Parkinson's disease, viii) the subject has not received dopamine agonist therapy for at least 30 days prior to dosing, ix) the subject is diagnosed as "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria, and x) the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of at least 25 Montreal Cognitive Assessment scores.

[0357] The MDS-UPDRS has four parts: Part I (Non-motor experiences of daily life), Part II (Motor experiences of daily life), Part III (Motor examination), and Part IV (Motor complications). Part I has two components. IA relates to several actions that are evaluated by the principal investigator of the clinical trial based on all relevant information from the patient and caregiver, and IB is filled out by the patient, regardless of caregiver assistance and independently of the principal investigator of the clinical trial. However, these sections can be reviewed by the evaluator to ensure that all questions have been clearly answered and to account for any ambiguity recognized by the evaluator. Part II is designed as a self-administered questionnaire but can be reviewed by the principal investigator of the clinical trial to ensure completeness and clarity. Part III has instructions for the evaluator to give to or demonstrate to the patient, which the evaluator fills out.

[0358] In one embodiment of any of the methods described herein, administration of the compound of formula I or a pharmaceutically acceptable salt thereof slows the progression of the overall severity of Parkinson's disease in a subject as measured by the Clinical Global Impression of Severity (CGIS) scale. The severity of the disease is evaluated as follows: 1: Normal 2: Borderline 3: Mild 4: Moderate 5: Caution 6: Severe 7: Most severely ill patients

[0359] In one embodiment of any of the methods and uses described herein, the subject is not concomitantly using a symptomatic therapy drug for Parkinson's disease.

[0360] In one embodiment of any of the methods and uses described herein, the subject is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state.

[0361] In one embodiment of any of the methods and uses described herein, the subject is administered a compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state at least 1 hour prior to administration.

[0362] In one embodiment of any of the methods and uses described herein, the subject is administered a compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state at least 2 hours prior to administration.

[0363] In one embodiment of any of the methods and uses described herein, the subject is 50 years of age or older. In another embodiment of any of the methods and uses described herein, the subject is 40 years of age or older. In one embodiment of any of the methods and uses described herein, the subject is 30 years of age or older. In one embodiment of any of the methods and uses described herein, the subject is 20 years of age or older.

[0364] In one embodiment of any of the methods and uses described herein, the subject is not concomitantly using a dopamine replacement drug.

[0365] In one embodiment of any of the methods and uses described herein, the subject is not concomitantly using a symptomatic therapy drug for a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease).

[0366] In one embodiment of any of the methods and uses described herein, the subject has a body mass index of ≧18.5 kg / m 2 and ≦45 kg / m 2 of body mass index.

[0367] In one embodiment of any of the methods and uses described herein, the subject is administered about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., orally).

[0368] In one embodiment of any of the methods and uses described herein, the subject is administered orally once a day, in the form of an aqueous suspension, about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0369] In one embodiment of any of the methods and uses described herein, the subject is administered orally an amount of the compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms sufficient to achieve the same bioavailability as an aqueous suspension containing about 192 mg or about 384 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0370] In one embodiment of any of the methods and uses described herein, the subject is administered orally once a day, in the form of a solid dosage form, about 134 mg or about 269 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0371] In one embodiment of any of the methods and uses described herein, the subject has a disease severity of ≦2 according to the modified Hoehn and Yahr severity. The modified Hoehn and Yahr scale is shown below. For example, Goetz et al., Movement Disorder Society Task Force Report on the Hoehn and Yahr Staging Scale: Status and Recommendations, Mov. Disord. Off. J. Mov. Disord. Soc., 19:1020-1028, 2004; Hoehn M, Yahr M (1967). "Parkinsonism: onset, progression and mortality” .Neurology. 17(5):427-42 ; The Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease”. Movement Disorders. 19(9):1020 - 1028 See. These are incorporated herein by reference.

Table 1

[0372] In one embodiment of any of the methods and uses described herein, the subject has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0373] In one embodiment of any of the methods and uses described herein, the subject has not received dopamine treatment other than a monoamine oxidase-B (MAO-B) inhibitor.

[0374] In one embodiment of any of the methods and uses described herein, the subject is (i) at least 50 years old, (ii) has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, (iii) has a modified Hoehn and Yahr severity score of 2 or less, and (iv) has not received dopamine treatment other than a monoamine oxidase-B (MAO-B) inhibitor.

[0375] In one embodiment of any of the methods and uses described herein, the subject has received a stable dose of one or more monoamine oxidase B (MAOB) inhibitors for at least 10 days, preferably 20 days, more preferably 30 days.

[0376] In one embodiment of any of the methods and uses described herein, the subject has received a stable dose of one or more monoamine oxidase B (MAOB) inhibitors or an equivalent dose of a different MAOB inhibitor for at least 10 days, preferably 20 days, more preferably 30 days.

[0377] In one embodiment of any of the methods and uses described herein, the aqueous suspension is prepared immediately prior to administration by adding a powder comprising a compound of formula I or a pharmaceutically acceptable salt thereof to water or any suitable aqueous vehicle and mixing uniformly with a spoon or other stirrer.

[0378] In one embodiment of any of the methods and uses described herein, the suspension further comprises (i) a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, (ii) colloidal silicon dioxide, (iii) sodium lauryl sulfate, (iv) crospovidone, (v) mannitol, and (vi) a flavoring agent.

[0379] In one embodiment of any of the methods and uses described herein, the compound of formula I is administered in free base form.

[0380] In one embodiment of any of the methods and uses described herein, the subject has received treatment with a monoamine oxidase B (MAOB) inhibitor.

[0381] In one embodiment of any of the methods and uses described herein, the subject has not received dopamine agonist therapy for at least 30 days prior to administration of or treatment with the compound of formula I or a pharmaceutically acceptable salt thereof.

[0382] In one embodiment of any of the methods and uses described herein, the subject exhibits a Montreal Cognitive Assessment score of at least 25. For example, https: / / www.mocatest.org See.

[0383] In one embodiment of any of the methods and uses described herein, about 192 mg or about 384 mg of the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject.

[0384] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0385] In one embodiment of any of the methods and uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject twice daily.

[0386] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an average plasma AUC in a subject in the range of about 30,000 ng*h / mL to about 50,000 ng*h / mL. 0-24 It is administered in an amount sufficient to achieve.

[0387] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a plasma C in the range of about 3,000 ng / mL to about 7,000 ng / mL. max It is administered in an amount sufficient to achieve.

[0388] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a CSF concentration of at least about 0.6 ng / mL to about 2.7 ng / mL.

[0389] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max It is administered in an amount sufficient to achieve.

[0390] In one embodiment of any of the methods and uses described herein, Parkinson's disease includes early Parkinson's disease.

[0391] In one embodiment of any of the methods and uses described herein, if an adverse event occurs, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced by half. BRIEF DESCRIPTION OF THE DRAWINGS

[0392]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0393] Definitions The terms "adverse event (AE)", "severe adverse reaction", "severe adverse event", "toxicity", "treatment-emergent adverse event (TEAE)" are used interchangeably and mean an event that did not exist prior to treatment of the present invention or existed at a lesser intensity and occurred or worsened after treatment was initiated in the patient. Such events are undesirable, unfavorable, and unintended signs, symptoms, or diseases that may be attributable to the use or treatment with the agent. Based on the intensity and effect of the adverse event, those skilled in the art may have to modify the treatment conditions.

[0394] The terms "QTcF" and "corrected QT interval according to Fridericia" are used interchangeably and their meaning is well known to those skilled in the art.

[0395] As used herein, the terms "treating" or "treatment" refer to the complete or partial cure, alleviation, remission, improvement, reduction, prevention, or delay in the onset, inhibition of progression, reduction in severity, and / or reduction in incidence of a particular disease or the disease itself or disorder, and / or one or more symptoms or characteristics of a condition. For the purposes of the present invention, the terms treating or treatment are used to refer to the treatment or prevention of a neurodegenerative disease or early neurodegenerative disease. In a more specific example, the terms treating or treatment are used to refer to the treatment or prevention or alleviation of at least one symptom of Parkinson's disease or early Parkinson's disease in a subject.

[0396] As used herein, the term "subject" refers to either a human or a non-human animal. Such terms include mammals such as humans, primates, livestock animals (e.g., cows and pigs), companion animals (e.g., dogs and cats), and rodents (e.g., mice and rats). For the purposes of the present invention, a "subject" is one who has a neurodegenerative disease, or who has begun to exhibit symptoms of a neurodegenerative disease, or who is at risk of developing a neurodegenerative disease. In one aspect of the present invention, a "subject" is one who has, or has begun to exhibit symptoms of, or is at risk of developing, a disease selected from synucleinopathies such as Parkinson's disease, AD, or LBD, REM sleep behavior disorder, or MSA. In one aspect of the present invention, a "subject" is one who has, or has begun to exhibit symptoms of, or is at risk of developing, a neurodegenerative disease such as Parkinson's disease. Methods for identifying a subject are well known to physicians or those of ordinary skill in the art. One of ordinary skill in the art will understand that some preliminary studies are conducted with healthy volunteers. Such healthy volunteers are also referred to as subjects for the purposes of the present invention. However, this subject is for demonstration purposes only.

[0397] As used herein, the term "about", when appearing before a range, should be understood to refer to both endpoints of the range. In such instances, the range should also be understood to include the range defined by the specific endpoints recited, as well as sub-ranges within the recited endpoints. When "about" appears before a number, the number should be understood to include the range of + / - 5%.

[0398] As used herein, the term "between", when appearing before a range, should be understood to refer to both endpoints of the range. In such instances, the range should also be understood to include the range defined by the specific endpoints recited, as well as sub-ranges within the recited endpoints.

[0399] As used herein, the term "therapeutically effective amount" means an amount of a drug, e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, which, when administered to a subject in need thereof, has the desired effect of reducing, curing, or alleviating a disease or its symptoms. For the purposes of the present invention, a therapeutically effective amount is an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof that is used for the treatment of a neurodegenerative disease or for the delay, inhibition, or suppression of its progression. A therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof can be administered to a subject in need thereof as such or in the form of a pharmaceutical formulation. In particular, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject as a solid oral dosage form.

[0400] As used herein, the term of delaying or inhibiting or suppressing the progression of a disease such as a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease), or reducing the rate of progression, means reducing the decline experienced by a subject or patient, as quantified, for example, by UDPRS, MDS-UPDRS score, or one or more of any other method described in the present invention or a general standard method known in the art.

[0401] Early Parkinson's disease or Parkinson's disease can be diagnosed by those skilled in the art based on their experience and / or by common standard methods / techniques known in the art, such as, for example, Kinmber TE. Approach to the patient with early Parkinson disease: diagnosis and management. Intern Med J. 2021 Jan;51(1):20-26; Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015;30:1591-9; Hassin-Baer S et al. Identification of an early-stage Parkinson’s disease neuromarker using event-related potentials, brain network analytics and machine-learning, 2022, PLoS ONE 17(1)).

[0402] Early Parkinson's disease or Parkinson's disease can be so identified by those skilled in the art by performing relevant tests or by identifying symptoms according to common standard known methods / techniques. Generally, early Parkinson's disease or Parkinson's disease is as follows: a) Tremor such as rolling a pill at rest in one hand; b) Tremor that is maximal at rest, decreases during movement, and disappears during sleep; c) Rigidity and bradykinesia (slowness of movement), hypokinesia (decrease in movement), and difficulty initiating movement (akinesia); d) The face becomes mask-like, the mouth opens, blinking decreases, and it may be confused with depression; e) The posture becomes stooped; f) Difficulty initiating walking; g) The stride becomes short, the arms are held flexed at the waist, and do not swing with walking; h) Occasionally, the gait becomes unexpectedly fast, and the subject sometimes starts running (accelerated walking) so as not to fall; i) Due to the loss of postural reflexes, when the center of gravity moves, there is a tendency to fall forward (propulsion) or backward (retropulsion); j) There is dysphonia, accompanied by a characteristic and monotonous stuttering dysarthria; k) Due to hypokinesia and impaired control of the distal muscle system, micrographia occurs, increasing the difficulty of daily living activities; l) There are few blinks and the expression is lacking; m) Decreased movement; n) Postural reflex disorder; and o) It can be identified by one or more of characteristic gait abnormalities.

[0403] Pharmacokinetics (PK) evaluation is one of the endpoints of clinical trials, and the interaction between the subject's body and the administered substance (or drug) throughout the exposure period is studied mathematically. As is known to those skilled in the art, PK evaluation includes, for example, C max , T max , half-life, terminal velocity constant (Kel), AUC 0-24 , area under the concentration-time curve from time 0 to the final quantifiable time point (AUC 0-tau ), oral clearance (CL / F), apparent volume of distribution (V / F), and determination of dose normalization [AUC( 0-tau ) / dose or (C max / dose)].

[0404] As used herein, AUC 0-24 refers to the area under the steady-state plasma concentration-time curve from 0 hours to 24 hours after administration of the drug (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof). The plasma concentrations called C min and C max are the minimum and maximum steady-state effective concentrations of the drug in plasma during a specific dosing interval, respectively. The time to reach the maximum plasma concentration after administration of the dose is called T max .

[0405] The terms "time (hour)", "time (hr)", "time (h)", "time (hours)", and "time (hrs)" are used interchangeably and mean units of time.

[0406] As used herein, the term "neurodegenerative disease" includes, but is not limited to, Parkinson's disease (PD), Alzheimer's disease (AD), synucleinopathy, Lewy body dementia (LBD), rapid eye movement (REM) sleep behavior disorder, multiple system atrophy (MSA), early Parkinson's disease, early Alzheimer's disease, early synucleinopathy, early Lewy body dementia, early rapid eye movement, early sleep behavior disorder, and early multiple system atrophy.

[0407] Abnormal synuclein deposition can be determined, for example, by skin punch biopsy as described in Swallow et al., Acta Neurol Scand., 130(2):59-72, 2014. Epub 2014 Apr 5, PMID: 24702516, which is incorporated herein by reference.

[0408] The compound of formula I is a breakpoint cluster region (BCR)-Abelson leukemia virus oncogene (ABL) tyrosine kinase inhibitor (TKI) being investigated for the treatment of neurodegenerative diseases (ND). As described above, the compound of formula I has been shown to be effective in the treatment of Parkinson's disease, AD, and other synucleinopathies by in vitro and in vivo studies in mice.

[0409] In one embodiment, the present invention relates to a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease in a subject in need thereof. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0410] In one embodiment, the subject is a mammal, preferably a human.

[0411] In one embodiment, the present invention relates to a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression, in an adult subject in need thereof. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0412] In one embodiment, the present invention relates to a method for treating Parkinson's disease (PD), or delaying, inhibiting, or suppressing its progression, in an adult subject. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0413] In one embodiment, the present invention relates to a method for treating early Parkinson's disease (PD), or delaying, inhibiting, or suppressing its progression, in an adult subject. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0414] In one embodiment, the present invention relates to a method for treating Alzheimer's disease (AD), or delaying, inhibiting, or suppressing its progression, in an adult subject. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0415] In one embodiment, the present invention relates to a method for treating Lewy body dementia (LBD), or delaying, inhibiting, or suppressing its progression, in an adult subject. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0416] In one embodiment, the present invention relates to a method for treating rapid eye movement (REM) sleep behavior disorder, or delaying, inhibiting, or suppressing its progression, in an adult subject. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0417] In one embodiment, the present invention relates to a method for treating, or delaying, inhibiting, or suppressing the progression of multiple system atrophy (MSA) in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0418] In one embodiment, the present invention relates to a method for reducing the rate of progression of early Parkinson's disease in a subject having a disease severity ≦2 according to the modified Hoehn and Yahr severity, preferably in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0419] In one embodiment, the present invention relates to a method for reducing the rate of progression of a movement disorder caused by Parkinson's disease in a subject suffering from early Parkinson's disease and having a disease severity ≦2 according to the modified Hoehn and Yahr severity, preferably in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0420] In one embodiment, the present invention relates to a method for regulating or maintaining autonomic function in a subject suffering from early Parkinson's disease and having a disease severity ≦2 according to the modified Hoehn and Yahr severity, preferably in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0421] In one embodiment, the present invention relates to a method for reducing the decline in autonomic function caused by early Parkinson's disease in a subject in need thereof having a disease severity ≦2 according to the modified Hoehn and Yahr severity, preferably in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0422] In one embodiment, the present invention relates to a method of treating Parkinson's disease in a subject suffering from early Parkinson's disease and having a disease severity ≦ 2 according to the modified Hoehn and Yahr severity, preferably in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0423] In one embodiment, the present invention relates to a method of treating Parkinson's disease in a subject having a disease severity ≦ 2 according to the modified Hoehn and Yahr severity, preferably in an adult subject. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily to a subject in need thereof.

[0424] A variety of techniques are available for assessing the severity and / or improvement of Parkinson's disease or its symptoms. In some embodiments, one or more of the following scales may be used in accordance with the methods of the present disclosure. Hoehn and Yahr severity scale, Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA) criteria, Clinical Global Impression of Severity (CGIS), Clinical Global Impression of Improvement (CGII), Clinical Global Impression of Efficacy (CGIE), Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease - Motor Function Rating Scale (SCOPA-Motor), Schwab and England Activities of Daily Living Scale (SES), Self-Assessment Parkinson's Disease Disability Scale (SPDDS), Postural Instability and Gait Disorder score (PIGD), Freezing of Gait Questionnaire (FOGQ), Non-Motor Symptoms Questionnaire (NMSQuest), Non-Motor Symptoms Scale (NMSS), Unified Dyskinesia Rating Scale (UDysRS), Wear-Out Questionnaire (WOQ), total sleep time self-reported on the Pittsburgh Sleep Questionnaire, Beck Depression Inventory, Insomnia Severity Index, or a combination thereof. These techniques are well known in the art and are hereby incorporated by reference in their entirety, as are all publications cited herein. For example, Fahn, S., Elton, R. and committee, UPDRS program members, Unified Parkinson’s disease rating scale. In S. Fahn, C. Mardsen and M. Goldstein (Eds.), Recent development in a Parkinson’s disease, Macmillan, New York, 1987, pp. 153-167; Hoehn M and Yahr M D(1967)Parkinsonism: onset, progression and mortality. Neurology 17(5):427-442; MoCA - Montreal cognitive assessment Test (developed by Dr. Ziad Nasreddine, 1996); Goetz, Christopher G., et al. “MDS - UPDRS”, Movement Disorder Society, Jul. 1, 2008; Goetz et al., Movement Disorder Society Task Force Report on the Hoehn and Yahr Staging Scale: Status and Recommendations, Mov. Disord. Off. J. Mov. Disord. Soc., 19:1020 - 1028, 2004; Hoehn M, Yahr M(1967). “ Parkinsonism: onset, progression and mortality” .Neurology.17(5):427 - 42 ; The Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease”. Movement Disorders. 19(9):1020 - 1028; Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry(Edgmont). 2007 Jul;4(7):28 - 37; CGI (Clinical Global Impression), ECDEU assessment manual, US Department of Health, Education and Welfare, p. 218 - 221; Auluck P K, Chan H Y, Trojanowski J Q, Lee V M and Bonini N M (2002) Chaperone suppression of alpha - synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295(5556):865 - 868; Akdemir UO, Bora Tokcaer A, Atay LO. Dopamine transporter SPECT imaging in Parkinson’s disease and parkinsonian disorders. Turk J Med Sci. 2021 Apr 30;51(2):400 - 410; Refer to Malek N, Swallow D, Grosset KA, Anichtchik O, Spillantini M, Grosset DG. Alpha - synuclein in peripheral tissues and body fluids as a biomarker for Parkinson’s disease - a systematic review. Acta Neurol Scand. 2014 Aug;130(2):59 - 72.

[0425] According to any one of the foregoing embodiments, the treatment method includes administering a compound of formula I. The compound of formula I has the following chemical name and formula.

[0426] Chemical name: N’-(2 - chloro - 6 - methylbenzoyl)-4 - methyl - 3 - [2-(3 - quinolyl)ethynyl]-benzohydrazide, and [Chemical formula]

[0427] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered to a subject as such. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered in a dosage form. In certain embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered in an oral dosage form.

[0428] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered as an oral dosage form comprising the compound of formula I or a pharmaceutically acceptable salt thereof in an amorphous form and a pharmaceutically acceptable excipient.

[0429] In some embodiments, the oral dosage form may be a tablet.

[0430] In some embodiments, the oral dosage form may be a hard gelatin capsule.

[0431] In some embodiments, the oral dosage form may be a sachet containing a powder for oral suspension.

[0432] Examples of pharmaceutically acceptable excipients that may be used in the oral dosage forms of the present invention include, for example, polyvinyl caprolactam, polyvinyl acetate, polyethylene glycol graft copolymer, silicon dioxide, sodium lauryl sulfate, microcrystalline cellulose silicate, crospovidone, gelatin, and one or more of any combination of the foregoing.

[0433] In one embodiment, the oral dosage form comprises (i) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, (ii) colloidal silicon dioxide, (iii) sodium lauryl sulfate, (iv) crospovidone, (v) mannitol, (vi) a flavoring agent, and any combination of the foregoing.

[0434] In one embodiment, the oral dosage form is selected from a solid oral dosage form or an aqueous suspension.

[0435] The desired dosage form of the compound of formula I is an oral dosage form containing from about 10 mg to about 400 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the oral dosage form contains from about 20 mg to about 400 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof. In another embodiment, the oral dosage form contains from about 30 mg to about 400 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the oral dosage form contains from about 40 mg to about 400 mg of the compound of formula I, or a pharmaceutically acceptable salt thereof.

[0436] Generally, the daily dose may be administered over the course of one to four administrations per day. In certain embodiments, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the dosage form is from about 10 mg to about 400 mg as measured by the amount of the compound of formula I or a pharmaceutically acceptable salt thereof administered per day.

[0437] The dose may be administered once daily.

[0438] The total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof to be administered to a subject may be from about 10 mg to about 400 mg. In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 10 mg. In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 20 mg. In some embodiments, the total daily dose of the compound of formula I is about 24 mg. In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 30 mg. In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 40 mg. In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 48 mg. In other embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 96 mg. In other embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 192 mg. In other embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 384 mg. In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 400 mg.

[0439] In one embodiment, the present invention provides a method for treating a neurodegenerative disease or for delaying, inhibiting, or suppressing progression, the method comprising administering to a subject in need thereof (e.g., orally) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0440] According to one embodiment, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is from about 10 mg to about 400 mg (e.g., for oral administration). According to another embodiment, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is from about 20 mg to about 400 mg. According to yet another embodiment, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is from about 30 mg to about 400 mg. In one embodiment, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is from about 40 mg to about 400 mg. In another embodiment, a therapeutically effective amount of the compound of Formula I is about 48 mg, about 192 mg, or about 384 mg.

[0441] In one embodiment of the invention, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve plasma PK effective for the treatment of a neurodegenerative disease or for delaying, inhibiting, or suppressing progression. In one embodiment, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL effective for the treatment of a neurodegenerative disease or for delaying, inhibiting, or suppressing progression 0-24 is sufficient to achieve. In another embodiment, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL effective for the treatment of a neurodegenerative disease or for delaying, inhibiting, or suppressing progression max is sufficient to achieve.

[0442] In another embodiment of the invention, a method for treating a neurodegenerative disease or for delaying, inhibiting, or suppressing progression is provided, the method comprising administering to a subject in need thereof (e.g., orally) the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 is sufficient to achieve.

[0443] According to another aspect, a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression is provided, the method comprising administering to a subject in need thereof (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max in an amount sufficient to achieve max , and administering to a subject in need thereof (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof.

[0444] According to another aspect, a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression is provided, the method comprising achieving an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , and plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max in an amount sufficient to achieve max , and administering to a subject in need thereof (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof.

[0445] In one embodiment of the invention, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve CSF PK effective for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression. In another embodiment, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL effective for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression. In another embodiment, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL effective for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression. max to achieve max .

[0446] According to another aspect, a method for treating a neurodegenerative disease, or delaying, inhibiting, or suppressing its progression is provided, the method comprising administering to a subject in need thereof (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max in an amount sufficient to achieve max , and administering to a subject in need thereof (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof.

[0447] According to another aspect, a method for treating, delaying the progression of, inhibiting, or suppressing a neurodegenerative disease is provided, the method comprising administering to a subject in need thereof (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL.

[0448] According to yet another aspect, a method for treating, delaying the progression of, inhibiting, or suppressing a neurodegenerative disease is provided, the method comprising administering to a subject in need thereof (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a CSF concentration of at least about 0.2 ng / mL.

[0449] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 0.5 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a minimum concentration in CSF of about 0.7 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 0.9 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 1 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 1.2 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 1.5 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 1.8 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 2 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 2.2 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 2.5 ng / mL or more. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount sufficient to achieve a minimum concentration in CSF of about 2.7 ng / mL or more.

[0450] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a minimum concentration in CSF of from about 0.5 ng / mL to about 2.7 ng / mL. For example, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of from about 10 mg to about 400 mg.

[0451] According to yet another aspect, a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease is provided, the method comprising administering to a subject in need thereof (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an average CSF C avg of from about 0.3 ng / mL to about 4.0 ng / mL.

[0452] According to yet another aspect, a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease is provided, the method comprising administering to a subject in need thereof (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a CSF C max in the range of from about 0.4 ng / mL to about 7.0 ng / mL, a CSF concentration of at least from about 0.2 ng / mL to about 2.7 ng / mL, and an average CSF C avg of from about 0.3 ng / mL to about 4.0 ng / mL.

[0453] According to one aspect of the invention, a method for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease is provided, the method comprising administering to a subject in need thereof a c-Abl inhibitor in an amount sufficient to achieve a ratio of average CSF C max of c-Abl inhibition to IC 50 of 1 or greater.

[0454] The IC 50 of c-Abl inhibition of the compound of Formula I is 0.9 nM compared to 20 nM for nilotinib, as measured using a kinase assay against native Abl (human). Thus, the compound of Formula I has been shown to be 20-fold more potent than nilotinib. The compound of Formula I has a lower IC 50shows a value and is therefore potentially more effective. Furthermore, the concentration of the compound of formula I in the CSF is more than half of its maximum inhibitory concentration, ensuring optimal inhibition of c-Abl.

[0455] According to one embodiment, the methods and uses of the present invention comprise administering to a subject in need thereof (e.g., orally) a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1 or more.

[0456] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount sufficient to achieve a ratio of the average CSF C of c-Abl inhibition max to IC 50 of 1. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount sufficient to achieve a ratio of the average CSF C of c-Abl inhibition max to IC 50 of more than 1. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount sufficient to achieve a ratio of the average CSF C of c-Abl inhibition max to IC 50 of about 1 to 14. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount sufficient to achieve a ratio of the average CSF C of c-Abl inhibition max to IC 50 of about 14.

[0457] In one embodiment, a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising administering a c-Abl inhibitor to a subject in need thereof a) that passes through the blood-brain barrier b) to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max and c) to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL. d) Average CSF C of c-Abl inhibition max vs. IC 50 to achieve a ratio of 1 or more, or e) providing a method comprising administering in a sufficient amount (e.g., orally) in any combination of a), b), c), and d).

[0458] According to one embodiment, the c-Abl inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. According to yet another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg to about 400 mg. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at about 40 mg to about 400 mg.

[0459] According to a further embodiment, a method for treating, or delaying, inhibiting, or suppressing the progression of a neurodegenerative disease, comprising orally administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 40 mg to about 400 mg, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, provides an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , passes through the blood-brain barrier, and provides a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , and the average CSF C of the compound of formula I max is at least the IC of c-Abl inhibition 50 , and the IC 50 is measured using an hAbl kinase assay, and provides a method.

[0460] In one embodiment, the present invention provides a c-Abl inhibitor for the preparation of a medicament, which is used for the treatment of, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease.

[0461] According to one embodiment, the c-Abl inhibitor used in the preparation of the medicament is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0462] According to one embodiment, the agent is for oral or parenteral administration.

[0463] According to certain embodiments, the agent is for oral administration.

[0464] According to one embodiment, the agent is a tablet, capsule, or sachet containing a powder for suspension. According to one embodiment, the agent is a dosage form comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one excipient. According to certain embodiments, the agent is a dosage form comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more of the excipients selected from polyvinyl caprolactam, polyvinyl acetate, polyethylene glycol graft copolymer, silicon dioxide, sodium lauryl sulfate, microcrystalline cellulose silicate, crospovidone, gelatin, and any combination of any of the foregoing.

[0465] One of ordinary skill in the art would understand that the agent described herein, when the agent comprises a c-Abl inhibitor such as a compound of formula I or a pharmaceutically acceptable salt thereof, is in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL 0-24 , a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , cross the blood-brain barrier, achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max , achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, and / or an average CSF C of c-Abl inhibition max to IC 50 ratio of 1 or more, can be used in the methods described herein for treating, or delaying, inhibiting, or suppressing the progression of, a neurodegenerative disease. In one embodiment, the amount of the compound of formula I or a pharmaceutically acceptable salt thereof is present in the agent in an amount of about 40 mg to about 400 mg.

[0466] In one aspect, the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases, or for delaying, inhibiting, or suppressing progression, which has a CSF C max to IC 50 ratio of 1 or more, safely achieving the desired effect, provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0467] A compound of formula I or a pharmaceutically acceptable salt thereof is said to "safely" achieve the desired effect when administered to a subject in an amount that does not cause adverse events and / or cardiovascular toxicity.

[0468] When administered to both healthy volunteers and patients in an amount sufficient to achieve the desired effect in the treatment of neurodegenerative diseases, or for delaying, inhibiting, or suppressing progression, the compound of formula I or a pharmaceutically acceptable salt thereof did not show adverse events or cardiovascular toxicity. As can be seen from Tables 5 and 6 below, the adverse events were mild and could be controlled, alleviated, or removed with minimal care or medication. No subjects experienced SAE or severe AE.

[0469] The in vitro cardiovascular safety of the compound of formula I is shown in WO2017 / 208267A1, pages 11 and later, and in Example 5. It was also observed that no subjects reported having an absolute QTcF > 450 ms in healthy volunteers (Study b). During the study, no AE related to ECG parameters was reported in any group, indicating that the compound of formula I is safe for the heart. It was found that subjects did not show large QTcF fluctuations even at plasma concentrations of the compound of formula I as high as 384 mg.

[0470] In one aspect of the present invention, there is provided a method for reducing the rate of progression of early neurodegenerative diseases such as early Parkinson's disease, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0471] According to any one of the embodiments described herein, the neurodegenerative disease is selected from synucleinopathies such as Parkinson's disease, AD, or Lewy body dementia (LBD), rapid eye movement (REM) sleep behavior disorder, or multiple system atrophy (MSA). In one embodiment, the neurodegenerative disease is Parkinson's disease. In certain embodiments, the present invention provides a method for treating Parkinson's disease (PD), or delaying, inhibiting, or suppressing the progression, in a subject in need thereof, comprising administering to the subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method for reducing the rate of progression of early Parkinson's disease, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in n...

Claims

1. A method for reducing the progression rate of early Parkinson's disease in a human subject having a disease severity of ≤2 according to the severity of the modified Hoehn and Yahr, the method comprising administering to the subject an effective amount of a compound of formula I: 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof.

2. A method for reducing the progression rate of movement disorders caused by Parkinson's disease in a human subject suffering from early Parkinson's disease and having a disease severity of ≤2 according to the severity of the modified Hoehn and Yahr, the method comprising administering to the subject an effective amount of a compound of formula I: [Chemical 2] or a pharmaceutically acceptable salt thereof.

3. A method for regulating or maintaining autonomic function in a human subject having early Parkinson's disease and a disease severity of ≤2 according to the severity of the modified Hoehn and Yahr, the method comprising administering to the subject an effective amount of a compound of formula I: [Chemical Formula 3] or a pharmaceutically acceptable salt thereof.

4. A method for reducing the decline in autonomic function due to early Parkinson's disease in a human subject in need thereof and having a disease severity of ≤2 according to the severity of the modified Hoehn and Yahr, the method comprising administering to the subject an effective amount of a compound of formula I: 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof.

5. A method for treating Parkinson's disease or delaying, inhibiting, or suppressing its progression in a human subject having early Parkinson's disease and a disease severity of ≤2 according to the severity of the modified Hoehn and Yahr, the method comprising administering to the subject an effective amount of a compound of formula I: 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof.

6. A method for treating Parkinson's disease or delaying, inhibiting, or suppressing its progression in a human subject having a disease severity of ≤2 according to the severity of the modified Hoehn and Yahr, the method comprising administering to the subject an effective amount of a compound of formula I: 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the subject is diagnosed as "highly likely to have Parkinson's disease clinically" according to the MDS clinical diagnostic criteria.

8. The method according to any one of claims 1 to 7, wherein the subject has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with the diagnosis of Parkinson's disease.

9. The method according to any one of claims 1 to 8, wherein the subject exhibits abnormal synuclein deposition determined by a skin punch biopsy. **Claim 10** The method according to any one of claims 1 to 9, wherein the administration of the compound of formula I or a pharmaceutically acceptable salt thereof extends the time to significant worsening of the subject in MDS-UPDRS Parts II and III. The method according to any one of claims 1 to 9, wherein the administration of the compound of formula I or a pharmaceutically acceptable salt thereof extends the time to significant worsening of the subject in Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I, II, and III. **Claim 11** The method according to any one of claims 1 to 10, wherein the administration of the compound of formula I or a pharmaceutically acceptable salt thereof delays the progression of the overall severity of Parkinson's disease in the subject as measured by the Clinical Global Impression of Severity (CGIS) scale. **Claim 12** The method according to any one of claims 1 to 11, wherein the subject is not concomitantly using a symptomatic therapy drug for Parkinson's disease. **Claim 13** The method according to any one of claims 1 to 12, wherein the subject is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state. **Claim 14** The method according to any one of claims 1 to 13, wherein the subject is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state at least 1 hour prior to administration. **Claim 15** The method according to any one of claims 1 to 14, wherein the subject is administered the compound of formula I or a pharmaceutically acceptable salt thereof in a fasting state at least 2 hours prior to administration. **Claim 16** The method according to any one of claims 1 to 15, wherein the subject is 50 years of age or older. **Claim 17** The method according to any one of claims 1 to 16, wherein the subject is 20 years of age or older. **Claim 18** The method according to any one of claims 1 to 17, wherein the subject is not concomitantly using a dopamine replacement drug. **Claim 19** wherein the subject has a body mass index of 18.5 kg / m ２ or more and 45 kg / m ２ or less, preferably 30 kg / m ２ or less, and the method according to any one of claims 1 to 18 。 **Claim 20** The method according to any one of claims 1 to 19, wherein the subject is administered from about 5 mg to about 480 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. **Claim 21** The method according to any one of claims 1 to 20, wherein the subject is administered from about 48 mg to about 480 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. **Claim 22** The method according to any one of claims 1 to 21, wherein the subject is administered a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 48 mg, about 96 mg, about 144 mg, about 192 mg, about 240 mg, about 288 mg, about 336 mg, about 384 mg, about 432 mg, or about 480 mg.

23. The method according to any one of claims 1 to 22, wherein the subject is administered a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 134 mg to about 384 mg.

24. The method according to any one of claims 1 to 23, wherein the subject is administered a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 192 mg or about 384 mg.

25. The method according to any one of claims 1 to 24, wherein the subject is administered a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of about 192 mg or about 384 mg in the form of a solid dosage form.

26. The method according to any one of claims 1 to 25, wherein the subject has not received dopamine therapy other than a monoamine oxidase - B (MAO - B) inhibitor.

27. The method according to any one of claims 1 to 26, wherein the subject (i) is at least 50 years old, (ii) has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, (iii) has a modified Hoehn - Yahr severity score of 2 or less, and (iv) has not received dopamine therapy other than a monoamine oxidase - B (MAO - B) inhibitor.

28. The method according to claim 25, wherein the solid dosage form comprises (i) a polyvinylcaprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, (ii) colloidal silicon dioxide, (iii) sodium lauryl sulfate, (iv) crospovidone, (v) mannitol, (vi) a flavoring agent, and any combination of the foregoing.

29. The method according to any one of claims 1 to 28, wherein the compound of formula I is administered in free base form.

30. The method according to any one of claims 1 to 29, wherein the subject has received treatment with a monoamine oxidase B (MAOB) inhibitor.

31. The method according to any one of claims 1 to 30, wherein the subject has not received dopamine agonist therapy for at least 30 days prior to the administration.

32. The method according to any one of claims 1 to 31, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

33. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL ０－２４ The method according to any one of claims 1 to 32, wherein the administration is carried out in an amount sufficient to achieve ０－２４ .

34. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an average plasma AUC in the range of about 20,000 ng*h / mL to about 60,000 ng*h / mL ０－２４ The method according to any one of claims 1 to 33, wherein the administration is carried out in an amount sufficient to achieve ０－２４ .

35. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL ｍａｘ The method according to any one of claims 1 to 34, wherein the administration is carried out in an amount sufficient to achieve the above.

36. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a plasma C in the range of about 1800 ng / mL to about 12,000 ng / mL ｍａｘ The method according to any one of claims 1 to 35, wherein the method is administered in an amount sufficient to achieve the above.

37. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL ｍａｘ The method according to any one of claims 1 to 36, wherein the method is administered in an amount sufficient to achieve the above.

38. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a cerebrospinal fluid C in the range of about 2 ng / mL to about 7 ng / mL ｍａｘ The method according to any one of claims 1 to 37, wherein the method is administered in an amount sufficient to achieve the above.

39. The method according to claim 38 or 39, wherein the subject achieves ｍａｘ cerebrospinal fluid C within 6 hours from the administration of the compound of formula I or a pharmaceutically acceptable salt thereof.

40. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a cerebrospinal fluid C ａｖｇ concentration of from about 0.2 ng / mL to about 2.7 ng / mL, the method according to any one of claims 1 to 39.

41. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a cerebrospinal fluid C concentration of from about 0.6 ng / mL to about 2.7 ng / mL ａｖｇ The method according to any one of claims 1 to 40, wherein the method is administered in an amount sufficient to achieve a concentration of

42. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an average cerebrospinal fluid C of about 0.3 ng / mL to about 4.0 ng / mL ａｖｇ The method according to any one of claims 1 to 41, wherein the method is administered in an amount sufficient to achieve the above.

43. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve an average cerebrospinal fluid C of about 2.0 ng / mL to about 3.0 ng / mL ａｖｇ The method according to any one of claims 1 to 42, wherein the administration is carried out in an amount sufficient to achieve the above.

44. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a ratio of 1 or more of cerebrospinal fluid C of c-Abl inhibition ｍａｘ vs IC ５０ The method according to any one of claims 1 to 43, wherein the method is administered in an amount sufficient to achieve the ratio.

45. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a ratio of mean cerebrospinal fluid C ｍａｘ to IC50 for c-Abl inhibition of 1 to 14, a method according to any one of claims 1 to 44.

46. The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a ratio of more than 5 of C ｍａｘ to IC ５０ The method according to any one of claims 1 to 45.

47. The method according to any one of claims 1 to 46, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to cross the blood-brain barrier.

48. A method for treating Parkinson's disease, or delaying, inhibiting, or suppressing its progression, in a human subject, comprising (i) administering about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemical Formula 7】 administering to the subject an amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension or in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL ｍａｘ , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL ０－２４ , or (iii) a cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL ｍａｘ , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL ａｖｇ in an amount sufficient to achieve, a method.

49. A method for reducing the rate of progression of Parkinson's disease in a human subject, comprising (i) administering about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, [Chemical Formula 8] administering to the subject an amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension or in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL ｍａｘ , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL ０－２４ , or (iii) a cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL ｍａｘ , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL ａｖｇ in an amount sufficient to achieve, a method.

50. A method for reducing the rate of progression of dyskinesia caused by Parkinson's disease in a human subject, comprising (i) administering about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemical Formula 9】 administering to the subject an amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension or in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL ｍａｘ , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL ０－２４ , or (iii) a cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL ｍａｘ , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL ａｖｇ in an amount sufficient to achieve, a method.

51. A method for reducing the decline in autonomic function due to Parkinson's disease in a human subject, comprising (i) administering about 192 mg or about 384 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemical 10】 administering to the subject an amount of the compound of formula I or a pharmaceutically acceptable salt thereof in the form of an aqueous suspension or in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves (i) plasma C in the range of about 500 ng / mL to about 15,000 ng / mL ｍａｘ , (ii) an average plasma AUC in the range of about 5,000 ng*h / mL to about 75,000 ng*h / mL ０－２４ , or (iii) cerebrospinal fluid C in the range of about 0.4 ng / mL to about 7.0 ng / mL ｍａｘ , and (iv) an average cerebrospinal fluid C in the range of about 0.3 ng / mL to about 4.0 ng / mL ａｖｇ in an amount sufficient to achieve, a method.

52. The method according to any one of claims 1 to 51, wherein the Parkinson's disease is early Parkinson's disease.

53. The method according to any one of claims 1 to 52, wherein when an adverse event occurs, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is reduced by half.

54. The method according to any one of claims 1 to 53, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered orally.

55. The method according to any one of claims 1 to 54, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once a day.

56. The method according to any one of claims 1 to 55, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered twice a day.

57. The method according to any one of claims 1 to 56, wherein the subject has received an initial diagnosis of Parkinson's disease.

58. The method according to any one of claims 1 to 57, wherein the subject has received an initial diagnosis of Parkinson's disease within 3 years from the start of treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

59. The method according to any one of claims 1 to 58, wherein the reduction in the progression of Parkinson's disease or the reduction in symptom exacerbation is achieved by increasing the time to progression from the score of part 1 to part 2 to the score of part 2 to part 3 of the subject, as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS - UPDRS).

60. The method according to any one of claims 1 to 59, wherein the time to progression of the subject to the score of part 1 to part 2 increases by at least 40 weeks.

61. The method according to any one of claims 1 to 60, wherein the time to progression of the subject to the score of part 2 to part 3 increases by at least 40 weeks.

62. The method according to any one of claims 1 to 61, wherein the time to progression of the subject from the score of part 1 to part 2 to the score of part 2 to part 3 increases by at least 40 weeks.

63. An oral dosage form for reducing the progression rate of early Parkinson's disease in a human subject having a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, wherein the dosage form comprises an effective amount of a compound of formula I: 【Chemical 11】 or a pharmaceutically acceptable salt thereof, an oral dosage form.

64. An oral dosage form for reducing the progression rate of movement disorders caused by Parkinson's disease in a human subject suffering from early Parkinson's disease and having a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, wherein the dosage form comprises an effective amount of a compound of formula I: 【Chemical 12】 or a pharmaceutically acceptable salt thereof, an oral dosage form.

65. An oral dosage form for regulating or maintaining autonomic function in a human subject having early Parkinson's disease and a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, wherein the dosage form comprises an effective amount of a compound of formula I: 【Chemical 13】 or a pharmaceutically acceptable salt thereof, an oral dosage form.

66. An oral dosage form for reducing the decrease in autonomic function caused by early Parkinson's disease in a human subject in need thereof and having a disease severity of ≤ 2 according to the modified Hoehn and Yahr severity, wherein the dosage form comprises an effective amount of a compound of formula I: 【Chemical 14】 or a pharmaceutically acceptable salt thereof, an oral dosage form.

67. An oral dosage form for treating Parkinson's disease, or delaying, inhibiting, or suppressing progression thereof, in a human subject having a disease severity ≦ 2 according to the severity of modified Hoehn and Yahr, said dosage form comprising an effective amount of a compound of formula I: 【Chemical Formula 15】 or a pharmaceutically acceptable salt thereof, oral dosage form.

68. An oral dosage form for treating Parkinson's disease, or delaying, inhibiting, or suppressing progression thereof, in a human subject having a disease severity ≦ 2 according to the severity of modified Hoehn and Yahr, said dosage form comprising an effective amount of a compound of formula I: 【Chemical 16】 or a pharmaceutically acceptable salt thereof, oral dosage form.

69. The oral dosage form according to any one of claims 63 to 68, wherein the oral dosage form is selected from a solid oral dosage form or an aqueous suspension.

70. The oral dosage form according to claim 69, wherein the oral dosage form comprises (i) a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, (ii) colloidal silicon dioxide, (iii) sodium lauryl sulfate, (iv) crospovidone, (v) mannitol, (vi) a flavoring agent, and any combination of any of the foregoing.

71. The oral dosage form according to claim 69, wherein the aqueous suspension is prepared immediately prior to administration by adding a powder comprising a compound of formula I or a pharmaceutically acceptable salt thereof to water and mixing uniformly with a spoon or other stirrer.

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