Vorcobatinib for reducing progression of Parkinson's disease

Abstract

The present disclosure relates to a c-Abl inhibitor vodopatinib, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease, preferably early Parkinson's disease, in a subject, in delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, preferably early Parkinson's disease.

Description

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

[0002] The present invention relates to a method of treating and / or reducing the progression of a neurodegenerative disease in a subject (e.g., a human subject in need thereof) by administering a c-Abl inhibitor (e.g., vodobatinib or a pharmaceutically acceptable salt thereof) to the subject, wherein the neurodegenerative disease is 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, a stage of synucleinopathy, early Lewy body dementia, early REM, early sleep behavior disorder, and early multiple system atrophy. Background Art

[0003] Neurodegenerative diseases (NDs) occur when nerve cells in the brain or peripheral nervous system lose function over time and eventually die. These diseases cannot be completely cured, however, there are several treatments for relieving some of the symptoms associated with the disease (Fernando et al. Pharmaceuticals 2018, 11, 44).

[0004] For patients with advanced neurodegenerative diseases, some surgical procedures are an option, however, these procedures are risky for the elderly population (the population most often suffering from advanced neurodegenerative diseases) and the procedures do not prevent the progression of the disease.

[0005] Nilotinib has been tested in three randomized clinical trials for the treatment of Parkinson's disease (see, e.g., 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). Although nilotinib showed improvements in some cerebrospinal fluid (CSF) biomarker levels, poor efficacy on motor outcomes suggests that nilotinib has no clinical advantage (Xie et al., Front Aging Neurosci. 2022, 14:996-17).

[0006] Nilotinib has also been shown to be unsuccessful in slowing the progression of Parkinson's disease (PD) (Simuni et al., JAMA Neurol, 2021;78(3):312-320). The failure of nilotinib at the maximum allowed dose of 300 mg was attributed to insufficient brain penetration, as the concentration of nilotinib found in the cerebrospinal fluid (CSF) was below its IC for c-Abl. 50 Simuni specifically noted that the low CSF exposure, lack of biomarker effect, and negative trend in efficacy data suggest that nilotinib should not be tested further in Parkinson's disease.

[0007] Vodobatinib (N'-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide) (a c-Abl inhibitor) is represented by Formula I (hereinafter interchangeably referred to as vodobatinib or a compound of Formula I)

[0008]

[0009] International Publication Nos. WO 2017 / 208267A1, WO 2020 / 250133A1, and WO 2022 / 024072A1 disclose methods for using compounds of Formula I for treating Parkinson's disease, synucleinopathy, and Alzheimer's disease (AD), respectively, and the International Publications are hereby incorporated by reference.

[0010] There is a continuing need for effective and safe methods for treating and delaying the progression of neurodegenerative diseases, including in the early stages of the disease.

[0011] Purpose of the invention

[0012] One object of the present invention is a method for treating a neurodegenerative disease (including an early stage of a neurodegenerative disease) in a human subject in need and delaying the progression of the neurodegenerative disease, more specifically for treating Parkinson's disease (such as early Parkinson's disease), Alzheimer's disease and other synucleinopathies associated with c-Abl and / or delaying the progression of the Parkinson's disease, Alzheimer's disease and other synucleinopathies associated with c-Abl. In addition, one object of the present invention is to provide a highly effective and safe method for treating a neurodegenerative disease in a human subject, preferably for treating Parkinson's disease, more preferably for treating early Parkinson's disease. Another object of the present invention is to provide a method for reducing the rate of progression of early Parkinson's disease. Another object of the present invention is to provide a method for reducing the rate of progression of motor deficits caused by Parkinson's disease. Another object of the present invention is to provide a method for regulating or maintaining autonomic function in a subject (e.g., a human) suffering from early Parkinson's disease. Another object of the present invention is to provide a method for reducing the deterioration of autonomic function in a subject (e.g., a human) suffering from early Parkinson's disease.

[0013] Another object of the invention is a method of treating or delaying or inhibiting or curbing the progression of a neurodegenerative disease (e.g., Parkinson's disease) in a subject. An object of the invention is to provide a method of treating or delaying or inhibiting or curbing the progression of a neurodegenerative disease, wherein the subject is diagnosed at an early stage of the disease.

[0014] Yet another object of the invention is a method of delaying the progression of Parkinson's disease in a subject.Another specific object of the 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.

[0015] Yet another object is a method for eliminating symptoms associated with a neurodegenerative disease in a subject in need thereof. Specifically, 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 in the early stages 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 in the early stages of the disease.

[0016] Yet another object of the present invention is the use of a c-Abl inhibitor for any of the purposes and / or methods described herein.

[0017] Yet another object of the present invention is a compound of formula I;

[0018]

[0019] or a pharmaceutically acceptable salt thereof for use in any of the purposes and / or methods described herein.

[0020] Another object of the present invention is to provide a c-Abl inhibitor for treating a neurodegenerative disease in a subject in need thereof or delaying, inhibiting or curbing the progression of the neurodegenerative disease, wherein the c-Abl inhibitor is effective and safe. Therefore, an object of the present invention is to provide a c-Abl inhibitor for treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease, wherein the c-Abl inhibitor delays the progression of the neurodegenerative disease in a subject in the early stages of the disease, reduces the rate of progression of the disease or eliminates symptoms associated with the neurodegenerative disease.

[0021] 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, wherein the composition is effective and safe. Preferably, the composition effectively reduces the rate of progression of the disease in a subject in the early stages of a neurodegenerative disease or eliminates symptoms associated with the disease.

[0022] 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 purposes and / or methods described herein. Summary of the invention

[0023] The inventors have surprisingly found that vodobatinib delays (or reduces) the progression (or rate of progression) of a neurodegenerative disease, and in particular early Parkinson's disease, in a subject (eg, a human subject).

[0024] One aspect of the invention is a method for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease by administering (e.g., an effective amount of) a c-Abl inhibitor to the subject.

[0025] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoehn & Yahr stage.

[0026] Yet another aspect of the invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits a Montreal cognitive assessment score of at least 25.

[0027] Yet another aspect of the invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease in a subject (e.g., a human subject) in need thereof, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) scan consistent with a diagnosis of Parkinson's disease.

[0028] Yet another aspect of the invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0029] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0030] Yet another aspect of the invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0031] i) disease severity according to the modified Hoya stage ≤2;

[0032] ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with diagnosis of neurodegenerative diseases such as Parkinson's disease or early Parkinson's disease;

[0033] iii) abnormal synuclein deposits as determined by skin biopsy;

[0034] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0035] v) Initial diagnosis of neurodegenerative diseases (such as Parkinson's disease or early Parkinson's disease);

[0036] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0037] vii) the subject is not concomitantly administered symptomatic medication for a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease);

[0038] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0039] ix) the subject has been diagnosed as having a "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

[0040] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0041] Yet another aspect of the present invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a compound of Formula I to the subject, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0042] i) disease severity according to the modified Hoya stage ≤2;

[0043] ii) dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with diagnosis of neurodegenerative diseases such as Parkinson's disease or early Parkinson's disease;

[0044] iii) abnormal synuclein deposits as determined by skin biopsy;

[0045] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0046] v) Initial diagnosis of neurodegenerative diseases (such as Parkinson's disease or early Parkinson's disease);

[0047] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0048] vii) the subject is not concomitantly administered symptomatic medication for a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease);

[0049] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0050] ix) the subject has been diagnosed as having a "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

[0051] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0052] Yet another aspect of the invention is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., an effective amount of) a c-Abl inhibitor to the subject, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0053] i) disease severity according to the modified Hoya stage ≤2;

[0054] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0055] iii) abnormal synuclein deposits as determined by skin biopsy;

[0056] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0057] v) initial diagnosis of Parkinson's disease;

[0058] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0059] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0060] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0061] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0062] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0063] In a preferred embodiment, the c-Abl inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0064] For compounds that are effective in the treatment of neurodegenerative diseases, it is necessary that the compound is present in the brain in an effective amount. There are several c-Abl inhibitors that have been shown to be present in the brain but have not shown much effect in the treatment of neurodegenerative diseases. For example, nilotinib is ineffective in Parkinson's patients at the administered doses (150 mg and 300 mg), and one of the reasons for its failure is believed to be the lack of sufficient CSF exposure [see Simuni et al., "Jama Neurology", 2021; 78 (3): 312-320]. There are limitations because higher doses may cause cardiovascular toxicity.

[0065] Surprisingly, the inventors have found that compounds of Formula I exhibit higher CSF exposure when administered in therapeutically effective amounts compared to other c-Abl inhibitors.

[0066] Furthermore, the inventors unexpectedly discovered that, when administered to a subject in a therapeutically effective amount, the compound of Formula I causes the concentration of the compound of Formula I or a pharmaceutically acceptable salt thereof in CSF to be comparable to the IC of c-Abl inhibition. 50 The ratio of is not less than 1. This is particularly surprising because this ratio for nilotinib is about 0.2 when administered at the highest dose, which is much lower than the ratio produced by administering the lowest therapeutically effective amount of the compound of Formula I.

[0067] Additionally, the inventors have observed that the compounds of Formula I, when administered in therapeutically effective amounts, produce plasma concentrations such that CSF exposure is safe and effective for treating neurodegenerative diseases or delaying, inhibiting or arresting the progression of such neurodegenerative diseases.

[0068] Therefore, in one embodiment, the present invention provides a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, the method comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., orally).

[0069] 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 an amount sufficient to achieve a mean plasma AUC in the range of about 5000 ng*hour / ml to about 75000 ng*hour / ml. 0-24 The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0070] 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 an amount sufficient to achieve a mean plasma AUC in the range of about 20,000 ng*hr / ml to about 60,000 ng*hr / ml. 0-24 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (e.g., a human) in an amount of

[0071] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to a subject sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15000 ng / mL. max The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0072] 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 dose sufficient to achieve a plasma C in the range of about 1800 ng / mL to about 12,000 ng / mL. max The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0073] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject 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 subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0074] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to the subject an amount sufficient to achieve a cerebrospinal fluid C in the range of about 2.0 ng / mL to about 7.0 ng / mL. max The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0075] In one embodiment of any of the methods and uses described herein, wherein the subject (e.g., human) achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof max .

[0076] 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 cerebral spinal concentration of about 0.2 ng / mL to about 2.7 ng / mL.

[0077] 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 cerebral spinal concentration of about 0.6 ng / mL to about 2.7 ng / mL.

[0078] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering an amount sufficient to achieve a mean cerebrospinal fluid (CSF) concentration of about 0.3 ng / mL to about 4.0 ng / mL. avg The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0079] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering an amount sufficient to achieve a mean cerebrospinal fluid (CSF) concentration of about 2.0 ng / mL to about 3.0 ng / mL. avg The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of

[0080] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to a subject sufficient to achieve cerebrospinal fluid (CSF) max The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount such that the ratio of the IC50 for inhibition of cAbl is not less than 1.

[0081] Yet another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to a subject sufficient to achieve a mean cerebral spinal cord C max The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount that provides an IC50 ratio of 1 to 14 for inhibition of cAbl.

[0082] Another aspect is a method of treating a neurodegenerative disease in a subject (e.g., a human), the method comprising administering to a subject sufficient to achieve C max With IC 50 The subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount such that the ratio of % to 5 is greater than 5.

[0083] Another aspect is a method of treating a neurodegenerative disease in a subject (eg, 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 cross the blood-brain barrier.

[0084] In one embodiment of any of the methods and uses described herein, the 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.

[0085] In one embodiment of any of the methods and uses described herein, the subject (e.g., human) has been preliminarily diagnosed as suffering from a neurodegenerative disease. In a preferred embodiment, the subject (e.g., human) has been preliminarily diagnosed as suffering from Parkinson's disease.

[0086] In one embodiment of any of the methods and uses described herein, the subject (eg, human) has been initially diagnosed with a neurodegenerative disease within 3 years of initiating treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment of any of the methods and uses described herein, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof reduces the progression of a neurodegenerative disease in the subject (eg, human).

[0088] In one embodiment of any of the methods and uses described herein, the reduction in progression of the neurodegenerative disease is achieved by increasing the time to progression of the subject (e.g., human) from a Part 1 to Part 2 score to a Part 2 to Part 3 score as measured on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

[0089] Yet another embodiment is a method for reducing the rate of progression of a neurodegenerative disease or reducing the worsening of a symptom of a neurodegenerative disease, the method 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 of progression of the subject (e.g., human) from Part 1 to Part 2 score to Part 2 to Part 3 score as measured on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). In a preferred embodiment, the time of progression of the subject (e.g., human) from Part 1 to Part 2 score is increased by at least 40 weeks. In another embodiment, the time of progression of the subject (e.g., human) from Part 2 to Part 3 score is increased by at least 40 weeks.

[0090] In one embodiment of any of the methods and uses described herein, the time to progression of the subject (eg, human) from a Part 1 to Part 2 score to a Part 2 to Part 3 score is increased by at least 40 weeks.

[0091] In one embodiment of any of the methods and uses described herein, the administration of the 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, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof reduces the rate of progression of motor deficits caused by a neurodegenerative disease in a subject (e.g., a human). In yet another embodiment of any of the methods and uses described herein, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof regulates or maintains autonomic function in a human subject suffering from a neurodegenerative disease.

[0092] In one embodiment of any of the methods and uses described herein, the subject (e.g., human) suffers from a neurodegenerative disease and has a disease severity of ≤2 according to the modified Hoya stage. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) has been receiving treatment with a monoamine oxidase-B (MAOB) inhibitor. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) is not treated with any dopamine other than a monoamine oxidase-B (MAO-B) inhibitor. In another embodiment of any of the methods and uses described herein, the subject (e.g., human) has not received dopaminergic therapy for at least 30 days prior to the administration. In yet another embodiment of any of the methods and uses described herein, the subject (e.g., human) exhibits a Montreal Cognitive Assessment score of at least 25. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) is not concomitantly administered symptomatic medication for Parkinson's disease. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) has been diagnosed as suffering from "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria. In another embodiment of any of the methods and uses described herein, the subject (e.g., 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, the subject (e.g., human) exhibits abnormal 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 stage neurodegenerative disease (e.g., early stage Parkinson's disease).

[0093] In one embodiment of any of the methods and uses described herein, the subject (eg, human) has been initially diagnosed with Parkinson's disease.

[0094] In one embodiment of any of the methods and uses described herein, the subject (eg, human) has been initially diagnosed with Parkinson's disease within 3 years of initiating treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment of any of the methods and uses described herein, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof reduces the progression of Parkinson's disease in the subject (eg, human).

[0096] In one embodiment of any of the methods and uses described herein, the reduction in progression of Parkinson's disease is achieved by increasing the time to progression of the subject (e.g., human) from a Part 1 to Part 2 score to a Part 2 to Part 3 score as measured on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

[0097] 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, the method 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 of progression of the subject (e.g., human) from the score of Part 1 to Part 2 to the score of Part 2 to Part 3 as measured on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). In a preferred embodiment, the time of progression of the subject (e.g., human) from the score of Part 1 to Part 2 is increased by at least 40 weeks. In another embodiment, the time of progression of the subject (e.g., human) from the score of Part 2 to Part 3 is increased by at least 40 weeks.

[0098] In one embodiment of any of the methods and uses described herein, the time to progression of the subject (eg, human) from a Part 1 to Part 2 score to a Part 2 to Part 3 score is increased by at least 40 weeks.

[0099] In one embodiment of any of the methods and uses described herein, the Parkinson's disease is early Parkinson's disease. In one embodiment of any of the methods and uses described herein, the administration of the 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, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof reduces the rate of progression of movement defects caused by Parkinson's disease in human subjects with early Parkinson's disease. In yet another embodiment of any of the methods and uses described herein, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof regulates or maintains the autonomic function of human subjects with early Parkinson's disease. In another embodiment of any of the methods and uses described herein, the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof reduces the rate of deterioration of autonomic function caused by early Parkinson's disease.

[0100] In one embodiment of any of the methods and uses described herein, the subject (eg, human) has early-stage Parkinson's disease and has a disease severity of ≤2 according to the modified Hoya stage.

[0101] In one embodiment of any of the methods and uses described herein, the subject (e.g., human) has been receiving treatment with a monoamine oxidase-B (MAOB) inhibitor. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) is not treated with any dopamine other than a monoamine oxidase-B (MAO-B) inhibitor. In another embodiment of any of the methods and uses described herein, the subject (e.g., human) has not received dopaminergic therapy for at least 30 days prior to the administration. In yet another embodiment of any of the methods and uses described herein, the subject (e.g., human) exhibits a Montreal Cognitive Assessment score of at least 25. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) is not concomitantly administered symptomatic medication for Parkinson's disease. In one embodiment of any of the methods and uses described herein, the subject (e.g., human) has been diagnosed as suffering from "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria. In another embodiment of any of the methods and uses described herein, the subject (e.g., 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, the subject (e.g., human) exhibits abnormal synuclein deposition as determined by skin punch biopsy.

[0102] 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, increases the time to significant deterioration in the subject (e.g., human) on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and Part III.

[0103] 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, increases the time to significant deterioration in the subject (e.g., human) on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, Part II, and Part III.

[0104] In yet another embodiment of any of the methods and uses described herein, the 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 the subject (e.g., human) as measured by the Clinical Global Impression of Severity (CGIS) scale.

[0105] 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 (e.g., human) in a fasting state. 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 (e.g., human) in a fasting state at least 1 hour prior to administration. In another 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 (e.g., human) in a fasting state at least 2 hours prior to administration.

[0106] 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 (e.g., human) in a fed state. 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 (e.g., human) shortly after completing a meal, preferably after 10 minutes, more preferably after 30 minutes.

[0107] In one embodiment of any of the methods and uses described herein, the subject (e.g., human) is 50 years old or older. In another embodiment of any of the methods and uses described herein, the subject (e.g., human) is 20 years old or older.

[0108] In one embodiment of any of the methods and uses described herein, the subject (eg, human) is not concomitantly receiving a dopamine replacement medication.

[0109] In another embodiment of any of the methods and uses described herein, the subject (e.g., human) has a body mass index ≥ 18.5 kg / m 2 And ≤45kg / m 2 .

[0110] In one embodiment of any of the methods and uses described herein, about 5 mg to about 480 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (e.g., humans). In one embodiment of any of the methods and uses described herein, about 48 mg to about 480 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (e.g., humans). In another embodiment, 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 is administered to the subject (e.g., humans). In a preferred embodiment, about 134 mg to about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (e.g., humans). In a more preferred embodiment, about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (e.g., humans).

[0111] In one embodiment of any of the methods and uses described herein, about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof in a solid dosage form is administered to the subject (eg, human).

[0112] In one embodiment of any of the methods and uses described herein, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced by half following the occurrence of an adverse event.

[0113] 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.

[0114] 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 a day.

[0115] 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.

[0116] In one embodiment of any of the methods and uses described herein, the subject (e.g., human) is (i) at least 50 years old, (ii) has been preliminarily diagnosed with Parkinson's disease within 3 years of starting treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, (iii) has a modified Hoya staging score of 2 or less, and (iv) is not treated with any dopamine therapy other than a monoamine oxidase-B (MAO-B) inhibitor. Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the subject (e.g., an effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0117]

[0118] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the subject (e.g., an effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0119]

[0120] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0121] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the subject (e.g., an effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0122]

[0123] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0124] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the subject (e.g., an effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0125]

[0126] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0127] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the subject (e.g., an effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0128]

[0129] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0130] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease) in a subject (e.g., a human subject) in need thereof, or delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the subject (e.g., an effective amount of) a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0131]

[0132] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0133] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) in need thereof in the following amount:

[0134]

[0135] The amount is sufficient to achieve a mean 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 .

[0136] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) in need thereof in the following amount,

[0137]

[0138] The amount is sufficient to achieve a mean plasma AUC ranging from about 5,000 ng*hour / ml to about 75,000 ng*hour / ml 0-24 , wherein the subject exhibits disease severity according to the modified Hoya stage ≤2.

[0139] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) in need thereof in the following amount,

[0140]

[0141] The amount is sufficient to achieve a mean plasma AUC ranging from about 5,000 ng*hour / ml to about 75,000 ng*hour / ml 0-24 , wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0142] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0143]

[0144] The amount is sufficient to achieve a mean plasma AUC ranging from about 5,000 ng*hour / ml to about 75,000 ng*hour / 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.

[0145] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0146]

[0147] The amount is sufficient to achieve a mean plasma AUC ranging from about 5,000 ng*hour / ml to about 75,000 ng*hour / ml0-24 , wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0148] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0149]

[0150] The amount is sufficient to achieve a mean plasma AUC ranging from about 5,000 ng*hour / ml to about 75,000 ng*hour / ml 0-24 , wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[0151] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject in need thereof in an amount as follows:

[0152]

[0153] The amount is sufficient to achieve a mean plasma AUC ranging from about 5,000 ng*hour / ml to about 75,000 ng*hour / ml 0-24 , wherein the subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0154] i) disease severity according to the modified Hoya stage ≤2;

[0155] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0156] iii) abnormal synuclein deposits as determined by skin biopsy;

[0157] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0158] v) initial diagnosis of Parkinson's disease;

[0159] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0160] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0161] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0162] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0163] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0164] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0165]

[0166] The amount is sufficient to achieve a plasma C in the range of about 100 ng / mL to about 15,000 ng / mL. max , preferably in the range of about 500 ng / mL to about 15,000 ng / mL of plasma C max , more preferably a plasma Cmax in the range of about 1800 ng / mL to about 12,000 ng / mL.

[0167] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0168]

[0169] The amount is sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max .

[0170] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0171]

[0172] The amount is sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max , wherein the subject exhibits disease severity according to the modified Hoya stage ≤2.

[0173] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0174]

[0175] The amount is sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max , wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0176] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0177]

[0178] The amount is sufficient to achieve a 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.

[0179] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0180]

[0181]

[0182] The amount is sufficient to achieve a 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.

[0183] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0184]

[0185] The amount is sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max , wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[0186] Yet another aspect is a method for treating a neurodegenerative disease (such as Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in the following amount,

[0187]

[0188] The amount is sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max , wherein the subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0189] i) disease severity according to the modified Hoya stage ≤2;

[0190] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0191] iii) abnormal synuclein deposits as determined by skin biopsy;

[0192] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0193] v) initial diagnosis of Parkinson's disease;

[0194] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0195] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0196] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0197] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0198] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0199] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount of

[0200]

[0201] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL, preferably about 2 ng / mL to about 7.0 ng / mL. max In a preferred embodiment, the subject achieves cerebrospinal fluid C no later than 6 hours after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0202] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount of

[0203]

[0204] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max , wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya stage. In a preferred embodiment, the subject achieves cerebrospinal fluid C no later than 6 hours after administration of the compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0205] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0206]

[0207] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25. In a preferred embodiment, the subject achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0208] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0209]

[0210] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 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. In a preferred embodiment, the subject achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0211] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0212]

[0213] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor. In a preferred embodiment, the subject achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0214] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0215]

[0216] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max , wherein the subject is not concomitantly administered symptomatic drugs for Parkinson's disease. In a preferred embodiment, the subject achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0217] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0218]

[0219] The amount is sufficient to achieve a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL. max , wherein the subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0220] i) disease severity according to the modified Hoya stage ≤2;

[0221] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0222] iii) abnormal synuclein deposits as determined by skin biopsy;

[0223] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0224] v) initial diagnosis of Parkinson's disease;

[0225] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0226] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0227] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0228] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0229] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0230] In one embodiment of any of the methods and uses described herein, wherein the subject achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. max .

[0231] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0232]

[0233] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL.

[0234] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0235]

[0236] The amount is sufficient to achieve a CSF concentration of at least about 0.6 ng / mL to about 2.7 ng / mL.

[0237] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0238]

[0239] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, wherein the subject exhibits a disease severity of ≤ 2 according to the modified Hoya stage.

[0240] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0241]

[0242] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0243] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0244]

[0245] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0246] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0247]

[0248] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0249] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0250]

[0251] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[0252] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0253]

[0254] The amount is sufficient to achieve a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL, wherein the subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0255] i) disease severity according to the modified Hoya stage ≤2;

[0256] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0257] iii) abnormal synuclein deposits as determined by skin biopsy;

[0258] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0259] v) initial diagnosis of Parkinson's disease;

[0260] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0261] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0262] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0263] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0264] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0265] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0266]

[0267] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg .

[0268] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0269]

[0270] The amount is sufficient to achieve a mean CSF C of about 2.0 ng / mL to about 3.5 ng / mL. avg .

[0271] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0272]

[0273] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg , wherein the subject exhibits disease severity according to the modified Hoya stage ≤2.

[0274] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0275]

[0276] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0277] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0278]

[0279] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg , wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0280] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0281]

[0282] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg , wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0283] Yet another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease or early Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount as follows:

[0284]

[0285] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg , wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[0286] Another aspect is a method for treating a neurodegenerative disease (e.g., Parkinson's disease) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount of

[0287]

[0288] The amount is sufficient to achieve a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL. avg , wherein the subject exhibits one or more (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0289] i) disease severity according to the modified Hoya stage ≤2;

[0290] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0291] iii) abnormal synuclein deposits as determined by skin biopsy;

[0292] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0293] v) initial diagnosis of Parkinson's disease;

[0294] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0295] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0296] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0297] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0298] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0299] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50A c-Abl inhibitor (such as vodobatinib or a pharmaceutically acceptable salt thereof) is administered (eg, orally) to a subject (eg, a human subject) in need thereof in an amount such that the ratio of wt% to wt% is not less than 1.

[0300] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor (vodobatinib or a pharmaceutically acceptable salt thereof) is administered (e.g., orally) to a subject in need thereof (e.g., a human subject) in an amount such that the ratio of vodobatinib to 1 is not less than 1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0301] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor (vodobatinib or a pharmaceutically acceptable salt thereof) is administered (e.g., orally) to a subject (e.g., a human subject) in need thereof in an amount such that the ratio of vodobatinib to 1 is not less than 1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0302] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor (vodobatinib or a pharmaceutically acceptable salt thereof) is administered (e.g., orally) to a subject in need thereof (e.g., a human subject) in an amount such that the ratio of vodobatinib to 1 is not less than 1, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) scan consistent with a diagnosis of Parkinson's disease.

[0303] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor (vodobatinib or a pharmaceutically acceptable salt thereof) is administered (e.g., orally) to a subject (e.g., a human subject) in need thereof in an amount in which the ratio of vodobatinib to 1 is not less than 1, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0304] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The invention relates to administering a c-Abl inhibitor (vodobatinib or a pharmaceutically acceptable salt thereof) to a subject in need thereof (e.g., a human subject) (e.g., orally) in an amount such that the ratio of vodobatinib to 1 is not less than 1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0305] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering to the patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The invention relates to administering a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof (e.g., orally) in an amount in which the ratio of α to β is not less than 1, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0306] i) disease severity according to the modified Hoya stage ≤2;

[0307] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0308] iii) abnormal synuclein deposits as determined by skin biopsy;

[0309] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0310] v) initial diagnosis of Parkinson's disease;

[0311] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0312] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0313] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0314] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0315] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0316] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0317] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0318] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0319] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max .

[0320] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0321] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0322] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0323] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ,

[0324] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0325] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0326] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0327] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0328] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ,

[0329] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0330] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0331] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0332] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0333] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ,

[0334] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0335] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0336] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0337] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0338] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ,

[0339] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0340] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0341] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0342] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0343] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ,

[0344] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0345] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to achieve:

[0346] i) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0347] ii) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;or

[0348] iii) mean plasma AUC ranging from about 5,000 ng*hr / ml to about 75,000 ng*hr / ml 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[0349] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0350] i) disease severity according to the modified Hoya stage ≤2;

[0351] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0352] iii) abnormal synuclein deposits as determined by skin biopsy;

[0353] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0354] v) initial diagnosis of Parkinson's disease;

[0355] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0356] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0357] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0358] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0359] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0360] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0361] a) Crossing the blood-brain barrier;

[0362] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0363] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0364] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0365] e) Any combination of a), b), c) and d).

[0366] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0367] a) Crossing the blood-brain barrier;

[0368] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0369] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0370] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0371] e) any combination of a), b), c) and d);

[0372] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0373] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0374] a) Crossing the blood-brain barrier;

[0375] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0376] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0377] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0378] e) any combination of a), b), c) and d);

[0379] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0380] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0381] a) Crossing the blood-brain barrier;

[0382] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0383] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0384] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0385] e) any combination of a), b), c) and d);

[0386] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0387] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0388] a) Crossing the blood-brain barrier;

[0389] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0390] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0391] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0392] e) any combination of a), b), c) and d);

[0393] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0394] Yet another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0395] a) Crossing the blood-brain barrier;

[0396] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0397] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0398] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0399] e) any combination of a), b), c) and d);

[0400] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0401] Yet another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0402] a) Crossing the blood-brain barrier;

[0403] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0404] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0405] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0406] e) any combination of a), b), c) and d);

[0407] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0408] i) disease severity according to the modified Hoya stage ≤2;

[0409] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0410] iii) abnormal synuclein deposits as determined by skin biopsy;

[0411] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0412] v) initial diagnosis of Parkinson's disease;

[0413] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0414] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0415] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0416] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0417] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0418] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to:

[0419] a) Crossing the blood-brain barrier;

[0420] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0421] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0422] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0423] e) Any combination of a), b), c) and d).

[0424] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to:

[0425] a) Crossing the blood-brain barrier;

[0426] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0427] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0428] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0429] e) any combination of a), b), c) and d);

[0430] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0431] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to:

[0432] a) Crossing the blood-brain barrier;

[0433] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0434] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0435] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0436] e) any combination of a), b), c) and d);

[0437] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0438] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to cross the blood-brain barrier.

[0439] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof, wherein the subject has been preliminarily diagnosed with Parkinson's disease.

[0440] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof, wherein the subject (e.g., a human) has been initially diagnosed with Parkinson's disease within 3 years of initiating treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0441] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to:

[0442] a) Crossing the blood-brain barrier;

[0443] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0444] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0445] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0446] e) any combination of a), b), c) and d);

[0447] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0448] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to:

[0449] a) Crossing the blood-brain barrier;

[0450] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0451] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0452] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0453] e) any combination of a), b), c) and d);

[0454] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0455] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., a human subject) in an amount sufficient to:

[0456] a) Crossing the blood-brain barrier;

[0457] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0458] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0459] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0460] e) any combination of a), b), c) and d);

[0461] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0462] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises orally administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to:

[0463] a) Crossing the blood-brain barrier;

[0464] b) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0465] c) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0466] d) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0467] e) any combination of a), b), c) and d);

[0468] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0469] i) disease severity according to the modified Hoya stage ≤2;

[0470] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0471] iii) abnormal synuclein deposits as determined by skin biopsy;

[0472] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0473] v) initial diagnosis of Parkinson's disease;

[0474] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0475] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0476] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0477] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0478] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0479] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0480] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0481] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0482] c) cross the blood-brain barrier;

[0483] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0484] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0485] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0486] g) Any combination of a), b), c), d), e) and f).

[0487] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0488] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0489] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0490] c) cross the blood-brain barrier;

[0491] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0492] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0493] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0494] g) any combination of a), b), c), d), e) and f),

[0495] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0496] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0497] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0498] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0499] c) cross the blood-brain barrier;

[0500] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0501] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0502] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0503] g) any combination of a), b), c), d), e) and f),

[0504] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0505] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0506] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0507] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0508] c) cross the blood-brain barrier;

[0509] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0510] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0511] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0512] g) any combination of a), b), c), d), e) and f),

[0513] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0514] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0515] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0516] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0517] c) cross the blood-brain barrier;

[0518] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0519] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0520] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0521] g) any combination of a), b), c), d), e) and f),

[0522] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0523] Another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0524] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0525] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0526] c) cross the blood-brain barrier;

[0527] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0528] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0529] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0530] g) any combination of a), b), c), d), e) and f),

[0531] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0532] Yet another aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a c-Abl inhibitor to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0533] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0534] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0535] c) cross the blood-brain barrier;

[0536] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0537] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0538] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0539] g) any combination of a), b), c), d), e) and f);

[0540] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0541] i) disease severity according to the modified Hoya stage ≤2;

[0542] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0543] iii) abnormal synuclein deposits as determined by skin biopsy;

[0544] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0545] v) initial diagnosis of Parkinson's disease;

[0546] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0547] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0548] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0549] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0550] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0551] Another aspect of the invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0552] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0553] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0554] c) cross the blood-brain barrier;

[0555] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0556] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0557] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0558] g) Any combination of a), b), c), d), e) and f).

[0559] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0560] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0561] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0562] c) cross the blood-brain barrier;

[0563] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0564] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0565] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0566] g) any combination of a), b), c), d), e) and f),

[0567] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0568] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0569] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0570] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0571] c) cross the blood-brain barrier;

[0572] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0573] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0574] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0575] g) any combination of a), b), c), d), e) and f),

[0576] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0577] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0578] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0579] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0580] c) cross the blood-brain barrier;

[0581] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0582] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0583] f) Achieve average CSF C maxIC of c-Abl inhibition 50 is not less than 1; or

[0584] g) any combination of a), b), c), d), e) and f),

[0585] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0586] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0587] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0588] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0589] c) cross the blood-brain barrier;

[0590] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0591] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0592] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0593] g) any combination of a), b), c), d), e) and f),

[0594] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0595] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0596] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0597] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0598] c) cross the blood-brain barrier;

[0599] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0600] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0601] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0602] g) any combination of a), b), c), d), e) and f),

[0603] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0604] Yet another aspect of the present invention is a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., orally) in an amount sufficient to:

[0605] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0606] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0607] c) cross the blood-brain barrier;

[0608] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0609] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0610] f) Achieve average CSF C max IC of c-Abl inhibition50 is not less than 1; or

[0611] g) any combination of a), b), c), d), e) and f);

[0612] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0613] i) disease severity according to the modified Hoya stage ≤2;

[0614] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0615] iii) abnormal synuclein deposits as determined by skin biopsy;

[0616] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0617] v) initial diagnosis of Parkinson's disease;

[0618] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0619] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0620] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0621] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0622] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0623] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0624] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0625] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0626] c) cross the blood-brain barrier;

[0627] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0628] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0629] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0630] g) Any combination of a), b), c), d), e) and f).

[0631] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0632] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0633] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0634] c) cross the blood-brain barrier;

[0635] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0636] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0637] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0638] g) any combination of a), b), c), d), e) and f),

[0639] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0640] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0641] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0642] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0643] c) cross the blood-brain barrier;

[0644] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0645] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0646] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0647] g) any combination of a), b), c), d), e) and f),

[0648] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0649] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0650] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0651] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0652] c) cross the blood-brain barrier;

[0653] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0654] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0655] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0656] g) any combination of a), b), c), d), e) and f),

[0657] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0658] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0659] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0660] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0661] c) cross the blood-brain barrier;

[0662] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0663] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0664] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0665] g) any combination of a), b), c), d), e) and f),

[0666] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0667] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0668] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0669] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0670] c) cross the blood-brain barrier;

[0671] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0672] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0673] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0674] g) any combination of a), b), c), d), e) and f),

[0675] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0676] Yet another aspect is the use of a c-Abl inhibitor for the preparation of a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof, or for delaying, inhibiting, or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the c-Abl inhibitor in an amount sufficient to:

[0677] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0678] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0679] c) cross the blood-brain barrier;

[0680] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mLmax ;

[0681] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0682] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0683] g) any combination of a), b), c), d), e) and f);

[0684] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0685] i) disease severity according to the modified Hoya stage ≤2;

[0686] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0687] iii) abnormal synuclein deposits as determined by skin biopsy;

[0688] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0689] v) initial diagnosis of Parkinson's disease;

[0690] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0691] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0692] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0693] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0694] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0695] Yet another aspect of the present invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject in need thereof (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0696] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0697] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0698] c) cross the blood-brain barrier;

[0699] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0700] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0701] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0702] g) Any combination of a), b), c), d), e) and f).

[0703] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0704] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0705] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0706] c) cross the blood-brain barrier;

[0707] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0708] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0709] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0710] g) any combination of a), b), c), d), e) and f),

[0711] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0712] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0713] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0714] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0715] c) cross the blood-brain barrier;

[0716] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0717] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0718] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0719] g) any combination of a), b), c), d), e) and f),

[0720] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0721] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0722] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0723] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0724] c) cross the blood-brain barrier;

[0725] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0726] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0727] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0728] g) any combination of a), b), c), d), e) and f),

[0729] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0730] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0731] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0732] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0733] c) cross the blood-brain barrier;

[0734] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0735] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0736] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0737] g) any combination of a), b), c), d), e) and f),

[0738] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0739] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0740] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0741] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0742] c) cross the blood-brain barrier;

[0743] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0744] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0745] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0746] g) any combination of a), b), c), d), e) and f),

[0747] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0748] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a neurodegenerative disease in a subject (e.g., a human subject) in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the medicament comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to perform the following:

[0749] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0750] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[0751] c) cross the blood-brain barrier;

[0752] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0753] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0754] f) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0755] g) any combination of a), b), c), d), e) and f);

[0756] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0757] i) disease severity according to the modified Hoya stage ≤2;

[0758] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0759] iii) abnormal synuclein deposits as determined by skin biopsy;

[0760] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0761] v) initial diagnosis of Parkinson's disease;

[0762] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0763] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0764] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0765] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0766] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0767] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount with a ratio of not less than 1.

[0768] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1.

[0769] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1, wherein the subject exhibits disease severity according to the modified Hoya stage ≤ 2.

[0770] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0771] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0772] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0773] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1, wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[0774] Yet another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof safely achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[0775] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0776] i) disease severity according to the modified Hoya stage ≤2;

[0777] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0778] iii) abnormal synuclein deposits as determined by skin biopsy;

[0779] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0780] v) initial diagnosis of Parkinson's disease;

[0781] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0782] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0783] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0784] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0785] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0786] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount in which the ratio is not less than 1.

[0787] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early-stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (eg, orally) in an amount in which the ratio is not less than 1.

[0788] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early-stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (eg, orally) in an amount in which the ratio is not less than 1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0789] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early-stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (eg, orally) in an amount in which the ratio is not less than 1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0790] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early-stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50 A compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (e.g., orally) in an amount in which the ratio is not less than 1, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0791] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early-stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to the subject in an amount in which the ratio is not less than 1, wherein the subject is undergoing treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0792] Another aspect is a method for reducing the rate of progression of Parkinson's disease, preferably early-stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (eg, orally) in an amount in which the ratio is not less than 1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0793] Yet another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, in a subject (e.g., a human subject), wherein the method comprises administering to a subject sufficient to achieve CSF C max IC of c-Abl inhibition 50 administering to the subject (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount not less than 1;

[0794] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0795] i) disease severity according to the modified Hoya stage ≤2;

[0796] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0797] iii) abnormal synuclein deposits as determined by skin biopsy;

[0798] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0799] v) initial diagnosis of Parkinson's disease;

[0800] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0801] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0802] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0803] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0804] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0805] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject (eg, a human subject) in need thereof in an amount of

[0806] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) to a subject (e.g., a human subject) in need thereof in an amount of, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0807] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject (eg, a human subject) in need thereof in an amount of, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0808] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) to a subject (e.g., a human subject) in need thereof in an amount of, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0809] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) to a subject (e.g., a human subject) in need thereof in an amount of, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0810] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject (eg, a human subject) in need thereof in an amount of, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0811] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of said neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein said compound of formula I or a pharmaceutically acceptable salt thereof achieves an average plasma AUC in the range of about 30,000 ng*hour / ml to about 50,000 ng*hour / ml 0-24 and / or a plasma C ranging from about 3,000 ng / mL to about 7,000 ng / mL max .

[0812] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of said neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein said compound of formula I or a pharmaceutically acceptable salt thereof achieves an average plasma AUC in the range of about 40,000 ng*hour / ml to about 60,000 ng*hour / ml 0-24 and / or a plasma C ranging from about 5,000 ng / mL to about 9,000 ng / mL max .

[0813] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of said neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein said compound of formula I or a pharmaceutically acceptable salt thereof achieves an average plasma AUC in the range of about 15,000 ng*hour / ml to about 40,000 ng*hour / ml 0-24 and / or a plasma C ranging from about 1,000 ng / mL to about 4,000 ng / mL max .

[0814] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, in a subject (e.g., a human subject) or delaying, inhibiting or suppressing the progression of said neurodegenerative disease, preferably Parkinson's disease, more preferably early Parkinson's disease, wherein said compound of formula I or a pharmaceutically acceptable salt thereof achieves an average plasma AUC in the range of about 25,000 ng*hour / ml to about 50,000 ng*hour / ml 0-24 and / or a plasma C ranging from about 2,000 ng / mL to about 6,000 ng / mL max .

[0815] Yet another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, preferably early stage Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL maxadministering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount of

[0816] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0817] i) disease severity according to the modified Hoya stage ≤2;

[0818] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0819] iii) abnormal synuclein deposits as determined by skin biopsy;

[0820] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0821] v) initial diagnosis of Parkinson's disease;

[0822] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[0823] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[0824] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0825] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0826] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0827] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0828] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0829] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0830] c) Achieve average CSF Cmax IC of c-Abl inhibition 50 is not less than 1; or

[0831] e) Any combination of a), b) and c).

[0832] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0833] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0834] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0835] c) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0836] d) any combination of a), b) and c),

[0837] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[0838] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0839] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0840] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0841] c) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0842] d) any combination of a), b) and c),

[0843] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0844] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0845] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0846] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0847] c) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0848] d) any combination of a), b) and c),

[0849] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0850] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0851] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0852] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0853] c) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0854] d) any combination of a), b) and c),

[0855] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0856] Another aspect of the invention is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject (e.g., a human subject) in need thereof in an amount sufficient to:

[0857] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0858] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL;

[0859] c) Achieve average CSF C max IC of c-Abl inhibition 50 is not less than 1; or

[0860] d) any combination of a), b) and c),

[0861] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[0862] Yet another aspect is a method for reducing the rate of progression of an early stage neurodegenerative disease, wherein the method comprises 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:

[0863] a) Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0864] b) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[0865] c) Provides average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[0866] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0867] i) disease severity according to the modified Hoya stage ≤2;

[0868] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0869] iii) abnormal synuclein deposits as determined by skin biopsy;

[0870] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0871] v) initial diagnosis of Parkinson's disease;

[0872] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0873] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0874] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0875] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0876] x) Montreal Cognitive Assessment score of at least 25.

[0877] Another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[0878] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0879] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[0880] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[0881] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[0882] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[0883] And wherein the composition is used to treat neurodegenerative diseases or delay, inhibit or suppress the progression of neurodegenerative diseases.

[0884] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for treating a neurodegenerative disease in a subject or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[0885] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL0-24 ;

[0886] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[0887] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[0888] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[0889] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[0890] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0891] i) disease severity according to the modified Hoya stage ≤2;

[0892] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0893] iii) abnormal synuclein deposits as determined by skin biopsy;

[0894] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0895] v) initial diagnosis of Parkinson's disease;

[0896] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0897] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0898] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0899] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0900] x) Montreal Cognitive Assessment score of at least 25.

[0901] According to the present invention, the neurodegenerative diseases (ND) mentioned herein include but are not limited to Parkinson's disease (PD), Alzheimer's disease (AD) or synuclein diseases, such as 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 neurodegenerative diseases, which include but are not limited to early Parkinson's disease (PD), early Alzheimer's disease (AD) and early synuclein diseases, including early Lewy body dementia (LBD), early rapid eye movement (REM) sleep behavior disorder and early multiple system atrophy (MSA).

[0902] Another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the compound.

[0903] Yet another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of 1:1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0904] Yet another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of 1:1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0905] Yet another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount consistent with a diagnosis of Parkinson's disease, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT).

[0906] Yet another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the subject, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0907] Yet another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of about 1:1 to about 1:1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0908] Yet another aspect is a method for treating Parkinson's disease (PD) in a subject in need thereof or delaying, inhibiting or arresting the progression of said PD, the method comprising administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount of 500 mg / kg to a subject, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0909] i) disease severity according to the modified Hoya stage ≤2;

[0910] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0911] iii) abnormal synuclein deposits as determined by skin biopsy;

[0912] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0913] v) initial diagnosis of Parkinson's disease;

[0914] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0915] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0916] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0917] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0918] x) Montreal Cognitive Assessment score of at least 25.

[0919] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the compound.

[0920] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of 1:1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0921] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of 1:1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0922] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount consistent with a diagnosis of Parkinson's disease, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT).

[0923] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the subject, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0924] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of about 1:1 to about 1:1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0925] Yet another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount; wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0926] i) disease severity according to the modified Hoya stage ≤2;

[0927] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0928] iii) abnormal synuclein deposits as determined by skin biopsy;

[0929] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0930] v) initial diagnosis of Parkinson's disease;

[0931] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0932] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0933] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0934] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0935] x) Montreal Cognitive Assessment score of at least 25.

[0936] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the compound.

[0937] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSFC sufficient to achieve a range of about 2 ng / mL to about 7 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the compound.

[0938] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of 1:1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0939] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of 1:1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0940] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. maxThe compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount consistent with a diagnosis of Parkinson's disease, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT).

[0941] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount appropriate for the subject, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0942] Another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) in an amount of about 1:1 to about 1:1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0943] Yet another aspect is a method for treating Parkinson's disease in a subject in need thereof or delaying, inhibiting or arresting the progression of Parkinson's disease, the method comprising administering a dose sufficient to achieve a CSF C level in the range of about 0.4 ng / mL to about 7.0 ng / mL. max The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (e.g., orally) in an amount of 500 mg / kg to a subject, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0944] i) disease severity according to the modified Hoya stage ≤2;

[0945] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0946] iii) abnormal synuclein deposits as determined by skin biopsy;

[0947] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0948] v) initial diagnosis of Parkinson's disease;

[0949] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0950] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0951] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0952] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0953] x) Montreal Cognitive Assessment score of at least 25.

[0954] Another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The c-Abl inhibitor is administered to a subject in need thereof (eg, orally) in an amount such that the ratio of 1:1 to 1:1 is not less than 1.

[0955] Yet another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The invention further comprises administering a c-Abl inhibitor to a subject in need thereof (e.g., orally) in an amount such that the ratio of α to β is not less than 1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0956] Yet another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The c-Abl inhibitor is administered (e.g., orally) to a subject in need thereof in an amount such that the ratio of % to % is not less than 1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0957] Yet another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor is administered (e.g., orally) to a subject in need thereof in an amount such that the ratio of % to % is not less than 1, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0958] Yet another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The c-Abl inhibitor is administered (eg, orally) to a subject in need thereof in an amount such that the ratio of α to β is not less than 1, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0959] Yet another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The c-Abl inhibitor is administered to a subject in need thereof (e.g., orally) in an amount such that the ratio of α to β is not less than 1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0960] Yet another aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 administering a c-Abl inhibitor to a subject in need thereof (e.g., orally) in an amount such that the ratio of α to β is not less than 1; wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[0961] i) disease severity according to the modified Hoya stage ≤2;

[0962] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0963] iii) abnormal synuclein deposits as determined by skin biopsy;

[0964] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0965] v) initial diagnosis of Parkinson's disease;

[0966] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0967] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0968] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0969] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0970] x) Montreal Cognitive Assessment score of at least 25.

[0971] One aspect is a method for treating Parkinson's disease or delaying, inhibiting or arresting the progression of Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The c-Abl inhibitor is administered to a subject in need thereof (eg, orally) in an amount ranging from 1 to 14.

[0972] In a preferred embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve C max With IC 50 The ratio is greater than 5.

[0973] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a subject (eg, human) in need thereof in an amount in which the ratio of 1 to 14 is between 1 and 14.

[0974] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 The c-Abl inhibitor is administered to a subject in need thereof in an amount in which the ratio of the c-Abl inhibitor to the c-Abl inhibitor is 1 to 14, preferably the c-Abl inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0975] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50A c-Abl inhibitor is administered (e.g., orally) to a subject in need thereof, preferably a compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount in which the ratio of 1 to 14 is 1 to 14, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[0976] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor, preferably a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof (e.g., orally) in an amount in which the ratio of 1 to 14 is 1 to 14, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[0977] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor, preferably a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered (e.g., orally) to a subject in need thereof in an amount in which the ratio of 1 to 14 is 1 to 14, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[0978] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 A c-Abl inhibitor, preferably a compound of Formula I or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof (e.g., orally) in an amount in which the ratio of 1 to 14 is 1 to 14, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[0979] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition50 A c-Abl inhibitor is administered to a subject in need thereof (e.g., orally) in an amount of 1 to 14 at a ratio of 1 to 14, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[0980] One aspect is a method for treating a neurodegenerative disease or delaying, inhibiting or arresting the progression of said neurodegenerative disease, preferably the neurodegenerative disease is Parkinson's disease or early Parkinson's disease, wherein said method comprises administering to said patient a dose sufficient to achieve a mean CSF C max IC of c-Abl inhibition 50 administering a c-Abl inhibitor to a subject in need thereof, preferably a compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount of 1 to 14 of a ratio of 1 to 14; wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[0981] i) disease severity according to the modified Hoya stage ≤2;

[0982] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[0983] iii) abnormal synuclein deposits as determined by skin biopsy;

[0984] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[0985] v) initial diagnosis of Parkinson's disease;

[0986] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[0987] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[0988] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[0989] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[0990] x) Montreal Cognitive Assessment score of at least 25.

[0991] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve Cmax With IC 50 The ratio is greater than 5.

[0992] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[0993] a. Achieve mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[0994] b. Achieve a plasma C range of about 500 ng / mL to about 15,000 ng / mL max ,

[0995] c. Cross the blood-brain barrier;

[0996] d. Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[0997] e. achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[0998] f. Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1.

[0999] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[1000] a. Achieve mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1001] b. Achieve a plasma C range of about 500 ng / mL to about 15,000 ng / mL max ,

[1002] c. Cross the blood-brain barrier;

[1003] d. Achieve a CSF C range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1004] e. achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1005] f. Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1006] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[1007] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[1008] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1009] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ,

[1010] c) cross the blood-brain barrier;

[1011] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1012] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1013] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1014] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1015] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[1016] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1017] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ,

[1018] c) cross the blood-brain barrier;

[1019] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1020] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1021] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1022] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1023] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[1024] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1025] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ,

[1026] c) cross the blood-brain barrier;

[1027] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1028] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1029] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1030] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[1031] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[1032] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1033] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ,

[1034] c) cross the blood-brain barrier;

[1035] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1036] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1037] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1038] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[1039] Yet another aspect is a method for treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to:

[1040] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1041] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ,

[1042] c) cross the blood-brain barrier;

[1043] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1044] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1045] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1046] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1047] i) disease severity according to the modified Hoya stage ≤2;

[1048] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1049] iii) abnormal synuclein deposits as determined by skin biopsy;

[1050] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1051] v) initial diagnosis of Parkinson's disease;

[1052] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1053] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1054] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1055] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1056] x) Montreal Cognitive Assessment score of at least 25.

[1057] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament, wherein the medicament comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to:

[1058] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1059] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[1060] c) cross the blood-brain barrier;

[1061] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1062] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1063] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1064] And wherein the drug is used to treat Parkinson's disease or early Parkinson's disease or delay, inhibit or suppress the progression of Parkinson's disease or early Parkinson's disease.

[1065] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating Parkinson's disease or early Parkinson's disease in a subject or delaying, inhibiting or arresting the progression of said Parkinson's disease or early Parkinson's disease, wherein the medicament comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to:

[1066] a) achieving a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1067] b) Achieving a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max ;

[1068] c) cross the blood-brain barrier;

[1069] d) achieving a CSF C in the range of about 0.4 ng / mL to about 7.0 ng / mL max ;

[1070] e) achieving a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1071] f) Achieve average CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1072] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1073] i) disease severity according to the modified Hoya stage ≤2;

[1074] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1075] iii) abnormal synuclein deposits as determined by skin biopsy;

[1076] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1077] v) initial diagnosis of Parkinson's disease;

[1078] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1079] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1080] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1081] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1082] x) Montreal Cognitive Assessment score of at least 25.

[1083] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof safely achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1.

[1084] Yet another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof safely achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1085] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1086] i) disease severity according to the modified Hoya stage ≤2;

[1087] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1088] iii) abnormal synuclein deposits as determined by skin biopsy;

[1089] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1090] v) initial diagnosis of Parkinson's disease;

[1091] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1092] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1093] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1094] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1095] x) Montreal Cognitive Assessment score of at least 25.

[1096] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering to the patient sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount in which the ratio is not less than 1.

[1097] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering to the patient sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount in which the ratio is not less than 1, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[1098] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering to the patient sufficient to achieve CSF C max IC of c-Abl inhibition 50A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount in which the ratio is not less than 1, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1099] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering to the patient sufficient to achieve CSF C max IC of c-Abl inhibition 50 A compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount in which the ratio is not less than 1, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1100] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering to the patient sufficient to achieve CSF C max IC of c-Abl inhibition 50 A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount not less than 1, wherein the subject is undergoing treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[1101] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering to the patient sufficient to achieve CSF C max IC of c-Abl inhibition 50 The compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount not less than 1, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[1102] Another aspect is a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the compound of formula I or a pharmaceutically acceptable salt thereof safely achieves CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1103] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1104] i) disease severity according to the modified Hoya stage ≤2;

[1105] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1106] iii) abnormal synuclein deposits as determined by skin biopsy;

[1107] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1108] v) initial diagnosis of Parkinson's disease;

[1109] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1110] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1111] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1112] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1113] x) Montreal Cognitive Assessment score of at least 25.

[1114] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of

[1115] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of , wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya staging system.

[1116] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of , wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1117] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of , wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1118] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of , wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[1119] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering a dose sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of 50 mg / kg to about 50 mg / kg, wherein the subject is not concomitantly administered a symptomatic drug for Parkinson's disease.

[1120] Another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / mL to about 75,000 ng*hr / mL. 0-24 and / or a plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., orally);

[1121] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1122] i) disease severity according to the modified Hoya stage ≤2;

[1123] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1124] iii) abnormal synuclein deposits as determined by skin biopsy;

[1125] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1126] v) initial diagnosis of Parkinson's disease;

[1127] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1128] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1129] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1130] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1131] x) Montreal Cognitive Assessment score of at least 25.

[1132] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1133] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1134] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1135] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1.

[1136] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1137] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1138] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1139] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1140] wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[1141] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1142] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1143] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1144] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1145] wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1146] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1147] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1148] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1149] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1150] wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1151] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1152] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1153] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1154] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1155] wherein the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[1156] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1157] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1158] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1159] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1160] The subject is not concomitantly taking symptomatic medication for Parkinson's disease.

[1161] Yet another aspect is a method for reducing the rate of progression of Parkinson's disease or early Parkinson's disease, wherein the method comprises 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:

[1162] a) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1163] b) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1164] c) Mean CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1165] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1166] i) disease severity according to the modified Hoya stage ≤2;

[1167] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1168] iii) abnormal synuclein deposits as determined by skin biopsy;

[1169] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1170] v) initial diagnosis of Parkinson's disease;

[1171] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1172] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1173] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1174] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1175] x) Montreal Cognitive Assessment score of at least 25.

[1176] 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 in a subject or delaying, inhibiting or suppressing the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[1177] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1178] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1179] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1180] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1181] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1.

[1182] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease in a human patient or delaying, inhibiting or arresting the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[1183] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1184] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1185] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1186] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1187] e)CSF C maxIC of c-Abl inhibition 50 The ratio is not less than 1,

[1188] The patients presented with disease severity of ≤2 according to the modified Hoya stage.

[1189] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease in a human patient or delaying, inhibiting or arresting the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[1190] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1191] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1192] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1193] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1194] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1195] wherein the patient exhibits a Montreal Cognitive Assessment score of at least 25.

[1196] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease in a human patient or delaying, inhibiting or arresting the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[1197] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1198] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1199] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1200] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1201] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1202] wherein the patient exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) scan consistent with a diagnosis of Parkinson's disease.

[1203] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease in a human patient or delaying, inhibiting or arresting the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[1204] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1205] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1206] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1207] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1208] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1209] wherein the patient is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[1210] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease in a human patient or delaying, inhibiting or arresting the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve:

[1211] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1212] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1213] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1214] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1215] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1,

[1216] The patient is not taking concomitant symptomatic medication for Parkinson's disease.

[1217] Yet another aspect is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating Parkinson's disease or early Parkinson's disease in a human patient or delaying, inhibiting or arresting the progression of Parkinson's disease or early Parkinson's disease, wherein the composition comprises the compound of Formula I in an amount sufficient to achieve:

[1218] a) Mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 ;

[1219] b) plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max ;

[1220] c) CSF C ranging from about 0.4 ng / mL to about 7.0 ng / mL max ;

[1221] d) a CSF concentration of at least about 0.2 ng / mL to about 2.7 ng / mL; and / or

[1222] e)CSF C max IC of c-Abl inhibition 50 The ratio is not less than 1;

[1223] The subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1224] i) disease severity according to the modified Hoya stage ≤2;

[1225] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1226] iii) abnormal synuclein deposits as determined by skin biopsy;

[1227] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1228] v) initial diagnosis of Parkinson's disease;

[1229] vi) currently receiving treatment with monoamine oxidase-B (MAO-B) inhibitors;

[1230] vii) no concomitant administration of symptomatic medication for Parkinson's disease;

[1231] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1232] ix) diagnosed with "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1233] x) Montreal Cognitive Assessment score of at least 25.

[1234] Another aspect of the invention relates to a method of reducing the rate of progression of Parkinson's disease or early stage Parkinson's disease in a human subject.

[1235] 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 exhibits a disease severity of ≤2 according to the modified Hoya stage.

[1236] Another aspect of the invention relates to a method of reducing the rate of progression of Parkinson's disease or early stage Parkinson's disease in a human subject, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1237] 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 exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1238] 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 is being treated with a monoamine oxidase-B (MAO-B) inhibitor.

[1239] 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 is not concomitantly administered symptomatic medication for Parkinson's disease.

[1240] Yet another aspect of the present 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 exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[1241] i) disease severity according to the modified Hoya stage ≤2;

[1242] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1243] iii) abnormal synuclein deposits as determined by skin biopsy;

[1244] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1245] v) initial diagnosis of Parkinson's disease;

[1246] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[1247] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[1248] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1249] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1250] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1251] Another aspect of the present invention relates to 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) with a disease severity of ≤2 according to the modified Hoya stage, the method comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the subject (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 a day. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice a day.

[1252] Another aspect of the present invention relates to 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 according to the modified Hoya stage ≤2, the method comprising administering to the subject (e.g., orally) once a day an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[1253] Another aspect of the invention is a method for reducing the rate of progression of movement deficits due to Parkinson's disease in a human subject with early-stage Parkinson's disease. Another aspect of the invention is a method for reducing the rate of progression of movement deficits due to Parkinson's disease in a human subject with early-stage Parkinson's disease, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya stage.

[1254] Another aspect of the invention is a method for reducing the rate of progression of motor deficits caused by Parkinson's disease in a human subject with early-stage Parkinson's disease, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1255] Another aspect of the invention is a method for reducing the rate of progression of movement deficits caused by Parkinson's disease in a human subject with early-stage Parkinson's disease, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1256] Another aspect of the invention is a method for reducing the rate of progression of movement deficits caused by Parkinson's disease in a human subject with early-stage Parkinson's disease, wherein the subject is being treated with a monoamine oxidase-B (MAO-B) inhibitor.

[1257] Another aspect of the invention is a method for reducing the rate of progression of movement deficits caused by Parkinson's disease in a human subject with early-stage Parkinson's disease, wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[1258] Another aspect of the invention is a method for reducing the rate of progression of movement deficits caused by Parkinson's disease in a human subject with early-stage Parkinson's disease, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[1259] i) disease severity according to the modified Hoya stage ≤2;

[1260] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1261] iii) abnormal synuclein deposits as determined by skin biopsy;

[1262] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1263] v) initial diagnosis of Parkinson's disease;

[1264] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[1265] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[1266] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1267] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1268] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1269] Another aspect of the present invention is a method for reducing the rate of progression of motor deficits caused by Parkinson's disease in a human subject with early Parkinson's disease and having a disease severity of ≤2 according to the modified Hoya stage, 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.

[1270] Yet another aspect of the present invention is a method for regulating or maintaining autonomic function in a human subject with Parkinson's disease or early Parkinson's disease. 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 a day. Yet another aspect of the present invention is a method for regulating or maintaining autonomic function in a human subject with Parkinson's disease or early Parkinson's disease, wherein the subject exhibits a disease severity of ≤2 according to the modified Hoya stage.

[1271] Yet another aspect of the invention is a method of regulating or maintaining autonomic function in a human subject having Parkinson's disease or early stage Parkinson's disease, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1272] Yet another aspect of the invention is a method of modulating or maintaining autonomic function in a human subject having Parkinson's disease or early stage Parkinson's disease, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease.

[1273] Yet another aspect of the invention is a method of regulating or maintaining autonomic function in a human subject having Parkinson's disease or early stage Parkinson's disease, wherein the subject is being treated with a monoamine oxidase-B (MAO-B) inhibitor.

[1274] Yet another aspect of the present invention is a method of regulating or maintaining autonomic function in a human subject suffering from Parkinson's disease or early stage Parkinson's disease, wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[1275] Yet another aspect of the invention is a method of regulating or maintaining autonomic function in a human subject suffering from Parkinson's disease or early stage Parkinson's disease, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1276] i) disease severity according to the modified Hoya stage ≤2;

[1277] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1278] iii) abnormal synuclein deposits as determined by skin biopsy;

[1279] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1280] v) initial diagnosis of Parkinson's disease;

[1281] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[1282] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[1283] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1284] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1285] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1286] 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.

[1287] Yet another aspect is a method of regulating or maintaining autonomic function in a human subject suffering from Parkinson's disease or early Parkinson's disease and having a disease severity of ≤2 according to the modified Hoya stage, 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.

[1288] Yet another aspect is a method of reducing autonomic deterioration caused by 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 a day.

[1289] Yet another aspect is a method of reducing autonomic deterioration caused by early-stage Parkinson's disease in a human subject in need thereof, wherein the subject exhibits disease severity of ≤2 according to the modified Hoya stage.

[1290] Yet another aspect is a method of reducing autonomic deterioration caused by early-stage Parkinson's disease in a human subject in need thereof, wherein the subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1291] Yet another aspect is a method of reducing autonomic deterioration caused by early-stage Parkinson's disease in a human subject in need thereof, wherein the subject exhibits a dopamine transporter single photon emission computed tomography (DaT SPECT) scan consistent with a diagnosis of Parkinson's disease.

[1292] Yet another aspect is a method of reducing autonomic deterioration caused by early-stage Parkinson's disease in a human subject in need thereof, wherein the subject is receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor.

[1293] Yet another aspect is a method of reducing autonomic deterioration caused by early-stage Parkinson's disease in a human subject in need thereof, wherein the subject is not concomitantly administered symptomatic medications for Parkinson's disease.

[1294] Another aspect of the invention is a method of reducing autonomic deterioration caused by Parkinson's disease or early Parkinson's disease in a human subject in need thereof, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[1295] i) disease severity according to the modified Hoya stage ≤2;

[1296] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1297] iii) abnormal synuclein deposits as determined by skin biopsy;

[1298] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1299] v) initial diagnosis of Parkinson's disease;

[1300] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[1301] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[1302] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1303] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1304] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1305] 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.

[1306] Yet another aspect is a method of reducing autonomic deterioration caused by Parkinson's disease or early Parkinson's disease in a human subject in need thereof and having a disease severity according to the modified Hoya stage ≤ 2, 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. Yet another aspect is a method of treating early Parkinson's disease, wherein the subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10) of the following:

[1307] i) disease severity according to the modified Hoya stage ≤2;

[1308] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1309] iii) abnormal synuclein deposits as determined by skin biopsy;

[1310] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1311] v) initial diagnosis of Parkinson's disease;

[1312] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[1313] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[1314] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1315] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1316] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1317] 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.

[1318] Yet another aspect of the present invention is a method for treating Parkinson's disease in a human subject having early Parkinson's disease and having a disease severity of ≤2 according to the modified Hoya stage, the method comprising administering to the subject (e.g., orally) once a day an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[1319] Yet another aspect is a method of treating Parkinson's disease in a human subject, the method comprising administering to the subject (e.g., orally) once daily (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 in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension (e.g., about 134 mg or about 269 mg), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve in the subject (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg , or any combination of (i), (ii), (iii) and (iv) orally administered in an amount of 1:1. In one embodiment, the human subject has a disease severity of ≤2 according to the modified Hoya stage. In one embodiment, the human subject exhibits a Montreal Cognitive Assessment score of at least 25. 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 administered a symptomatic medication for Parkinson's disease.

[1320] Yet another aspect of the present invention is a method of reducing the rate of progression of Parkinson's disease in a human subject, the method comprising orally administering to the subject once daily (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) a compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms in an amount sufficient to achieve the same bioavailability as the aqueous suspension (e.g., about 134 mg or about 269 mg) or (iii) a compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms in an amount sufficient to achieve the same bioavailability as the aqueous suspension (e.g., about 134 mg or about 269 mg), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve in the subject (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL. max, (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg , or any combination of (i), (ii), (iii) and (iv) orally administered in an amount of 1:1. In one embodiment, the human subject has a disease severity of ≤2 according to the modified Hoya stage. In one embodiment, the human subject exhibits a Montreal Cognitive Assessment score of at least 25. 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 administered a symptomatic medication for Parkinson's disease.

[1321] Yet another aspect of the present invention is a method of reducing the rate of progression of motor deficits caused by Parkinson's disease in a human subject, the method comprising orally administering to the subject once daily (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 in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension (e.g., about 134 mg or about 269 mg), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve in the subject (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg, or any combination of (i), (ii), (iii) and (iv) orally administered in an amount of 1:1. In one embodiment, the human subject has a disease severity of ≤2 according to the modified Hoya stage. In one embodiment, the human subject exhibits a Montreal Cognitive Assessment score of at least 25. 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 administered a symptomatic medication for Parkinson's disease.

[1322] Yet another aspect of the present invention is a method of reducing autonomic deterioration caused by Parkinson's disease in a human subject, the method comprising orally administering to the subject once daily (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 in one or more solid dosage forms sufficient to achieve the same bioavailability as the aqueous suspension (e.g., about 134 mg or about 269 mg), wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve in the subject (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg , or any combination of (i), (ii), (iii) and (iv) orally administered in an amount of 1:1. In one embodiment, the human subject has a disease severity of ≤2 according to the modified Hoya stage. In one embodiment, the human subject exhibits a Montreal Cognitive Assessment score of at least 25. 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 administered a symptomatic medication for Parkinson's disease.

[1323] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve C maxWith IC 50 The ratio is greater than about 5 (such as about 6, about 7, about 8, about 9, about 10, about 11, about 12 or about 13) when administered (e.g., orally).

[1324] In one embodiment of any of the methods and uses described herein, the subject has been diagnosed as having "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria. See, e.g., Pastuma et al., Movement Disorders, 30(12), 1591-1599, 2015. To account for multiple uses, the MDS-PD criteria include two different levels of diagnostic certainty. These diagnostic certainties are:

[1325] 1. Clinically established PD: Maximizing specificity, targeting the anchor category that the majority (ie, at least 90%) will have PD. It is presumed that many real PD cases will not meet this level of certainty.

[1326] 2. Clinically probable PD: balancing sensitivity and specificity, with the goal of anchoring the category with at least 80% of patients diagnosed with probable PD actually having PD and identifying 80% of true PD cases.

[1327] In one embodiment of any of the methods and uses described herein, the subject has a dopamine transporter single photon emission computed tomography (DaT SPECT) consistent with a diagnosis of Parkinson's disease. See, e.g., Akdemir et al., Turk. J. Med. Sci., 51(2)400-410, 2021.

[1328] In one embodiment of any of the methods and uses described herein, the subject exhibits abnormal synuclein deposition as determined by skin punch biopsy.

[1329] 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, increases the subject's time to significant worsening on MDS-UPDRS (Unified Parkinson's Disease Rating Scale) Part II and Part III.

[1330] 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, increases the time to significant worsening in the subject on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, Part II, and Part III.

[1331] In one embodiment of any of the methods and uses described herein, the c-Abl inhibitor is administered to the 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 a compound of Formula I or a pharmaceutically acceptable salt thereof.

[1332] 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 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 the 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 the 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 the aqueous suspension containing about 192 mg or about 384 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[1333] 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 human subject in a 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 the human subject in a 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 the human subject in a 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 the human subject in a 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 the human subject in a 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 the human subject in a 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 the human subject in a 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 the 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 the human subject in an amount of about 384 mg.

[1334] In one embodiment of any of the methods described herein, the compound of Formula I or its salt is administered orally to the human subject. In a more preferred embodiment, the compound of Formula I or its salt is administered to the human subject in the form of an aqueous suspension. In yet another embodiment, the compound of Formula I or its salt 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 its pharmaceutically acceptable salt.

[1335] In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the 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.

[1336] 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 human subject once a day. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the human subject twice a day. In a preferred embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally.

[1337] In one embodiment of any of the methods and uses described herein for treating a human subject, the human subject exhibits one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following:

[1338] i) disease severity according to the modified Hoya stage ≤2;

[1339] ii) dopamine transporter single photon emission computed tomography (DaTSPECT) consistent with a diagnosis of Parkinson's disease;

[1340] iii) abnormal synuclein deposits as determined by skin biopsy;

[1341] iv) The subject's body mass index is ≥ 18.5 kg / m 2 And ≤45kg / m 2 ;

[1342] v) initial diagnosis of Parkinson's disease;

[1343] vi) the subject is currently receiving treatment with a monoamine oxidase-B (MAO-B) inhibitor;

[1344] vii) the subject is not concomitantly taking symptomatic medication for Parkinson's disease;

[1345] viii) the subject has not received dopaminergic therapy for at least 30 days prior to the administration;

[1346] ix) the subject has been diagnosed as having "clinically possible Parkinson's disease" according to the MDS clinical diagnostic criteria; and

[1347] x) said subject exhibits a Montreal Cognitive Assessment score of at least 25.

[1348] 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 involves many behaviors assessed by the researcher with all relevant information from the patient or caregiver, and IB is completed by the patient with or without the help of a caregiver but independently of the researcher. However, the scorer can review these parts to ensure that all questions are answered clearly, and the scorer can help explain any perceived ambiguity. Part II is designed as a self-administered questionnaire, but can be reviewed by the researcher to ensure completeness and clarity. Part III has instructions for the scorer to provide or demonstrate to the patient; the part is completed by the scorer.

[1349] In one embodiment of any of the methods described herein, administration of the compound of Formula I or a pharmaceutically acceptable salt thereof slows progression of the overall severity of Parkinson's disease in the subject as measured by the Clinical Global Impression of Severity (CGIS) scale. Disease severity is measured as follows:

[1350] 1: Normal 2: Borderline 3: Mild

[1351] 4: Moderate

[1352] 4: Significant 6: Severe

[1353] 7: Among the sickest patients

[1354] In one embodiment of any of the methods and uses described herein, the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

[1355] 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 in the fasting state.

[1356] 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 in a fasting state at least 1 hour prior to administration.

[1357] 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 in a fasting state at least 2 hours prior to administration.

[1358] 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.

[1359] In one embodiment of any of the methods and uses described herein, the subject is not concomitantly receiving a dopamine replacement medication.

[1360] In one embodiment of any of the methods and uses described herein, the subject is not concomitantly administered symptomatic medication for a neurodegenerative disease such as Parkinson's disease or early Parkinson's disease.

[1361] In one embodiment of any of the methods and uses described herein, the subject has a body mass index ≥ 18.5 kg / m 2 And ≤45kg / m 2 .

[1362] In one embodiment of any of the methods and uses described herein, about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject (eg, orally).

[1363] In one embodiment of any of the methods and uses described herein, 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 is orally administered to the subject once daily.

[1364] In one embodiment of any of the methods and uses described herein, a compound of Formula I, or a pharmaceutically acceptable salt thereof, in one or more solid dosage forms is orally administered to the subject in an amount sufficient to achieve the same bioavailability as an aqueous suspension containing about 192 mg or about 384 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[1365] In one embodiment of any of the methods and uses described herein, about 134 mg or about 269 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof in a solid dosage form is orally administered to the subject once daily.

[1366] In one embodiment of any of the methods and uses described herein, the subject has a disease severity of ≤2 according to the modified Hoya scale. The modified Hoya scale is as follows. See, e.g., Goetz et al., Movement Disorder Society Task Force Report on the Hoehn and Yahr Staging Scale: Status and Recommendations, Movement Disorder: Official Journal of the Movement Disorder Society (Mov. Disord. Off. J. Mov. Disord. Soc.), 19: 1020-1028, 2004; Hoehn M, Yahr M (1967). "Parkinsonism: onset, progression, and mortality" progression and mortality)” .Neurology.17(5):427–42 About Parkinson's Disease The Movement Disorder Society Task Force on Rating Scales Rating-Scales for Parkinson's Disease). Movement Disorders. 19(9): 1020–1028， Said documents are hereby incorporated by reference.

[1367]

[1368]

[1369] In one embodiment of any of the methods and uses described herein, the subject has been initially diagnosed with Parkinson's disease within 3 years of initiating treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[1370] In one embodiment of any of the methods and uses described herein, the subject is not being treated with any dopamine therapy other than a monoamine oxidase-B (MAO-B) inhibitor.

[1371] In one embodiment of any of the methods and uses described herein, the subject (i) is at least 50 years old, (ii) has been initially diagnosed with Parkinson's disease within 3 years of initiating treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, (iii) has a modified Hoya stage score of 2 or less, and (iv) is not being treated with any dopamine therapy other than a monoamine oxidase-B (MAO-B) inhibitor.

[1372] In one embodiment of any of the methods and uses described herein, the subject has been receiving a stable dose of one or more monoamine oxidase B (MAOB) inhibitors for at least 10 days, preferably 20 days, more preferably 30 days.

[1373] In one embodiment of any of the methods and uses described herein, the subject has been receiving 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.

[1374] In one embodiment of any of the methods and uses described herein, the aqueous suspension is prepared by adding a powder comprising a compound of Formula I or a pharmaceutically acceptable salt thereof to water or any suitable water-based vehicle and mixing uniformly with a spoon or other stirrer just before administration.

[1375] In one embodiment of any of the methods and uses described herein, the suspension further comprises (i) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, (ii) colloidal silicon dioxide, (iii) sodium lauryl sulfate, (iv) crospovidone, (v) mannitol and (vi) flavoring.

[1376] In one embodiment of any of the methods and uses described herein, the compound of formula I is administered in the form of a free base.

[1377] In one embodiment of any of the methods and uses described herein, the subject has been receiving treatment with a monoamine oxidase B (MAOB) inhibitor.

[1378] In one embodiment of any of the methods and uses described herein, the subject has not received dopaminergic therapy for at least 30 days prior to administration or treatment with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[1379] In one embodiment of any of the methods and uses described herein, the subject exhibits a Montreal Cognitive Assessment score of at least 25. See, e.g., https: / / www.mocatest.org .

[1380] In one embodiment of any of the methods and uses described herein, about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject.

[1381] 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 once daily.

[1382] 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 twice daily.

[1383] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve a mean plasma AUC in the range of about 30,000 ng*hr / ml to about 50,000 ng*hr / ml in the subject. 0-24 The amount of administration.

[1384] 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 The amount of administration.

[1385] 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.

[1386] In one embodiment of any of the methods and uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is present 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 The amount of administration.

[1387] In one embodiment of any of the methods and uses described herein, the Parkinson's disease comprises early Parkinson's disease.

[1388] In one embodiment of any of the methods and uses described herein, the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced by half following the occurrence of an adverse event. BRIEF DESCRIPTION OF THE DRAWINGS

[1389] Figure 1 Shown are mean concentrations of vodobatinib in plasma following oral administration of 48, 192, or 384 vodobatinib to healthy human subjects.

[1390] Figure 2 Shown are mean concentrations of vodobatinib in cerebrospinal fluid (CSF) following oral administration of 48, 192, or 384 vodobatinib to healthy human subjects. DETAILED DESCRIPTION

[1391] definition

[1392] The terms "adverse event (AE)", "serious adverse reaction", "serious adverse event", "toxicity", "treatment-emergent adverse event (TEAE)" are used interchangeably and mean an event that was not present or was present at a lower intensity prior to the treatment of the present invention and that has occurred or worsened after the initiation of treatment in the patient. Such events are undesirable, unfavorable and unintended signs, symptoms or diseases that can be attributed to the use of the drug or treatment. Based on the intensity and impact of the adverse event, the skilled person may have to modify the treatment conditions.

[1393] The terms "QTcF" and "Fridericia-corrected QT interval" are used interchangeably and their meanings are well known to those skilled in the art.

[1394] As used herein, the term "treating" or "treatment" refers to complete or partial cure, alleviation, amelioration, improvement, alleviation, prevention of a particular disease or disease itself or one or more symptoms or features of a disorder and / or condition, or delaying the onset of one or more symptoms or features, inhibiting the progression of one or more symptoms or features, reducing the severity of one or more symptoms or features, and / or reducing the incidence of one or more symptoms or features. For the purposes of the present invention, the term treatment or therapy is used to refer to the treatment or prevention of a neurodegenerative disease or an early neurodegenerative disease. In a more specific example, the term treatment or therapy is used to refer to the treatment or prevention or improvement of Parkinson's disease or its early Parkinson's disease, or at least one symptom thereof, in a subject.

[1395] The term "subject" as used herein refers to a human or non-human animal. These terms include mammals, such as humans, primates, livestock (e.g., cattle and pigs), companion animals (e.g., canines and felines) and rodents (e.g., mice and rats). For the purposes of the present invention, a "subject" is a person suffering from a neurodegenerative disease or has begun to show symptoms of a neurodegenerative disease or a person at risk of suffering from a neurodegenerative disease. In one aspect of the present invention, a "subject" is a person suffering from a symptom selected from Parkinson's disease, AD or synuclein disease (e.g., LBD, REM, sleep behavior disorder or MSA) or has begun to show symptoms of the disease or a person at risk of suffering from the disease. In one aspect of the present invention, a "subject" is a person suffering from a neurodegenerative disease (e.g., Parkinson's disease) or has begun to show symptoms of a neurodegenerative disease or a person at risk of suffering from a neurodegenerative disease. The method of identifying a subject is well known to doctors or technicians in the art. Technicians will understand that some preliminary studies in preliminary studies are conducted in healthy volunteers. For the purposes of the present invention, such healthy volunteers are also referred to as subjects. However, these subjects are only used for demonstration purposes.

[1396] As used herein, the term "about" when preceding a range should be understood to refer to both endpoints of the range. In such cases, the range should also be understood to include the range defined by the specific endpoints listed, and also include sub-ranges within the listed endpoints. Where "about" precedes a number, it should be understood that the number includes a range of + / - 5%.

[1397] As used herein, the term "between" when preceding a range should be understood to refer to the two endpoints of the range. In such cases, the range should also be understood to include the range defined by the specific endpoints listed, and also include the sub-ranges within the listed endpoints.

[1398] As used herein, the term "therapeutically effective amount" means the amount of a drug (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) that has the desired effect of reducing, curing or alleviating a disease or its symptoms when administered to a subject in need. For 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 for treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease. A therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a subject in need as is or in the form of a pharmaceutical formulation. Specifically, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a subject as a solid oral dosage form.

[1399] As used herein, the term delaying or inhibiting or arresting 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 of the disease means reducing the deterioration experienced by a subject or patient, for example as quantified by one or more of the UPDRS, MDS-UPDRS scores, or any other method described herein or generally standard methods known in the art.

[1400] Early Parkinson's disease or Parkinson's disease can be diagnosed by a person skilled in the art based on their experience and / or by general standard methods / techniques known in the art; for example, Kimber TE. Approach to the patient with early Parkinson's 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. and machine-learning), 2022, PLoS ONE, 17(1).

[1401] Early Parkinson's disease or Parkinson's disease can be identified by relevant tests or identification symptoms according to generally standard known methods / techniques by those skilled in the art. Typically, early Parkinson's disease or Parkinson's disease can be identified by one or more of the following:

[1402] a) Pill-rolling tremor in one hand when it is still;

[1403] b) tremor that is greatest at rest, diminishes during movement, and is absent during sleep;

[1404] c) rigidity and slowing of movements (bradycardia), decreased movement (hypokinesia), and difficulty initiating movement (akinesia);

[1405] d) The face becomes mask-like, with an open mouth and decreased blinking, which may be confused with depression;

[1406] e) The posture becomes hunched;

[1407] f) Difficulty in starting to walk;

[1408] g) The gait becomes a shuffling walk, with the arms remaining bent at the waist so as not to swing with the stride;

[1409] h) the pace occasionally quickened inadvertently, and the subject occasionally ran to avoid falling (panicked gait);

[1410] i) a tendency to fall forward (propulsion) or backward (propulsion) due to loss of postural reflexes when the center of gravity is shifted;

[1411] j) Speech becomes muffled, with a characteristic monotonous stuttering dysarthria;

[1412] k) Hypokinesia and impaired control of distal musculature, leading to micrographia and increased difficulty with activities of daily living;

[1413] l) Infrequent blinking and lack of facial expression;

[1414] m) Decreased movement;

[1415] n) impaired postural reflexes; and

[1416] o) Characteristic gait abnormalities.

[1417] Pharmacokinetic (PK) evaluation is one of the endpoints of clinical trials, in which the interaction of the subject's body with the administered substance (or drug) over the entire exposure duration is mathematically studied. As known to those skilled in the art, PK evaluation includes, for example, determining C max , T max , half-life, terminal rate constant (Kel), AUC 0-24 , the area under the concentration-time curve (AUC) from time 0 to the last quantifiable time point 0-τ ), oral clearance (CL / F), apparent volume of distribution (V / F) and dose-normalized [AUC( 0-τ ) / dose or (C max / dose)].

[1418] As used herein, AUC 0-24Refers to the steady-state area under the plasma concentration versus time curve from time zero to twenty-four hours after administration of a drug (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof). min and C max The plasma concentrations of and are the minimum and maximum steady-state effective concentrations of the drug in plasma during a specific dosing interval, respectively. The time to reach maximum plasma concentration after administration of a dose is called T max .

[1419] The terms "hour", "hr", "h", "hours", and "hrs" are used interchangeably and refer to a unit of time.

[1420] The term "neurodegenerative disease" as used herein includes, but is not limited to, Parkinson's disease (PD), Alzheimer's disease (AD), synucleinopathies, Lewy body dementia (LBD), rapid eye movement (REM), sleep behavior disorder, multiple system atrophy (MSA), early Parkinson's disease, early Alzheimer's disease, early synucleinopathies, early Lewy body dementia, early rapid eye movement, early sleep behavior disorder, and early multiple system atrophy.

[1421] Abnormal synuclein deposition can be determined by skin punch biopsy, such as that described in Swallow et al., Acta Neurol Scand., 130(2):59-72, 2014. Epub 2014 Apr 5, PMID: 24702516, which is hereby incorporated by reference.

[1422] The compounds of Formula I are BCR (breakpoint cluster region)-ABL (Abelson leukemia viral oncogene) tyrosine kinase inhibitors (TKIs) under investigation for the treatment of neurodegenerative diseases (ND). As described above, compounds of Formula I have been shown to be effective in the treatment of Parkinson's disease, AD and other synucleinopathies through in vitro and in vivo studies in mice.

[1423] In one embodiment, the present invention relates to a method for treating a neurodegenerative disease in a subject in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1424] In one embodiment, the subject is a mammal, preferably a human.

[1425] In one embodiment, the present invention relates to a method for treating a neurodegenerative disease in an adult subject in need thereof or delaying, inhibiting or suppressing the progression of the neurodegenerative disease. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1426] In one embodiment, the present invention relates to a method for treating Parkinson's disease (PD) in an adult subject or delaying, inhibiting or suppressing the progress of the PD. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1427] In one embodiment, the present invention relates to a method for treating early Parkinson's disease (PD) in an adult subject or delaying, inhibiting or suppressing the progress of the PD. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need.

[1428] In one embodiment, the present invention relates to a method for treating Alzheimer's disease (AD) in an adult subject or delaying, inhibiting or suppressing the progression of the AD. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1429] In one embodiment, the present invention relates to a method for treating Lewy body dementia (LBD) in an adult subject or delaying, inhibiting or suppressing the progress of the LBD. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1430] In one embodiment, the present invention relates to a method for treating rapid eye movement (REM) sleep behavior disorder in adult subjects or delaying, inhibiting or suppressing the progress of the REM sleep behavior disorder. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once a day to a subject in need thereof.

[1431] In one embodiment, the present invention relates to a method for treating multiple system atrophy (MSA) in an adult subject or delaying, inhibiting or suppressing the progression of the MSA. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1432] In one embodiment, the present invention relates to a method of reducing the rate of progression of early Parkinson's disease in a subject (preferably an adult subject) having a disease severity of ≤ 2 according to the modified Hoya stage. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1433] In one embodiment, the present invention relates to a method for reducing the rate of progression of motor deficits caused by Parkinson's disease in a subject (preferably an adult subject) with early Parkinson's disease and having a disease severity according to the modified Hoya stage ≤ 2. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1434] In one embodiment, the present invention relates to a method of regulating or maintaining autonomic function in a subject (preferably, an adult subject) with early Parkinson's disease and having a disease severity according to the modified Hoya stage ≤ 2. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once a day to a subject in need thereof.

[1435] In one embodiment, the present invention relates to a method of reducing autonomic deterioration caused by early Parkinson's disease in a subject (preferably an adult subject) in need thereof and having a disease severity according to the modified Hoya stage ≤ 2. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1436] In one embodiment, the present invention relates to a method of treating Parkinson's disease in a subject (preferably an adult subject) with early Parkinson's disease and having a disease severity according to the modified Hoya stage ≤ 2. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof can be administered once daily to a subject in need thereof.

[1437] In one embodiment, the present invention relates to a method of treating Parkinson's disease in a subject (preferably an adult subject) having a disease severity according to the modified Hoya stage ≤ 2. In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof may be administered once daily to a subject in need thereof.

[1438] Various techniques can be used to assess the severity and / or improvement of Parkinson's disease or its symptoms. In some embodiments, methods according to the present disclosure can use one or more of the following scales: Hoya staging scale; Unified Parkinson's Disease Rating Scale (UPDRS); Montreal Cognitive Assessment (MoCA) criteria; Clinical Global Impression Severity (CGIS); Clinical Global Impression of Improvement (CGII); Clinical Global Impression of Efficacy (CGIE); Unified Parkinson's Disease Rating Scale-Revised Sponsored by the Movement Disorders Society (MDS-UPDRS); Parkinson's Disease Outcome Scale-Motor (SCOPA-Motor); Schw Ab and England Daily Living Activities Scale (SES); Parkinson's Disease Disability Self-Assessment Scale (SPDDS); Postural Instability and Gait Difficulty Score (PIGD); Freezing of Gait Questionnaire (FOGQ); Non-Motor Symptom Questionnaire (NMSQuest); Non-Motor Symptom Scale (NMSS); Unified Movement Disorder Rating Scale (UDysRS); End-of-Dose Phenomenon Questionnaire (WOQ); Self-reported total sleep time on the Pittsburgh Sleep Quality Index; Beck Depression Inventory; Insomnia Severity Index; or a combination thereof. These techniques are well known in the art and are incorporated herein by reference in their entirety as are all publications cited herein. See, for example:

[1439] Fahn, S., Elton, R. and committee, UPDRS project members, Unified Parkinson's disease rating scale. S. Fahn, C. Mardsen and M. Goldstein (eds.), Recent developments in a Parkinson's disease, Macmillan, New York, 1987, pp. 153-167;

[1440] Hoehn MM and Yahr MD (1967) Parkinson's disease: onset, progression, and mortality. Neurology 17(5):427-442.

[1441] MoCA-Montreal Cognitive Assessment (developed by Dr. Ziad Nasreddine, 1996);

[1442] Goetz, Christopher G., et al., “MDS-UPDRS,” Movement Disorder Society, July 1, 2008;

[1443] Goetz et al., Report of the Movement Disorder Society Task Force on the Hoya Staging Scale: Current Status and Recommendations, Movement Disorders: The Official Journal of the Movement Disorder Society, 19:1020-1028, 2004; Hoehn M, Yahr M (1967). "Parkinson's disease: Operation, progression and mortality” .Neurology.17(5):427–42 ; Dyskinesia Rating Scale for Parkinson's Disease Working Group. Movement Disorders. 19(9):1020–1028;

[1444] Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgemont). 2007 Jul;4(7):28-37.

[1445] CGI (Clinical Global Impression), ECDEU assessment manual, US Department of Health, Education and Welfare, pp. 218-221;

[1446] Auluck PK, Chan HY, Trojanowski JQ, Lee VM and Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295(5556):865-868;

[1447] Akdemir Bora A, Atay Dopamine transporter SPECT imaging in Parkinson's disease and parkinsonian disorders. Turkish Journal of Medical Sciences. 2021 Apr 30;51(2):400-410.

[1448] 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 Scandinavica 2014 Aug;130(2):59-72.

[1449] According to any of the preceding embodiments, the method of treatment comprises administering a compound of formula I. The compound of formula I has the following chemical name and formula:

[1450] Chemical name N'-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide, and

[1451]

[1452] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to a subject as is. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in the form of a dosage form. In a specific embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in the form of an oral dosage form.

[1453] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in the form of 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.

[1454] In some embodiments, the oral dosage form can be a tablet.

[1455] In some embodiments, the oral dosage form can be a hard gelatin capsule.

[1456] In some embodiments, the oral dosage form may be a sachet containing powder for oral suspension.

[1457] Examples of pharmaceutically acceptable excipients that can be used in the oral dosage forms of the invention include, for example, one or more of polyvinyl caprolactam, polyvinyl acetate, polyethylene glycol graft copolymers, silicon dioxide, sodium lauryl sulfate, silicified microcrystalline cellulose, crospovidone, gelatin, and any combination of any of the foregoing.

[1458] In one embodiment, the oral dosage form comprises (i) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, (ii) colloidal silicon dioxide, (iii) sodium lauryl sulfate, (iv) crospovidone, (v) mannitol, (vi) flavoring agents, and any combination of any of the foregoing.

[1459] In one embodiment, the oral dosage form is selected from a solid oral dosage form or an aqueous suspension.

[1460] The desired dosage form of the compound of Formula I is an oral dosage form containing 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 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 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 about 40 mg to about 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[1461] Typically, the daily dose can be administered in one to four administrations per day. In certain embodiments, the amount of the compound of Formula I or its pharmaceutically acceptable salt in the dosage form is between about 10 mg and about 400 mg, as measured by the amount of the compound of Formula I or its pharmaceutically acceptable salt administered daily.

[1462] The dosage may be administered as a single daily dose.

[1463] The total daily dose of the compound of Formula I or its pharmaceutically acceptable salt administered to the subject may be between about 10 mg and about 400 mg. In some embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 10 mg. In some embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt is about 30 mg. In some embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 40 mg. In some embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 48 mg. In other embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 96 mg. In other embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 192 mg. In other embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 384 mg. In some embodiments, the total daily dose of the compound of Formula I or its pharmaceutically acceptable salt is about 400 mg.

[1464] In one embodiment, the present invention provides a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease, the method comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof (e.g., orally).

[1465] According to one embodiment, the therapeutically effective amount of the compound of formula I or its pharmaceutically acceptable salt is about 10 mg to about 400 mg (e.g., oral administration). According to another embodiment, the therapeutically effective amount of the compound of formula I or its pharmaceutically acceptable salt is about 20 mg to about 400 mg. According to yet another embodiment, the therapeutically effective amount of the compound of formula I or its pharmaceutically acceptable salt is about 30 mg to about 400 mg. According to one embodiment, the therapeutically effective amount of the compound of formula I or its pharmaceutically acceptable salt is about 40 mg to about 400 mg. In another embodiment, the therapeutically effective amount of the compound of formula I is about 48 mg, about 192 mg, or about 384 mg.

[1466] In one embodiment of the present invention, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve a plasma PK that is effective in treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease. In one embodiment, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve an average plasma AUC of about 5,000 ng*h / ml to about 75,000 ng*h / ml that is effective in treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease. 0-24 In another embodiment, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL to effectively treat a neurodegenerative disease or delay, inhibit or suppress the progression of the neurodegenerative disease. max .

[1467] In another embodiment of the present invention, a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease is provided, wherein the method comprises administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hour / ml to about 75,000 ng*hour / ml. 0-24 A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of

[1468] According to another aspect, a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease is provided, wherein the method comprises administering a dose sufficient to achieve a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL.max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of

[1469] According to another aspect, a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease is provided, wherein the method comprises administering an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hour / ml to about 75,000 ng*hour / ml. 0-24 and plasma C ranging from about 500 ng / mL to about 15,000 ng / mL max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of

[1470] In one embodiment of the present invention, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve a CSF PK that is effective in treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease. In one embodiment, the therapeutically effective amount of the 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 that is effective in treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease. In another embodiment, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is sufficient to achieve a CSF C concentration of about 0.4 ng / mL to about 7.0 ng / mL that is effective in treating a neurodegenerative disease or delaying, inhibiting or curbing the progression of the neurodegenerative disease. max .

[1471] According to another aspect, a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease is provided, wherein the method comprises administering a CSF C concentration sufficient to achieve a CSF C concentration in the range of about 0.4 ng / mL to about 7.0 ng / mL. max A compound of Formula I or a pharmaceutically acceptable salt thereof is administered (eg, orally) to a subject in need thereof in an amount of

[1472] According to another aspect, a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease is provided, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof 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.

[1473] According to yet another aspect, a method for treating a neurodegenerative disease or delaying, inhibiting or suppressing the progression of the neurodegenerative disease is provided, wherein the method comprises administering (e.g., orally) a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof in an amount sufficient to achieve a CSF concentration of at least about 0.2 ng / mL.

[1474] 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 of not less than about 0.5 ng / mL in CSF (e.g., orally). 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 of not less than about 0.7 ng / mL in CSF. 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 of not less than about 0.9 ng / mL in CSF (e.g., orally). 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 of not less than about 1 ng / mL in CSF (e.g., orally). 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 of not less than about 1.2 ng / mL in CSF (e.g., orally). 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 of not less than about 1.5 ng / mL in CSF (e.g., orally). In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount (e.g., orally) sufficient to achieve a minimum concentration of not less than about 1.8 ng / mL in CSF. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount (e.g., orally) sufficient to achieve a minimum concentration of not less than about 2 ng / mL in CSF. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount (e.g., orally) sufficient to achieve a minimum concentration of not less than about 2.2 ng / mL ...

Claims

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

2. A method for reducing the rate of progression of motor deficits caused by Parkinson's disease in a human subject with early Parkinson's disease and having a disease severity of ≤2 according to the modified Hoya stage, the method comprising administering to the subject an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof.

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

4. A method of reducing autonomic deterioration caused by early Parkinson's disease in a human subject in need thereof and having a disease severity of ≤2 according to the modified Hoya stage, the method comprising administering to the subject an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof.

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

6. A method for treating Parkinson's disease in a human subject having a disease severity of ≤2 according to the modified Hoya staging system, or delaying, inhibiting or suppressing the progression of said Parkinson's disease, said method comprising administering to said subject an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof.

7. The method according to any one of the preceding claims, wherein the subject has been diagnosed as having "clinically probable Parkinson's disease" according to the MDS clinical diagnostic criteria.

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

9. The method of any one of the preceding claims, wherein the subject exhibits abnormal synuclein deposition as determined by skin punch biopsy.

10. The method according to any of the preceding claims, wherein administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, increases the time to significant worsening in the subject on MDS-UPDRS Part II and Part III. The method according to any of the preceding claims, wherein administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, increases the time to significant worsening in the subject on Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, Part II, and Part III.

11. The method according to any one of the preceding claims, wherein administration of the compound of Formula I or a pharmaceutically acceptable salt thereof slows progression of the overall severity of the subject's Parkinson's disease as measured by the Clinical Global Impression of Severity (CGIS) scale.

12. The method according to any one of the preceding claims, wherein the subject is not concomitantly administered symptomatic medication for Parkinson's disease.

13. The method according to any one of the preceding claims, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject in the fasting state.

14. The method according to any one of the preceding claims, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject in the fasting state at least 1 hour prior to administration.

15. The method according to any one of the preceding claims, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject in the fasting state at least 2 hours prior to administration.

16. The method of any one of the preceding claims, wherein the subject is 50 years of age or older.

17. The method of any one of the preceding claims, wherein the subject is 20 years of age or older.

18. The method of any one of the preceding claims, wherein the subject is not concomitantly receiving a dopamine replacement medication.

19. The method according to any one of the preceding claims, wherein the subject has a body mass index ≥ 18.5 kg / m 2 And ≤45kg / m 2 , preferably ≤30kg / m 2 。 20. The method of any one of the preceding claims, wherein about 5 mg to about 480 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject.

21. The method of any one of the preceding claims, wherein about 48 mg to about 480 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject.

22. The method of any one of the preceding claims, wherein 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 of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject.

23. The method of any one of the preceding claims, wherein about 134 mg to about 384 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject.

24. The method of any one of the preceding claims, wherein about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof is administered to the subject.

25. The method of any one of the preceding claims, wherein about 192 mg or about 384 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof in a solid dosage form is administered to the subject.

26. The method of any one of the preceding claims, wherein the subject is not being treated with any dopamine therapy other than a monoamine oxidase-B (MAO-B) inhibitor.

27. The method of any one of the preceding claims, wherein the subject (i) is at least 50 years old, (ii) has been initially diagnosed with Parkinson's disease within 3 years of initiating treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, (iii) has a modified Hoya stage score of 2 or less, and (iv) is not being treated with any dopamine therapy other than a monoamine oxidase-B (MAO-B) inhibitor.

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

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

30. The method of any one of the preceding claims, wherein the subject has been receiving treatment with a monoamine oxidase B (MAOB) inhibitor.

31. The method of any of the preceding claims, wherein the subject has not received dopaminergic therapy for at least 30 days prior to the administering.

32. The method of any one of the preceding claims, wherein the subject exhibits a Montreal cognitive assessment score of at least 25.

33. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at an amount sufficient to achieve a mean plasma AUC in the range of about 5,000 ng*hr / ml to about 75,000 ng*hr / ml. 0-24 The amount of administration.

34. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at an amount sufficient to achieve a mean plasma AUC in the range of about 20,000 ng*hr / ml to about 60,000 ng*hr / ml. 0-24 The amount of administration.

35. The method of any one of the preceding claims, wherein 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 amount of administration.

36. The method of any one of the preceding claims, wherein 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 amount of administration.

37. The method of any one of the preceding claims, wherein 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 amount of administration.

38. The method of any one of the preceding claims, wherein 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 amount of administration.

39. The method of claim 38 or 39, wherein the subject achieves cerebrospinal fluid C no later than 6 hours after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. max .

40. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to achieve a cerebrospinal fluid C level of about 0.2 ng / mL to about 2.7 ng / mL. avg The amount of concentration applied.

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

42. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve a mean cerebrospinal fluid C of about 0.3 ng / mL to about 4.0 ng / mL. avg The amount of administration.

43. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve a mean cerebrospinal fluid C of about 2.0 ng / mL to about 3.0 ng / mL. avg The amount of administration.

44. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve cerebrospinal fluid C max IC of c-Abl inhibition 50 The ratio is not less than 1 in amount.

45. The method of any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve a mean cerebrospinal fluid C max The amount administered was such that the IC50 ratio for c-Abl inhibition was between 1 and 14.

46. ​​The method according to any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is present in an amount sufficient to achieve C max With IC 50 The ratio is greater than 5.

47. The method of any one of the preceding claims, 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 in a human subject or delaying, inhibiting or suppressing the progression of Parkinson's disease, 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) a compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms in an amount sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg The amount of administration.

49. A method of reducing the rate of progression of 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) a compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms in an amount sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg The amount of administration.

50. A method of reducing the rate of progression of movement deficits caused by 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) a compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms in an amount sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg The amount of administration.

51. A method of reducing autonomic deterioration caused by 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) a compound of Formula I or a pharmaceutically acceptable salt thereof in one or more solid dosage forms in an amount sufficient to achieve the same bioavailability as the aqueous suspension, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in an amount sufficient to achieve (i) a plasma C in the range of about 500 ng / mL to about 15,000 ng / mL max , (ii) a mean plasma AUC ranging from about 5,000 ng*hr / mL to about 75,000 ng*hr / mL 0-24 , or (iii) cerebrospinal fluid C ranging from about 0.4 ng / mL to about 7.0 ng / mL max , and (iv) a mean CSF C of about 0.3 ng / mL to about 4.0 ng / mL avg The amount of administration.

52. The method of any one of the preceding claims, wherein the Parkinson's disease is early-stage Parkinson's disease.

53. The method according to any one of the preceding claims, wherein the daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced by half following the occurrence of an adverse event.

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

55. The method according to any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily.

56. The method according to any one of the preceding claims, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

57. The method of any one of the preceding claims, wherein the subject has been initially diagnosed as having Parkinson's disease.

58. The method according to any one of the preceding claims, wherein the subject has been initially diagnosed with Parkinson's disease within 3 years of initiating treatment with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

59. The method of any of the preceding claims, wherein the reduction in progression of Parkinson's disease or a reduction in worsening of symptoms of Parkinson's disease is achieved by increasing the subject's time to progression from a Part 1 to Part 2 score to a Part 2 to Part 3 score as measured on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

60. The method of any of the preceding claims, wherein the subject's time to progression from Part 1 to Part 2 score increases by at least 40 weeks.

61. The method of any of the preceding claims, wherein the subject's time to progression from Part 2 to Part 3 score increases by at least 40 weeks.

62. The method of any of the preceding claims, wherein the subject's time to progression from a Part 1 to Part 2 score to a Part 2 to Part 3 score increases by at least 40 weeks.

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

64. An oral dosage form for reducing the rate of progression of motor deficits caused by Parkinson's disease in a human subject with early Parkinson's disease and having a disease severity of ≤2 according to the modified Hoya stage, wherein the dosage form comprises an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof.

65. An oral dosage form for regulating or maintaining autonomic function in a human subject with early Parkinson's disease having a disease severity of ≤2 according to the modified Hoya stage, wherein the dosage form comprises an effective amount of a compound of formula I; or a pharmaceutically acceptable salt thereof.

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

67. An oral dosage form for treating Parkinson's disease in a human subject having early-stage Parkinson's disease with a disease severity of ≤2 according to the modified Hoya stage, or delaying, inhibiting or arresting the progression of said Parkinson's disease, wherein said dosage form comprises an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof.

68. An oral dosage form for treating Parkinson's disease in a human subject having a disease severity of ≤2 according to the modified Hoya staging system, or delaying, inhibiting or arresting the progression of said Parkinson's disease, wherein said dosage form comprises an effective amount of a compound of formula I; or a pharmaceutically acceptable salt thereof.

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

71. The oral dosage form of claim 69, wherein the aqueous suspension is prepared just 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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