Deuterated analogs of acetyl-leucine

Abstract

The present disclosure relates to deuterated analogs of acetyl-leucine, and specifically provides compounds represented by the following Formula I: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are as defined in the specification, and any one or more of R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 has a deuterium enrichment of about 15% or more, and pharmaceutically acceptable salts and solvates thereof. The disclosure also provides compounds of Formula I for treating or delaying the progression of a lysosomal storage disorder or a neurodegenerative disease in a subject, providing neuroprotection in a subject suffering from a lysosomal disorder, treating or preventing migraine and symptoms associated therewith in a subject, e.g., treating or preventing hemicranias in a subject suffering from a lysosomal disorder, or treating or preventing hemicranias in a subject suffering from a hemicranias in a subject suffering from a hemicranias in a subject suffering from a hemicranias. Or improving the mobility and / or cognitive function of the subject. # imgabs0 #

Description

[0001] This application is a divisional application. The international application number of its original application is PCT / IB2019 / 060525, the international filing date is December 6, 2019, the Chinese national application number is 201980090399.8, the date of entry into China is July 27, 2021, and the invention title is "Deuterated analogs of acetyl-leucine". Technical Field

[0002] The present disclosure provides deuterated DL-, D- and L-N-acetyl leucine analogs and pharmaceutically acceptable salts and solvates thereof, as well as deuterated DL-, D- and L-N-acetyl leucine alkyl ester analogs and pharmaceutically acceptable salts and solvates thereof. The present disclosure also provides methods for treating lysosomal storage disorders or delaying the progression of lysosomal storage disorders; methods for providing neuroprotection in a subject suffering from a lysosomal disorder; methods for treating or delaying the progression of a neurodegenerative disease in a subject, treating or delaying the progression of a neurodegenerative disease associated with a lysosomal storage defect in a subject, treating or preventing migraine and associated symptoms in a subject, treating or preventing restless legs syndrome and associated symptoms in a subject, treating or preventing vertigo and associated symptoms in a subject, or improving the mobility and / or cognitive function of a subject, comprising administering to the subject a deuterated N-acetyl leucine analog and pharmaceutically acceptable salts and solvates thereof, or a deuterated N-acetyl leucine alkyl ester analog and pharmaceutically acceptable salts and solvates thereof. Background Art

[0003] Neurodegenerative diseases affect neurons, and the degenerative process may involve progressive loss of neuronal structure, progressive loss of neuronal function, or progressive death of neuronal cells. Neurodegenerative diseases are generally associated with lysosomal storage defects. This includes neurodegenerative lysosomal storage disorders and many common neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, which have been considered to be related to lysosomal defects. Therapeutic agents with broad neuroprotective effects are generally applicable to neurodegenerative diseases, including diseases caused by potential lysosomal storage disorders and diseases caused by other processes.

[0004] Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by defects in lysosomal homeostasis. LSDs encompass more than 70 diseases, with an overall clinical frequency at live birth of 1:5000. These diseases can be classified into two major categories: primary storage diseases (usually lysosomal enzyme deficiencies) caused by direct defects in the degradation pathway and secondary storage diseases caused by downstream lysosomal protein dysfunction. Different LSDs caused by the inactivation of different lysosomal proteins usually have similar pathologies. In most cases, multiple organs and tissues are involved. Most of these diseases are characterized by region-specific neurodegeneration.

[0005] Migraine is characterized by recurrent moderate to severe headaches. Typically, the headache affects one half of the head, is pulsating in nature, and lasts from 2 to 72 hours. Migraine symptoms include nausea, vomiting, and sensitivity to light, sound, or smells. Physical activity usually exacerbates the pain. Approximately 15% of the world's population is affected by migraine.

[0006] Changes that occur with aging can lead to problems with people's ability to get around. Mobility problems can include unsteadiness when walking, difficulty getting up from a chair, or falling. Muscle weakness, joint problems, pain, illness, and nerve (brain and nervous system) difficulties (common in the elderly) can all contribute to mobility problems. Sometimes, several minor problems occur simultaneously and combine to severely affect mobility.

[0007] In addition to potential mobility problems, all elderly people will experience some degree of decline in cognitive ability, the symptoms of which typically include forgetfulness, decreased ability to maintain attention, decreased problem-solving ability, and / or decreased spatial awareness. The symptoms may progress to more severe conditions such as dementia and depression or even Alzheimer's disease.

[0008] Many factors are thought to contribute to age-related cognitive decline, including oxidative stress and free radical damage, declining hormone levels (such as estrogen, testosterone, DHEA, and pregnenolone), arterial intima (endothelial) dysfunction, insulin tolerance, overweight, nutritional deficiencies, loneliness, lack of social network, and stress.

[0009] Currently, the treatment methods for neurodegenerative diseases, LSDs, and migraines, as well as improving mobility and / or cognitive function, are limited. For example, some LSDs respond to bone marrow transplantation or enzyme replacement therapy. Some benefits have also been reported in clinical trials of substrate reduction therapy (SRT) using the inhibitor of glycosphingolipid (GSL) biosynthesis, the iminosugar drug miglustat. Patterson et al., Rev Neurol (separata) 43:8 (2006). Benefits have also been reported in case studies of patients with cerebellar ataxia (showing improved gait variability) and Niemann-Pick type C (NPC) (showing improved ataxia) using acetyl-DL-leucine. See Schniepp, R. et al., Cerebellum & Ataxias 3:8 (2016); Bremova, T. et al., Neurology 85:1368 (2015).

[0010] Despite the beneficial effects of N-acetyl leucine, there is still a need to improve the treatment of LSDs. There is also a need to develop improved treatments for neurodegenerative diseases, neurodegenerative diseases associated with lysosomal storage defects, migraines, restless legs syndrome, and vertigo. There is also a need to develop improved treatments for improving mobility and / or cognitive function. SUMMARY OF THE INVENTION

[0011] In one aspect, the present disclosure provides deuterated N-acetyl leucine analogs represented by any one of Formulas I-V, their pharmaceutically acceptable salts and solvates, and deuterated N-acetyl leucine alkyl ester analogs and their pharmaceutically acceptable salts and solvates, collectively referred to herein as "the compounds of the present disclosure". The compounds of the present disclosure are enriched with at least one deuterium atom, and its abundance is at least 1000 times greater than the natural abundance of deuterium.

[0012] In another aspect, the present disclosure provides a method for treating an LSD or delaying the progression of an LSD, the method comprising administering a therapeutically effective amount of the compounds of the present disclosure to a subject in need thereof.

[0013] In another aspect, the present disclosure provides a method for providing neuroprotection in a subject with an LSD, the method comprising administering a therapeutically effective amount of the compounds of the present disclosure to a subject in need thereof.

[0014] In another aspect, the present disclosure provides a method for treating a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect or delaying the progression of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect, the method comprising administering a therapeutically effective amount of the compounds of the present disclosure to a subject in need thereof.

[0015] In another aspect, the present disclosure provides a method for treating or preventing migraine and related symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0016] In another aspect, the present disclosure provides a method for improving mobility and / or cognitive function, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0017] In another aspect, the present disclosure provides a method for treating or preventing restless legs syndrome and related symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0018] In another aspect, the present disclosure provides a method for treating or preventing dizziness and related symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0019] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier.

[0020] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for treating LSD in a subject or delaying the progression of LSD.

[0021] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for providing neuroprotection in a subject with LSD.

[0022] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for treating a neurodegenerative disease in a subject or a neurodegenerative disease associated with lysosomal storage defects or delaying the progression of a neurodegenerative disease or a neurodegenerative disease associated with lysosomal storage defects.

[0023] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for treating or preventing migraine and related symptoms in a subject.

[0024] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for improving mobility and / or cognitive function in a subject.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for treating or preventing restless legs syndrome and related symptoms in a subject.

[0026] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for treating or preventing dizziness and related symptoms in a subject.

[0027] In another aspect, the present disclosure provides a compound of the present disclosure for treating LSD in a subject or delaying the progression of LSD.

[0028] In another aspect, the present disclosure provides a compound of the present disclosure for providing neuroprotection in a subject with LSD.

[0029] In another aspect, the present disclosure provides a compound of the present disclosure for treating a neurodegenerative disease in a subject or a neurodegenerative disease associated with lysosomal storage defects or delaying the progression of a neurodegenerative disease or a neurodegenerative disease associated with lysosomal storage defects.

[0030] In another aspect, the present disclosure provides a compound of the present disclosure for treating or preventing migraine and related symptoms in a subject.

[0031] In another aspect, the present disclosure provides a compound of the present disclosure for improving the mobility and / or cognitive function of a subject.

[0032] In another aspect, the present disclosure provides a compound of the present disclosure for treating or preventing restless legs syndrome and related symptoms in a subject.

[0033] In another aspect, the present disclosure provides a compound of the present disclosure for treating or preventing dizziness and related symptoms in a subject.

[0034] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating LSD in a subject or delaying the progression of LSD.

[0035] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for providing neuroprotection in a subject with LSD.

[0036] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating a neurodegenerative disease in a subject or a neurodegenerative disease associated with lysosomal storage defects or delaying the progression of a neurodegenerative disease or a neurodegenerative disease associated with lysosomal storage defects.

[0037] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for treating or preventing migraine and associated symptoms in a subject.

[0038] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for improving the mobility and / or cognitive function of a subject.

[0039] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for treating or preventing restless legs syndrome and associated symptoms in a subject.

[0040] In another aspect, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for treating or preventing vertigo and associated symptoms in a subject.

[0041] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure and optionally a package insert containing instructions for use, for treating LSD, neurodegenerative diseases or neurodegenerative diseases associated with lysosomal storage defects in a patient.

[0042] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure and optionally a package insert containing instructions for use, for treating or preventing migraine and associated symptoms in a subject.

[0043] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure and optionally a package insert containing instructions for use, for improving the mobility and / or cognitive function of a subject.

[0044] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure and optionally a package insert containing instructions for use, for treating or preventing restless legs syndrome and associated symptoms in a subject.

[0045] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure and optionally a package insert containing instructions for use, for treating or preventing vertigo and associated symptoms in a subject.

[0046] In another embodiment, the present disclosure provides a personalized medical program for a subject suffering from LSD or a neurodegenerative disease, and includes selecting a treatment option that has the highest likelihood of a successful outcome for the individual LSD or neurodegenerative subject.

[0047] In another embodiment, the present disclosure provides a personalized medical program for a subject suffering from migraine and associated symptoms, and includes selecting a treatment option that has the highest likelihood of a successful outcome for treating or preventing migraine and associated symptoms in the subject.

[0048] In another embodiment, the present disclosure provides a personalized medical procedure for a subject in need of improved mobility and / or cognitive function, and includes selecting a treatment option with the highest likelihood of a successful outcome for improving the subject's mobility and / or cognitive function.

[0049] In another aspect, the present disclosure provides a method for preparing the compounds of the present disclosure.

[0050] Additional embodiments and advantages of the present disclosure will be set forth in part in the following description, and will become apparent from the description, or may be learned by practice of the present disclosure. The embodiments and advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0051] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is a line graph showing the effects of acetyl-leucine (designated IB1000) and acetyl-leucine-2,3,3,4-d4 (designated DIB1000) in an NPC cell phenotypic assay. NPC CHO cells were treated with 1, 10, 100, 1000, and 5000 μM of acetyl-leucine or acetyl-leucine-2,3,3,4-d4 for 7 days. The data shown are the mean ± SD of 1 - 3 biological replicates. The LysoTracker fluorescence is expressed as the fold change relative to the response obtained from the untreated sample (normalized to 1.0). Acetyl-leucine; 0.79 ± 0.05, acetyl-leucine-2,3,3,4-d4; 0.45 ± 0.03, unpaired t-test, two-tailed test, **p < 0.01, n = 3.

[0053] Figure 2 is a bar graph showing the effects of acetyl-leucine (designated IB1000) and acetyl-leucine-2,3,3,4-d4 (designated DIB1000) in a Tay-Sachs AB human fibroblast assay. Fibroblasts from a Tay-Sachs AB variant patient were treated with 1 mM acetyl-leucine or acetyl-leucine-2,3,3,4-d4 to compare the LysoTracker signal. Untreated; 1.00 ± 0.02, n = 3, acetyl-leucine; 0.97 ± 0.01, n = 3, acetyl-leucine-2,3,3,4-d4; 0.91 ± 0.02, n = 3. One-way ANOVA was performed for statistical analysis. * / **p < 0.003 / 0.02.

[0054] Figure 3A line graph showing the plasma concentration-time curves of N-acetyl-D-leucine (referred to as N-acetyl-D-leucine) and N-acetyl-L-leucine (referred to as N-acetyl-L-leucine) after oral administration of a saline solution containing N-acetyl-leucine (referred to as N-acetyl-DL-leucine) at a dose of 100 mg / kg to male BALB / c mice.

[0055] Figure 4 A line graph showing the plasma concentration-time curves of N-acetyl-D-leucine-2,3,3,4-d4 (referred to as N-acetyl-D-leucine-d4) and N-acetyl-L-leucine-2,3,3,4-d4 (1) (referred to as N-acetyl-L-leucine-d4) after oral administration of a saline solution containing N-acetyl-leucine-2,3,3,4-d4 (1-rac) (referred to as N-acetyl-DL-leucine-d4) at a dose of 100 mg / kg to male BALB / c mice.

[0056] Figure 5 A line graph showing the plasma concentration-time curves of N-acetyl-D-leucine (referred to as N-acetyl-D-leucine) and N-acetyl-L-leucine after oral administration of a saline solution containing N-acetyl-L-leucine (referred to as N-acetyl-L-leucine) at a dose of 100 mg / kg to male BALB / c mice.

[0057] Figure 6 A line graph showing the plasma concentration-time curves of N-acetyl-D-leucine-2,3,3,4-d4 (referred to as N-acetyl-D-leucine-d4) and N-acetyl-L-leucine-2,3,3,4-d4 (1) (referred to as N-acetyl-L-leucine-d4) after oral administration of a saline solution containing N-acetyl-L-leucine-2,3,3,4-d4 (1) at a dose of 100 mg / kg to male BALB / c mice. Detailed Description

[0058] The compounds of the present disclosure can be used to treat LSD in a subject or delay the progression of LSD, provide neuroprotection to a subject suffering from LSD, treat a neurodegenerative disease or delay the progression of a neurodegenerative disease, treat a neurodegenerative disease associated with lysosomal storage defects in a subject or delay the progression of a neurodegenerative disease associated with lysosomal storage defects, treat or prevent migraine and related symptoms in a subject, treat or prevent restless legs syndrome and related symptoms in a subject, treat or prevent vertigo and related symptoms in a subject, or be used to improve the mobility and / or cognitive function of a subject.

[0059] In one embodiment, the compounds of the present disclosure are compounds having Formula I:

[0060]

[0061] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0062] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0063] R 2 is C 1-6 alkyl; and

[0064] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0065] wherein at least one of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 is deuterium-enriched by about 15% or more.

[0066] In another embodiment, a compound of the present disclosure is a compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0067] (a) When R 13 is hydrogen, at least one of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 is hydrogen; and

[0068] (b) And the compound is not:

[0069]

[0070] In another embodiment, the compounds of the present disclosure are optically inactive compounds of Formula I or pharmaceutically acceptable salts or solvates thereof, i.e., the compounds are racemic.

[0071] In another embodiment, the compounds of the present disclosure are optically active compounds of Formula I or pharmaceutically acceptable salts or solvates thereof.

[0072] In another embodiment, the compounds of the present disclosure are compounds of Formula II:

[0073]

[0074] or pharmaceutically acceptable salts or solvates thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are as defined in connection with Formula I.

[0075] In another embodiment, the compounds of the present disclosure are compounds of Formula III:

[0076]

[0077] or pharmaceutically acceptable salts or solvates thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are as defined in connection with Formula I.

[0078] In another embodiment, the compounds of the present disclosure are compounds of Formula IV:

[0079]

[0080] or pharmaceutically acceptable salts or solvates thereof, wherein R 1 、R 2 、R 3 、R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 as defined in Formula I.

[0081] In another embodiment, a compound of the disclosure is a compound having Formula V:

[0082]

[0083] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 as defined in Formula I.

[0084] In another embodiment, a compound of the disclosure is a compound having any one of Formulas I-V, or a pharmaceutically acceptable salt or solvate thereof, having an enantiomeric excess (ee) of about 50% or more. In another embodiment, the ee is about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more. In another embodiment, the ee is about 100%.

[0085] In another embodiment, a compound of the disclosure is a compound having any one of Formulas I-V, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen.

[0086] In another embodiment, a compound of the disclosure is a compound having any one of Formulas I-V, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is methyl.

[0087] In another embodiment, a compound of the disclosure is a compound having any one of Formulas I-V, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is hydrogen.

[0088] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any two or more of them.

[0089] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any three or more of them.

[0090] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any four or more of them.

[0091] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any five or more of them.

[0092] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any six or more of them.

[0093] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any seven or more of them.

[0094] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any eight or more of them.

[0095] In another embodiment, the compounds of the present disclosure are compounds having any one of Formulas I-V, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0096] R 7 has a deuterium enrichment of about 15% or more;

[0097] R 10 has a deuterium enrichment of about 15% or more; and

[0098] R 6 , R 8 , R 9, R 11 and R 12 is hydrogen.

[0099] In another embodiment, a compound of the present disclosure is a compound having any one of Formulas I-V, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0100] R 7 and R 8 have a deuterium enrichment of about 15% or more;

[0101] R 10 and R 11 have a deuterium enrichment of about 15% or more; and

[0102] R 9 and R 12 is hydrogen.

[0103] In another embodiment, a compound of the present disclosure is a compound selected from the group consisting of:

[0104]

[0105]

[0106] or a pharmaceutically acceptable salt or solvate thereof.

[0107] In another embodiment, a compound of the present disclosure is a compound selected from the group consisting of:

[0108]

[0109] or a pharmaceutically acceptable salt or solvate thereof.

[0110] In another embodiment, a compound of the present disclosure is a compound selected from the group consisting of:

[0111]

[0112] or a pharmaceutically acceptable salt or solvate thereof.

[0113] In another embodiment, a compound of the present disclosure is a compound selected from the group consisting of:

[0114]

[0115] In another embodiment, a compound of the present disclosure is a compound selected from the group consisting of:

[0116]

[0117] In another embodiment, the compounds of the present disclosure are compounds selected from the group consisting of:

[0118]

[0119] In another embodiment, the compound of the present disclosure is:

[0120]

[0121] In another embodiment, the compound of the present disclosure is:

[0122]

[0123] In another embodiment, the compound of the present disclosure is:

[0124]

[0125] In another embodiment, the compound of the present disclosure is:

[0126]

[0127] The term "N-acetyl-DL-leucine" or "acetyl-leucine" refers to a compound having the following structure:

[0128]

[0129] The term "N-acetyl-D-leucine" or "acetyl-D-leucine" refers to a compound having the following structure:

[0130]

[0131] The term "N-acetyl-L-leucine" or "acetyl-L-leucine" refers to a compound having the following structure:

[0132]

[0133] As used herein, the term "C 1-6 alkyl" refers to a straight-chain or branched-chain aliphatic hydrocarbon containing one to six carbon atoms. In another embodiment, the alkyl group is selected from straight-chain C 1-6 alkyl groups. In another embodiment, the alkyl group is selected from branched-chain C 3-6 alkyl groups. In another embodiment, the alkyl group is selected from straight-chain C 1-4 alkyl groups. In another embodiment, the alkyl group is selected from branched-chain C 3-4 alkyl groups. The term C 1-6An alkyl group includes at least one deuterium-substituted analogue of hydrogen, having an abundance that is at least about 1000 times greater than the natural abundance of deuterium. Non-limiting exemplary C 1-6 alkyl groups include methyl, -CH2D, -CHD2, -CD3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, and hexyl.

[0134] When a position in any of Formulas I-V is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its natural abundance isotopic composition.

[0135] When a position in any of Formulas I-V is specifically designated as "D" or "deuterium", that position is understood to have deuterium with an abundance that is at least about 1000 times greater than the natural abundance of deuterium (which is about 0.015%).

[0136] As used herein, the term "deuterium enrichment" refers to the percentage of deuterium incorporated in place of hydrogen at a given position in any of Formulas I-V. In one embodiment, the deuterium enrichment is about 15% or more, i.e., at least about 1000 times greater than the natural abundance of deuterium. In another embodiment, the deuterium enrichment is about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more. In another embodiment, the deuterium enrichment is about 100%. Deuterium enrichment can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0137] As used herein, the term "stereoisomer" is a general term for all isomers of a single molecule that differ only in the spatial orientation of their atoms. It includes enantiomers and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).

[0138] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom that is attached to four different groups.

[0139] The terms "enantiomer" and "enantiomeric" refer to molecules that cannot be superimposed on their mirror images and thus have optical activity, where an enantiomer rotates the plane of polarized light in one direction, while its mirror image compound rotates the plane of polarized light in the opposite direction.

[0140] The term "racemic" refers to a mixture of equal portions of enantiomers and the mixture is optically inactive.

[0141] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0142] Unless otherwise stated, the stereochemical terms and conventions used in the specification are intended to be consistent with those described in Pure & Appl. Chem 68:2193 (1996).

[0143] The term "enantiomeric excess" or "ee" is a measure of how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the enantiomeric excess percentage is defined as │R - S│ * 100, where R and S are the respective molar or weight fractions of the enantiomers in the mixture such that R + S = 1. Based on knowledge of the optical rotation of chiral substances, the enantiomeric excess percentage is defined as ([α] obs / [α] max ) * 100, where [α] obs is the optical rotation of the enantiomeric mixture and [α] max is the optical rotation of the pure enantiomer. The enantiomeric excess can be determined using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry.

[0144] Salts and solvates (e.g., hydrates) of the compounds of the present disclosure can also be used in the methods disclosed herein.

[0145] This disclosure encompasses the preparation and use of salts of the compounds of this disclosure. As used herein, "pharmaceutically acceptable salts" refers to salts or zwitterionic forms of the compounds of this disclosure. The salts of the compounds of this disclosure can be prepared during the final isolation and purification of the compound, or separately by reacting the compound with an acid having a suitable cation. Pharmaceutically acceptable salts of the compounds of this disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids (such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (such as oxalic acid, maleic acid, succinic acid, and citric acid). Non-limiting examples of salts of the compounds of this disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethanesulfonate, salicylate, mesylate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, mesylate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate. Additionally, available amino groups present in the compounds of this disclosure can be quaternized with: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and dipentyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference to the compounds of this disclosure herein is intended to include the compounds of this disclosure and their pharmaceutically acceptable salts, hydrates, or solvates.

[0146] The present disclosure encompasses the preparation and use of solvates of the compounds of the present disclosure. Solvates generally do not significantly alter the physiological activity or toxicity of the compounds and can thus serve as pharmacologically equivalent substances. As used herein, the term "solvate" refers to a combination, physical association, and / or solvation of a compound of the present disclosure with solvent molecules, such as a disolvate, monosolvate, or hemisolvate, wherein the ratio of solvent molecules to the compound of the present disclosure is about 2:1, about 1:1, or about 1:2, respectively. Such physical associations involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Thus, "solvate" includes solution-phase and isolable solvates. The compounds of the present disclosure can exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol, and ethanol, and the present disclosure is intended to encompass both solvated and unsolvated forms of the compounds of the present disclosure.

[0147] One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates generally can serve as pharmacologically equivalent substances. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., 93(3):601 - 611 (2004), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described by van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004) and A. L. Bingham et al., Chem. Commun. 603 - 604 (2001). A typical non-limiting process for preparing a solvate would involve dissolving a compound of the present disclosure in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (such as filtration). Analytical techniques (such as infrared spectroscopy) can be used to confirm the presence of the solvent in the solvate crystals.

[0148] Unless otherwise indicated, in the context of describing the present disclosure (especially in the context of the claims), the use of the terms "a", "an", "the", and similar referents should be construed to cover both the singular and the plural. References to a range of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better illustrate the present disclosure and not to limit the scope of the present disclosure. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0149] Pharmaceutical composition

[0150] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0151] The compounds of the present disclosure are generally administered in admixture with pharmaceutical excipients selected according to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions used in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers, which carriers include excipients and / or auxiliaries that facilitate the processing of the compounds of the present disclosure.

[0152] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, pill coating, emulsifying, encapsulating, entrapping, or lyophilization processes. Appropriate formulations depend on the chosen route of administration. When a therapeutically effective amount of a compound of the present disclosure is administered orally, the composition is generally in the form of tablets, capsules, powders, solutions, or elixirs. When administered in tablet form, the composition can additionally contain solid carriers such as gelatin or adjuvants. Tablets, capsules, and powders contain from about 0.01% to about 95% (e.g., from about 1% to about 50%) of the compound of the present disclosure. When administered in liquid form, liquid carriers such as water, petroleum, or oils of animal or vegetable origin can be added. The liquid form of the composition can further contain physiological saline solutions, dextrose, or other sugar solutions, or glycols. When administered in liquid form, the composition contains from about 0.1% to about 90% by weight (e.g., from about 1% to about 50%) of the compound of the present disclosure.

[0153] When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, with due consideration of pH, isotonicity, stability, etc., is within the skill of the art. Compositions for intravenous, cutaneous, or subcutaneous injection generally contain an isotonic vehicle.

[0154] The compounds of the present disclosure can be readily combined with pharmaceutically acceptable carriers and excipients well-known in the art. Standard pharmaceutical carriers and excipients are described in Remington”s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed., 1995. Such carriers are capable of formulating the active agent into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained by the process of adding the compounds of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the granule mixture with suitable auxiliaries (if required) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrating agents can be added if required.

[0155] The compounds of the present disclosure can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Preparations for injection can be presented in unit dosage forms, for example, in ampoules or in multi-dose containers, together with the added preservatives. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and / or dispersing agents.

[0156] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of the compounds of the present disclosure can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers, or agents that increase the solubility of the compound and permit the preparation of highly concentrated solutions. Optionally, the compositions of the present invention can be in powder form for reconstitution prior to use with a suitable vehicle (e.g., sterile pyrogen-free water).

[0157] The compounds of the present disclosure can also be formulated into rectal compositions such as, for example, suppositories or retention enemas containing conventional suppository bases. In addition to the previously described formulations, the compounds of the present disclosure can be formulated into long-acting preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present disclosure can be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins.

[0158] In particular, the compounds of the present disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or beads, alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspending agents. The compounds of the present disclosure can also be administered parenterally, for example, by intravenous, intramuscular, subcutaneous, or intracoronary injection. For parenteral administration, the compounds of the present disclosure are generally used in the form of a sterile aqueous solution, which can contain other substances such as salts or monosaccharides, such as mannitol or glucose, to render the solution isotonic with blood.

[0159] In one embodiment, the pharmaceutically acceptable carrier is solid and the composition is in the form of a powder or a tablet. The solid pharmaceutically acceptable carrier can include one or more substances that can also serve as flavoring agents, buffering agents, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifying agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet disintegrants. The carrier can also be an encapsulating material. In a powder, the carrier is a finely divided solid mixed with the finely divided active agent according to the invention. In a tablet, the active agent can be mixed with a carrier having the necessary compression characteristics in a suitable proportion and pressed into the desired shape and size. Powders and tablets can contain up to 99% of the active agent. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. In another embodiment, the pharmaceutically acceptable carrier can be a gel and the composition can be in the form of a cream, etc.

[0160] The carrier can include one or more excipients or diluents. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, dibasic calcium phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc.

[0161] In another embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is in the form of a solution. Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds of the present disclosure may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmotic pressure regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing the above additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as diols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be an oil such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used for sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0162] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The active agent can be prepared as a sterile solid composition which can be dissolved or suspended at the time of administration using sterile water, saline or other suitable sterile injectable media.

[0163] The compounds and their compositions of the present disclosure can be administered orally in the form of a sterile solution or suspension which contains other solutes or suspending agents (e.g., saline or glucose sufficient to render the solution isotonic), bile salts, acacia, gelatin, sorbitan monooleate, polysorbate 80 (oleate ester of sorbitol and its anhydrides copolymerized with ethylene oxide), etc.

[0164] The compounds and their compositions of the present disclosure can also be administered orally in the form of liquid or solid compositions. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets and powders, and liquid forms such as solutions, syrups, elixirs and suspensions. Forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.

[0165] The compounds and their compositions of the present disclosure can alternatively be administered by inhalation (e.g., intranasal). The compositions can also be formulated for topical use. For example, creams or ointments can be applied to the skin.

[0166] The compounds and compositions of the present disclosure can be incorporated into slow or sustained release devices. Such devices can be inserted, for example, on or under the skin, and the drug can be released over weeks or even months. Such devices can be particularly advantageous when long-term treatment with the compounds of the present disclosure is required and frequent administration (e.g., at least daily) is typically necessary.

[0167] In another embodiment, the pharmaceutical composition is in the form of a tablet suitable for oral administration. In the tablet, the compounds of the present disclosure can be mixed with a vehicle having the necessary compression properties in a suitable ratio and pressed into the desired shape and size. The tablet can contain up to 99% by weight of the compounds of the present disclosure.

[0168] Solid oral dosage forms (such as tablets) of pharmaceutical preparations can be prepared by any method known in the pharmaceutical art. Pharmaceutical preparations are generally prepared by mixing the compounds of the present disclosure or their pharmaceutically acceptable salts with conventional pharmaceutically acceptable carriers, diluents, or excipients.

[0169] Method of Use

[0170] In another embodiment, the present disclosure provides a method for treating a lysosomal storage disorder or delaying the progression of a lysosomal storage disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of the present disclosure.

[0171] In another embodiment, the present disclosure provides a method for providing neuroprotection in a subject suffering from a lysosomal storage disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of the present disclosure.

[0172] In another embodiment, the present disclosure provides a method for treating a neurodegenerative disease or delaying the progression of a neurodegenerative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of the present disclosure.

[0173] In another embodiment, the present disclosure provides a method for treating a neurodegenerative disease associated with lysosomal storage defects or delaying the progression of a neurodegenerative disease associated with lysosomal storage defects, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of the present disclosure.

[0174] In another embodiment, the present disclosure provides a method for treating or preventing migraine and related symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of the present disclosure.

[0175] In another aspect, the present disclosure provides a method for improving mobility and / or cognitive function, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of the present disclosure.

[0176] In another aspect, the present disclosure provides a method for treating or preventing restless legs syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0177] In another aspect, the present disclosure provides a method for treating or preventing dizziness, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0178] The present invention also provides the following specific embodiments.

[0179] Embodiment I. A method for treating lysosomal storage disease or delaying the progression of lysosomal storage disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure having formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0180] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0181] R 2 is C 1-6 alkyl; and

[0182] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0183] wherein the deuterium enrichment of any one or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 is about 15% or more.

[0184] Embodiment II. A method for providing neuroprotection, treating neurodegenerative diseases or delaying the progression of neurodegenerative diseases, or treating or delaying the progression of neurodegenerative diseases associated with lysosomal storage defects, treating or preventing migraine and related symptoms, treating or preventing restless legs syndrome and related symptoms, treating or preventing dizziness and related symptoms, or improving mobility and / or cognitive function in a subject suffering from a lysosomal storage disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure having formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0185] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0186] R 2 is C 1-6 alkyl; and

[0187] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0188] wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 has a deuterium enrichment of about 15% or more for any one or more of them.

[0189] Embodiment III. The method according to Embodiment I or II, wherein the compound having formula I is optically active.

[0190] Embodiment IV. The method according to Embodiment III, wherein the optically active compound having formula I is a compound having formula II (see above).

[0191] Embodiment V. The method according to Embodiment III, wherein the compound having formula I is a compound having formula III (see above).

[0192] Embodiment VI. The method according to Embodiment III, wherein the compound having Formula I is a compound having Formula IV (see above).

[0193] Embodiment VII. The method according to Embodiment III, wherein the compound having Formula I is a compound having Formula V (see above).

[0194] Embodiment VIII. The method according to any one of Embodiments I-VII, wherein R 1 is hydrogen.

[0195] Embodiment IX. The method according to any one of Embodiments I-VIII, wherein:

[0196] R 2 is -CR 2a R 2b R 2c ; and

[0197] R 2a 、R 2b and R 2c are independently selected from the group consisting of hydrogen and deuterium,

[0198] wherein the deuterium enrichment of any one or more of R 2a 、R 2b and R 2c is about 15% or more. In another embodiment, R 2a 、R 2b and R 2c are each hydrogen, i.e., R 2 is methyl.

[0199] Embodiment X. The method according to any one of Embodiments I-IX, wherein R 13 is hydrogen.

[0200] Embodiment XI. The method according to any one of Embodiments I-X, wherein the deuterium enrichment of any two or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 is about 15% or more.

[0201] Embodiment XII. The method according to Embodiment XI, wherein R 3 、R 4 、R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any three or more of them.

[0202] Embodiment XIII. The method according to Embodiment XII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any four or more of them.

[0203] Embodiment XIV. The method according to Embodiment XIII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any five or more of them.

[0204] Embodiment XV. The method according to Embodiment XIV, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any six or more of them.

[0205] Embodiment XVI. The method according to Embodiment XV, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12The deuterium enrichment of any seven or more of them is about 15% or more.

[0206] Embodiment XVII. The method according to Embodiment XVI, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The deuterium enrichment of any eight or more of them is about 15% or more.

[0207] Embodiment XVIII. The method according to Embodiment XI, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0208] The deuterium enrichment of R 7 is about 15% or more;

[0209] The deuterium enrichment of R 10 is about 15% or more; and

[0210] R 6 , R 8 , R 9 , R 11 and R 12 are hydrogen.

[0211] Embodiment XIX. The method according to Embodiment XIII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0212] The deuterium enrichment of R 7 and R 8 is about 15% or more;

[0213] The deuterium enrichment of R 10 and R 11 is about 15% or more; and

[0214] R 9 and R 12 are hydrogen.

[0215] Embodiment XX. The method according to Embodiment I or II, wherein the compound having formula I is selected from the group consisting of:

[0216]

[0217] Embodiment XXI. The method according to Embodiment III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having formula I is selected from the group consisting of:

[0218]

[0219] Embodiment XXII. The method as described in Embodiment III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having the formula I is selected from the group consisting of:

[0220]

[0221]

[0222] Embodiment XXIII. A compound of the present disclosure having the formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0223] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0224] R 2 is C 1-6 alkyl; and

[0225] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0226] wherein the deuterium enrichment of any one or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 is about 15% or more,

[0227] The compound or a pharmaceutically acceptable salt or solvate thereof is used in a method for treating lysosomal storage diseases or delaying the progression of lysosomal storage diseases.

[0228] Embodiment XXIV. A compound of the present disclosure having the formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0229] R 1Selected from the group consisting of hydrogen and C 1-6 alkyl groups;

[0230] R 2 is C 1-6 alkyl; and

[0231] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 each independently selected from the group consisting of hydrogen and deuterium,

[0232] wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 is deuterium-enriched by about 15% or more for any one or more of,

[0233] The compound or a pharmaceutically acceptable salt or solvate thereof is used to provide neuroprotection in a subject suffering from a lysosomal disorder, treat a neurodegenerative disease or delay the progression of a neurodegenerative disease, treat a neurodegenerative disease associated with a lysosomal storage defect or delay the progression of a neurodegenerative disease associated with a lysosomal storage defect, treat or prevent migraine and related symptoms, treat or prevent restless legs syndrome and related symptoms, treat or prevent vertigo and related symptoms, or improve mobility and / or cognitive function.

[0234] Embodiment XXV. A compound as used in Embodiment XXIII or XXIV, wherein the compound of formula I is optically active.

[0235] Embodiment XXVI. A compound as used in Embodiment XXV, wherein the optically active compound of formula I is a compound of formula II (see above).

[0236] Embodiment XXVII. A compound as used in Embodiment XXV, wherein the compound of formula I is a compound of formula III (see above).

[0237] Embodiment XXVIII. A compound as used in Embodiment XXV, wherein the compound having Formula I is a compound having Formula IV (see above).

[0238] Embodiment XXIX. A compound as used in Embodiment XXV, wherein the compound having Formula I is a compound having Formula V (see above).

[0239] Embodiment XXX. A compound as used in any one of Embodiments XXIII - XXIX, wherein R 1 is hydrogen.

[0240] Embodiment XXXI. A compound as used in any one of Embodiments XXIII - XXX, wherein:

[0241] R 2 is -CR 2a R 2b R 2c ; and

[0242] R 2a , R 2b and R 2c are independently selected from the group consisting of hydrogen and deuterium,

[0243] wherein the deuterium enrichment of any one or more of R 2a , R 2b and R 2c is about 15% or more. In another embodiment, R 2a , R 2b and R 2c are each hydrogen, i.e., R 2 is methyl.

[0244] Embodiment XXXII. A compound as used in any one of Embodiments XXIII - XXXI, wherein R 13 is hydrogen.

[0245] Embodiment XXXIII. A compound as used in any one of Embodiments XXIII - XXXII, wherein the deuterium enrichment of any two or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 is about 15% or more.

[0246] Embodiment XXXIV. A compound as used in Embodiment XXXIII, wherein R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any three or more of them.

[0247] Embodiment XXXV. A compound as used in Embodiment XXXIV, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any four or more of them.

[0248] Embodiment XXXVI. A compound as used in Embodiment XXXV, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any five or more of them.

[0249] Embodiment XXXVII. A compound as used in Embodiment XXXVI, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any six or more of them.

[0250] Embodiment XXXVIII. A compound as used in Embodiment XXXVII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any seven or more of them.

[0251] Embodiment XXXIX. A compound as used in Embodiment XXXVIII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any eight or more of them.

[0252] Embodiment XL. A compound as used in Embodiment XXXIII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0253] R 7 has a deuterium enrichment of about 15% or more;

[0254] R 10 has a deuterium enrichment of about 15% or more; and

[0255] R 6 , R 8 , R 9 , R 11 and R 12 are hydrogen.

[0256] Embodiment XLI. A compound as used in Embodiment XXXV, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0257] R 7 and R 8 have a deuterium enrichment of about 15% or more;

[0258] R 10 and R 11 have a deuterium enrichment of about 15% or more; and

[0259] R 9 and R 12 are hydrogen.

[0260] Embodiment XLII. A compound as used in Embodiment XXIII or XXIV, wherein the compound having formula I is selected from the group consisting of:

[0261]

[0262] Embodiment XLIII. A compound as used in Embodiment XXV, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of:

[0263]

[0264] Embodiment XLIV. A compound as used in Embodiment XXV, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of:

[0265]

[0266]

[0267] Embodiment XLV. Use of a compound of the present disclosure of formula I (see above) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating lysosomal storage diseases or delaying the progression of lysosomal storage diseases, wherein:

[0268] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0269] R 2 is C 1-6 alkyl; and

[0270] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0271] wherein the deuterium enrichment of any one or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 is about 15% or more.

[0272] Embodiment XLVI. Use of a compound of the present disclosure having formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for providing neuroprotection, treating a neurodegenerative disease or delaying the progression of a neurodegenerative disease, treating a neurodegenerative disease associated with a lysosomal storage defect or delaying the progression of a neurodegenerative disease associated with a lysosomal storage defect, treating or preventing migraine and associated symptoms, treating or preventing restless legs syndrome and associated symptoms, treating or preventing vertigo and associated symptoms, or improving mobility and cognitive function in a subject suffering from a lysosomal disorder, wherein:

[0273] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0274] R 2 is C 1-6 alkyl; and

[0275] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0276] wherein the deuterium enrichment of any one or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 is about 15% or more.

[0277] Embodiment XLVII. Use according to Embodiment XLV or XLVI, wherein the compound having formula I is optically active.

[0278] Embodiment XLVIII. Use according to Embodiment XLVII, wherein the optically active compound having formula I is a compound having formula II (see above).

[0279] Embodiment XLIX. Use according to Embodiment XLVII, wherein the compound having formula I is a compound having formula III (see above).

[0280] Embodiment L. The use as described in Embodiment XLVII, wherein the compound having Formula I is a compound having Formula IV (see above).

[0281] Embodiment LI. The use as described in Embodiment XLVII, wherein the compound having Formula I is a compound having Formula V (see above).

[0282] Embodiment LII. The use as described in any one of Embodiments XLV-LI, wherein R 1 is hydrogen.

[0283] Embodiment LIII. The use as described in any one of Embodiments XLV-LII, wherein:

[0284] R 2 is -CR 2a R 2b R 2c ; and

[0285] R 2a 、R 2b and R 2c are independently selected from the group consisting of hydrogen and deuterium,

[0286] wherein the deuterium enrichment of any one or more of R 2a 、R 2b and R 2c is about 15% or more. In another embodiment, R 2a 、R 2b and R 2c are each hydrogen, i.e., R 2 is methyl.

[0287] Embodiment LIV. The use as described in any one of Embodiments XLV-LIII, wherein R 13 is hydrogen.

[0288] Embodiment LV. The use as described in any one of Embodiments XLV-LIV, wherein the deuterium enrichment of any two or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 is about 15% or more.

[0289] Embodiment LVI. The use as described in Embodiment LV, wherein R 3 、R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any three or more of them.

[0290] Embodiment LVII. The use as described in Embodiment LVI, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any four or more of them.

[0291] Embodiment LVIII. The use as described in Embodiment LVII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any five or more of them.

[0292] Embodiment LIX. The use as described in Embodiment LVIII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any six or more of them.

[0293] Embodiment LX. The use as described in Embodiment LIX, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 and R 12 the deuterium enrichment of any seven or more of them is about 15% or more.

[0294] Embodiment LXI. The use as described in Embodiment LX, wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 the deuterium enrichment of any eight or more of them is about 15% or more.

[0295] Embodiment LXII. The use as described in Embodiment LV, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0296] R 7 the deuterium enrichment is about 15% or more;

[0297] R 10 the deuterium enrichment is about 15% or more; and

[0298] R 6 、R 8 、R 9 、R 11 and R 12 are hydrogen.

[0299] Embodiment LXIII. The use as described in Embodiment LVII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0300] R 7 and R 8 the deuterium enrichment is about 15% or more;

[0301] R 10 and R 11 the deuterium enrichment is about 15% or more; and

[0302] R 9 and R 12 are hydrogen.

[0303] Embodiment LXIV. The use as described in Embodiment XLV or XLVI, wherein the compound having formula I is selected from the group consisting of:

[0304]

[0305] Use according to embodiment XLVII, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of:

[0306]

[0307]

[0308] Embodiment LXVI. Use according to embodiment XLVII, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of:

[0309]

[0310] Embodiment LXVII. A pharmaceutical composition comprising a compound of the present disclosure of formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0311] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0312] R 2 is C 1-6 alkyl; and

[0313] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0314] wherein the deuterium enrichment of any one or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 is about 15% or more,

[0315] The pharmaceutical composition is for use in a method of treating a lysosomal storage disorder or delaying the progression of a lysosomal storage disorder.

[0316] Embodiment LXVIII. A pharmaceutical composition comprising a compound of the present disclosure having formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0317] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0318] R 2 is C 1-6 alkyl; and

[0319] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0320] wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 has a deuterium enrichment of about 15% or more for any one or more of them,

[0321] The pharmaceutical composition is used to provide neuroprotection in a subject suffering from a lysosomal disorder, treat a neurodegenerative disease or delay the progression of a neurodegenerative disease, treat a neurodegenerative disease associated with a lysosomal storage defect or delay the progression of a neurodegenerative disease associated with a lysosomal storage defect, treat or prevent migraine and associated symptoms, treat or prevent restless legs syndrome and associated symptoms, treat or prevent dizziness and associated symptoms, or improve mobility and / or cognitive function.

[0322] Embodiment LXIX. The pharmaceutical composition according to Embodiment LXVII or LXVIII, wherein the compound having formula I is optically active.

[0323] Embodiment LXX. The pharmaceutical composition according to Embodiment LXIX, wherein the optically active compound having formula I is a compound having formula II (see above).

[0324] Embodiment LXXI. A pharmaceutical composition as described in Embodiment LXIX, wherein the compound having Formula I is a compound having Formula III (see above).

[0325] Embodiment LXXII. A pharmaceutical composition as described in Embodiment LXIX, wherein the compound having Formula I is a compound having Formula IV (see above).

[0326] Embodiment LXXIII. A pharmaceutical composition as described in Embodiment LXIX, wherein the compound having Formula I is a compound having Formula V (see above).

[0327] Embodiment LXXIV. A pharmaceutical composition as described in any one of Embodiments LXVII - LXXIII, wherein R 1 is hydrogen.

[0328] Embodiment LXXV. A pharmaceutical composition as described in any one of Embodiments LXVII - LXXIV, wherein:

[0329] R 2 is -CR 2a R 2b R 2c ; and

[0330] R 2a , R 2b and R 2c are independently selected from the group consisting of hydrogen and deuterium,

[0331] wherein the deuterium enrichment of any one or more of R 2a , R 2b and R 2c is about 15% or more. In another embodiment, R 2a , R 2b and R 2c are each hydrogen, i.e., R 2 is methyl.

[0332] Embodiment LXXVI. A pharmaceutical composition as described in any one of Embodiments LXVII - LXXV, wherein R 13 is hydrogen.

[0333] Embodiment LXXVII. A pharmaceutical composition as described in any one of Embodiments LXVII - LXXVI, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11and R 12 the deuterium enrichment of any two or more of them is about 15% or more.

[0334] Embodiment LXXVIII. A pharmaceutical composition as described in Embodiment LXXVII, wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 the deuterium enrichment of any three or more of them is about 15% or more.

[0335] Embodiment LXXIX. A pharmaceutical composition as described in Embodiment LXXVIII, wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 the deuterium enrichment of any four or more of them is about 15% or more.

[0336] Embodiment LXXX. A pharmaceutical composition as described in Embodiment LXXIX, wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 the deuterium enrichment of any five or more of them is about 15% or more.

[0337] Embodiment LXXXI. A pharmaceutical composition as described in Embodiment LXXX, wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 the deuterium enrichment of any six or more of them is about 15% or more.

[0338] Embodiment LXXXII. The pharmaceutical composition as described in Embodiment LXXXI, wherein the deuterium enrichment of any seven or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、and R 12 is about 15% or more.

[0339] Embodiment LXXXIII. The pharmaceutical composition as described in Embodiment LXXXII, wherein the deuterium enrichment of any eight or more of R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、and R 12 is about 15% or more.

[0340] Embodiment LXXXIV. The pharmaceutical composition as described in Embodiment LXXVII or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0341] The deuterium enrichment of R 7 is about 15% or more;

[0342] The deuterium enrichment of R 10 is about 15% or more; and

[0343] R 6 、R 8 、R 9 、R 11 、and R 12 are hydrogen.

[0344] Embodiment LXXXV. The pharmaceutical composition as described in Embodiment LXXIX or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0345] The deuterium enrichment of R 7 and R 8 is about 15% or more;

[0346] The deuterium enrichment of R 10 and R 11 is about 15% or more; and

[0347] R 9 and R 12 are hydrogen.

[0348] Embodiment LXXXVI. A pharmaceutical composition as in Embodiment LXVII or LXVIII, wherein the compound of formula I is selected from the group consisting of:

[0349]

[0350] Embodiment LXXXVII. A pharmaceutical composition as in Embodiment LXIX or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of:

[0351]

[0352]

[0353] Embodiment LXXXVIII. A pharmaceutical composition as in Embodiment LXIX or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is selected from the group consisting of:

[0354]

[0355] Embodiment LXXXIX. A kit that comprises a compound of the present disclosure of formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0356] R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0357] R 2 is C 1-6 alkyl; and

[0358] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from the group consisting of hydrogen and deuterium,

[0359] wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R12 and R 13 has a deuterium enrichment of about 15% or more for any one or more of them, and for administering the compound to a subject for treating a lysosomal storage disorder or delaying the progression of a lysosomal storage disorder, or for providing neuroprotection in a subject with a lysosomal disorder, or for treating a neurodegenerative disease or delaying the progression of a neurodegenerative disease, treating a neurodegenerative disease associated with a lysosomal storage defect or delaying the progression of a neurodegenerative disease associated with a lysosomal storage defect, treating or preventing migraine and associated symptoms, treating or preventing restless legs syndrome and associated symptoms, treating or preventing dizziness and associated symptoms, or improving mobility and / or cognitive function.

[0360] Embodiment XC. A kit as described in Embodiment LXXXIX, wherein the compound of Formula I is optically active.

[0361] Embodiment XCI. A kit as described in Embodiment XC, wherein the optically active compound of Formula I is a compound of Formula II (see above).

[0362] Embodiment XCII. A kit as described in Embodiment XC, wherein the compound of Formula I is a compound of Formula III (see above).

[0363] Embodiment XCIII. A kit as described in Embodiment XC, wherein the compound of Formula I is a compound of Formula IV (see above).

[0364] Embodiment XCIV. A kit as described in Embodiment XC, wherein the compound of Formula I is a compound of Formula V (see above).

[0365] Embodiment XCV. A kit as described in any one of Embodiments LXXXIX - XCIV, wherein R 1 is hydrogen.

[0366] Embodiment XCVI. A kit as described in any one of Embodiments LXXXIX - XCV, wherein:[[]]

[0367] R 2 is -CR 2a R 2b R 2c ; and

[0368] R 2a 、R 2b and R 2c are independently selected from the group consisting of hydrogen and deuterium,

[0369] wherein R 2a 、R 2band R 2c has a deuterium enrichment of about 15% or more. In another embodiment, R 2a , R 2b and R 2c are each hydrogen, i.e., R 2 is a methyl group.

[0370] Embodiment XCVII. A kit as described in any one of Embodiments LXXXIX - XCVI, wherein R 13 is hydrogen.

[0371] Embodiment XCVIII. A kit as described in any one of Embodiments LXXXIX - XCVII, wherein any two or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more.

[0372] Embodiment XCIX. A kit as described in Embodiment XCVIII, wherein any three or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more.

[0373] Embodiment C. A kit as described in Embodiment XCIX, wherein any four or more of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more.

[0374] Embodiment CI. A kit as described in Embodiment C, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any five or more of them.

[0375] Embodiment CII. A kit as described in Embodiment CI, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any six or more of them.

[0376] Embodiment CIII. A kit as described in Embodiment CII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any seven or more of them.

[0377] Embodiment CIV. A kit as described in Embodiment CIII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have a deuterium enrichment of about 15% or more for any eight or more of them.

[0378] Embodiment CV. A kit as described in Embodiment XCVIII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0379] R 7 has a deuterium enrichment of about 15% or more;

[0380] R 10 has a deuterium enrichment of about 15% or more; and

[0381] R 6 , R 8 , R9 , R 11 and R 12 is hydrogen.

[0382] Embodiment CVI. A kit as described in Embodiment C, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0383] R 7 and R 8 have a deuterium enrichment of about 15% or more;

[0384] R 10 and R 11 have a deuterium enrichment of about 15% or more; and

[0385] R 9 and R 12 is hydrogen.

[0386] Embodiment CVII. A kit as described in Embodiment LXXXIX, wherein the compound having Formula I is selected from the group consisting of:

[0387]

[0388] Embodiment CVIII. A kit as described in Embodiment XC, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0389]

[0390]

[0391] Embodiment CIX. A kit as described in Embodiment XC, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0392]

[0393] In another embodiment, the compounds of the present disclosure are administered in combination with a second therapeutic agent useful for treating LSD, neurodegenerative diseases or migraines, restless legs syndrome or dizziness, or useful for improving mobility and / or cognitive function. The second therapeutic agent is different from the compounds of the present disclosure. The compounds of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. Additionally, the compounds of the present disclosure and the second therapeutic agent can be administered by a single composition or two separate compositions.

[0394] The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. The effective dose range for each second therapeutic agent is generally known in the art, and the second therapeutic agent is administered to a subject in need thereof within such determined range.

[0395] The compounds of the present disclosure and the second therapeutic agent can be administered together as a single unit dose or separately as multiple unit doses, wherein the compounds of the present disclosure are administered before the second therapeutic agent and vice versa. One or more doses of the compounds of the present disclosure and / or one or more doses of the second therapeutic agent can be administered.

[0396] As used herein, the term "subject" can be a vertebrate, a mammal, or a domestic animal. Thus, the compositions according to the present disclosure can be used to treat any mammal, such as livestock (e.g., horses, cows, sheep, or pigs), pets (e.g., cats, dogs, rabbits, or guinea pigs), laboratory animals (e.g., mice or rats), or can be used for other veterinary applications. In one embodiment, the subject is a human.

[0397] Unless otherwise indicated, the term "treatment" as used herein refers to eliminating, alleviating, or ameliorating a disease or disorder and / or the symptoms associated therewith. Although not excluded, treating a disease or disorder does not necessarily require complete elimination of the disease, disorder, or the symptoms associated therewith. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of the compounds of the present disclosure to a subject in need thereof. Treatment can be directed at symptoms, e.g., suppressing symptoms. It can act in the short term, be directed at the medium term, or can be long-term treatment, e.g., in the context of maintenance treatment.

[0398] As used herein, the term "prevention" refers to a method of preventing the onset of a disease or disorder and / or its attendant symptoms or preventing a subject from contracting a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its attendant symptoms and reducing the risk of a subject contracting a disease. The term "prevention" can include "preventive treatment", which refers to reducing the likelihood of a subject contracting a disease or a previously controlled disease or disorder recurring in a subject who does not have the disease or disorder or a recurrence of the disease or disorder, but is at risk of contracting the disease or disorder or a recurrence of the disease or disorder or is prone to contracting the disease or disorder or a recurrence of the disease or disorder.

[0399] As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of the compounds of the present disclosure that is sufficient to deliver a compound for treating a disorder or disease of interest to a subject in need thereof and to produce the desired effect in the subject when administered by the methods of the present disclosure. In the case of LSD or neurodegenerative diseases, a therapeutically effective amount of the compounds of the present disclosure can, for example, delay the onset of symptoms of LSD or markers associated with LSD or delay the onset of symptoms of neurodegenerative diseases.

[0400] As used herein, the term "lysosomal storage disorder" or "LSD" refers to any disorder involving dysfunction or disruption of the secondary endosomal / lysosomal system. LSD can involve an increase in the volume and / or pH of the endosomal / lysosomal system. LSD can also involve an increase in the storage of lipids or non-lipids.

[0401] LSD can be due to a primary lysosomal hydrolase deficiency, a post-translational processing defect of lysosomal enzymes, a lysosomal enzyme trafficking defect, a lysosomal enzyme protection defect, a soluble non-enzymatic lysosomal protein defect, a transmembrane (non-enzymatic) protein defect, or an unclassified defect.

[0402] Primary lysosomal hydrolase deficiencies include, but are not limited to, Gaucher disease (glucocerebrosidase deficiency), GM1 gangliosidosis (GM1-β-galactosidase deficiency), Tay-Sachs disease (β-hexosaminidase A deficiency), Sandhoff disease (β-hexosaminidase A + B deficiency), Fabry disease (α-galactosidase A deficiency), Krabbe disease (β-galactosylceramidase deficiency), Niemann-Pick disease types A and B (sphingomyelinase deficiency), metachromatic leukodystrophy (arylsulfatase A deficiency), MPS IH (Hurler syndrome; α-L-iduronidase deficiency), MPS IS (Scheie syndrome; α-L-iduronidase deficiency), MPS IH-S (Hurler-Scheie syndrome; α-L-iduronidase deficiency), MPS II (Hunter syndrome; iduronate sulfatase deficiency), MPS IIIA (Sanfilippo A syndrome; heparan sulfamidase deficiency), MPS IIIB (Sanfilippo B syndrome; N-acetyl-α-glucosaminidase deficiency), MPS IIIC (Sanfilippo C syndrome; acetyl-CoA:α-glucosaminide N-acetyltransferase deficiency), MPS IIID (Sanfilippo D syndrome; N-acetylglucosamine-6-sulfatase deficiency), MPS IV A (Morquio A disease; N-acetylgalactosamine-6-sulfatase deficiency), MPS IVB (Morquio B disease; β-galactosidase deficiency), MPS V (renamed MPS IS), MPS VI (Maroteaux Lamy syndrome; N-acetylgalactosamine-4-sulfatase (arylsulfatase B) deficiency), MPS VII (Sly syndrome; β-glucuronidase deficiency), MPS IX (hyaluronidase deficiency), Wolman disease (WD; acid lipase deficiency), Farber disease (acid ceramidase deficiency), cholesterol ester storage disease (acid lipase deficiency), Pompe disease (type II; α1,4-glucosidase deficiency), aspartylglucosaminuria (glycosylasparaginase deficiency), fucosidosis (α-fucosidase deficiency), α-mannosidosis (α-mannosidase deficiency), β-mannosidosis (β-mannosidase deficiency), Schindler disease (N-acetylgalactosaminidase deficiency), sialidosis (α-neuraminidase deficiency), infantile neuronal ceroid lipofuscinosis (CLN1; palmitoyl-protein thioesterase deficiency), late infantile neuronal ceroid lipofuscinosis (CLN2; carboxypeptidase deficiency), early infantile GM1 gangliosidosis, late infantile GM1 gangliosidosis, adult infantile GM1 gangliosidosis, type 1 Gaucher disease (non-neuronal lesions), type 2 / 3 Gaucher disease (neuronal lesions), ML1 (MLI;Sialidosis, α-N-acetylneuraminidase (sialidase) deficiency), ML2 (MLII, I-cell disease; N-acetylglucosamine phosphotransferase deficiency), ML3 (MLIII, pseudo-Hurler polydystrophy; N-acetylglucosamine phosphotransferase deficiency), ML4 (MLIV, mucolipin 1 deficiency), neuronal ceroid lipofuscinosis type 4 (CLN4; Kufs disease; adult NCL; palmitoyl protein thioesterase-1 deficiency (type A); cathepsin F deficiency (type B)), neuronal ceroid lipofuscinosis type 8 - Northern epilepsy type (CLN8), neuronal ceroid lipofuscinosis type 8 - Turkish late infantile type (CLN8), neuronal ceroid lipofuscinosis type 9 - German / Serbian late infantile type (CLN9), neuronal ceroid lipofuscinosis type 10 (CLN10; congenital cathepsin D deficiency), pycnodysostosis (cathepsin K deficiency), infantile Pompe disease, late-onset Pompe disease, and cholesterol ester storage disease.;

[0403] Post-translational processing defects of lysosomal enzymes include, but are not limited to, mucopolysaccharidosis (MSD; multiple sulfatase deficiency).

[0404] Transport defects of lysosomal enzymes include, but are not limited to, mucolipidosis type II (I-cell disease; N-acetylglucosamine phosphotransferase deficiency), mucolipidosis type IDA (pseudo-Hurler polydystrophy; N-acetylglucosamine phosphotransferase deficiency), and mucolipidosis type IIIC.

[0405] Protection defects of lysosomal enzymes include, but are not limited to, galactosialidosis (protective protein cathepsin A (PPCA) deficiency), β-galactosidase deficiency, and neuraminidase deficiency. Defects of soluble non-enzymatic lysosomal proteins include, but are not limited to, GM2 activator protein deficiency (variant AB), sphingolipid activator protein (SAP) deficiency, and neuronal ceroid lipofuscinosis (NCL) (CLN5).

[0406] Transmembrane (non-enzymatic) protein defects include, but are not limited to, Danon disease (lysosome-associated membrane protein 2 (LAMP2) deficiency), NPC (NPC1 and / or NPC2 deficiency), cystinosis (cystine transporter deficiency), infantile free sialic acid storage disease (ISSD; sialic acid transporter deficiency), sialic acid storage disease (free sialic acid storage; sialic acid transporter deficiency), juvenile neuronal ceroid lipofuscinosis (CLN3, Batten disease), neuronal ceroid lipofuscinosis (NCL) (CLN6 and CLN8), and mucolipidosis type IV (mucolipin deficiency).

[0407] Unclassified deficiencies include, but are not limited to, neuronal ceroid lipofuscinosis (NCL) (CLN4 and CLN7).

[0408] The LSDs to be treated, delayed or improved by the compounds, compositions and methods of the present disclosure are any of the following: NPC (NPC1 and / or NPC2 deficiency, primary or secondary), Smith-Lemli-Opitz syndrome (SLOS), congenital cholesterol synthesis error, Tangier disease, Pelizaeus-Merzbacher disease, neuronal ceroid lipofuscinosis, primary glycosphingolipidosis (i.e., Gaucher disease, Fabry disease, GM1, GM2 gangliosidosis, Krabbe disease and metachromatic leukodystrophy (MLD)), Farber disease and multiple sulfatase deficiency.

[0409] In some embodiments, LSDs that significantly implicate the central nervous system (CNS) (such as NPC, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis or Fabry disease) are treated or delayed by the compounds of the present disclosure and the compositions and methods described herein.

[0410] Niemann-Pick disease is a heterogeneous group of autosomal recessive LSDs. Common cellular features include abnormal storage of sphingomyelin (SM) in mononuclear phagocytes and parenchyma, and (hepato) splenomegaly. Among the three main subgroups (A-C), NPC (previously classified as NPC and NPD, now considered a single disease) is classified as a fatal neurovisceral LSD caused by the accumulation induced by abnormal intracellular cholesterol transport of unesterified cholesterol in the secondary endosome / lysosome compartment.

[0411] Outside the CNS, cellular hallmarks of NPC include abnormal accumulation of unesterified cholesterol and other lipids (e.g., GSLs) in secondary endosomal / lysosomal compartments. In contrast, there is no net increase in cholesterol in the CNS (although its distribution does change), but levels of GSLs are high. The progressive neurodegeneration is characterized in particular by the continuous degeneration of GABAergic Purkinje neurons in the cerebellum, which coincides with the onset and progression of cerebellar ataxia and other aspects of neurological dysfunction seen during the course of NPC. Genetic studies have shown that NPC disease is caused by mutations in either the Npc1 or Npc2 genes. The precise mechanistic link between these two genes remains unknown, and the functional roles of these proteins remain a mystery. NPC1 encodes a multimembrane spanning protein of the limiting membrane of secondary endosomes / lysosomes, while NPC2 is a soluble cholesterol-binding protein of lysosomes. When NPC1 is inactive, sphingosine is the first lipid to be stored, suggesting that NPC1 plays a role in the transport of sphingosine from lysosomes, where it is normally produced as part of sphingolipid catabolism. Elevated sphingosine in turn causes a defect in the entry of calcium into acidic stores, resulting in greatly reduced calcium release from this compartment. This prevents secondary endosome-lysosome fusion, a calcium-dependent process, and leads to the subsequent accumulation of lipids (cholesterol, sphingomyelin, and glycosphingolipids), which are cargoes transported via the secondary endocytic pathway.

[0412] Other secondary consequences of inhibiting NPC1 function include the generation of endocytosis defects and an inability to clear autophagic vacuoles. It has been shown that the NPC1 / NPC2 cellular pathway is targeted by pathogenic mycobacteria to favor their survival in secondary endosomes. In one embodiment, Niemann-Pick disease is Niemann-Pick disease type A, B, C1 or C2.

[0413] Tay-Sachs is a fatal genetic disorder of lipid metabolism characterized by a lack of the A (acidic) isozyme of β-hexosaminidase, particularly in CNS tissues. Mutations in the HEXA gene, which encodes the α subunit of β-hexosaminidase, result in a lack of the A isozyme. Tay-Sachs is the prototype of a group of disorders, namely GM2 gangliosidosis, characterized by a defect in the degradation of GM2 gangliosides. GM2 ganglioside (monosialyl ganglioside 2) begins to accumulate in neurons during the fetal period. In one embodiment, Tay-Sachs is the AB variant of Tay-Sachs.

[0414] Sandhof disease is caused by a deficiency of the A and B (basic) isozymes of β-hexosaminidase. Mutations in the HEXB gene (which encodes the β subunit of β-hexosaminidase) result in a deficiency of the B isozyme.

[0415] GM1 gangliosidosis is caused by a deficiency of β-galactosidase, which results in the accumulation of GM1 ganglioside (monosialosylganglioside 1) in lysosomes.

[0416] Fabry disease is caused by a deficiency of α-galactosidase, which results in the accumulation of ceramide trihexoside in lysosomes.

[0417] As used herein, the term "neurodegenerative disease" refers to any disorder that affects neurons and involves a progressive loss of neuronal structure, a progressive loss of neuronal function, or a progressive death of neuronal cells.

[0418] Neurodegenerative diseases include, but are not limited to, alcoholism, Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, neuronal ceroid lipofuscinosis, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, cerebral palsy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal degeneration, Gaucher's disease, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, Lewy body dementia, lysosomal storage disorders, neuroborreliosis, Machado-Joseph disease, multiple system atrophy, multiple sclerosis, multiple sulfatase deficiency, mucolipidosis, narcolepsy, Niemann-Pick disease type C, Niemann-Pick disease, Parkinson's disease, parkinsonism plus, Pelizaeus-Merzbacher disease, Pick's disease, Pompe disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum's disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Batten disease, cerebellar ataxia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, Tay-Sachs disease, dentatorubropallidoluysian atrophy, episodic ataxia (EA) 1, episodic ataxia (EA) 2, episodic ataxia (EA) 3, episodic ataxia (EA) 4, episodic ataxia (EA) 5, episodic ataxia (EA) 6, episodic ataxia (EA) 7, Charlevoix-Saguenay autosomal recessive spastic ataxia (ARSACS), autosomal recessive cerebellar ataxia type 1 (Beauce recessive ataxia (RAB)), autosomal recessive cerebellar ataxia type 2 (spinocerebellar ataxia autosomal recessive 9,SCAR9), ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), ataxia with vitamin E deficiency (AVED), Friedreich ataxia (FRDA), mitochondrial recessive ataxia syndrome (MIRAS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), sensory ataxia neuropathy dysarthria ophthalmoplegia (SANDO), ataxia with coenzyme Q10 deficiency, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke syndrome (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), Kearns-Sayre disease (KSS), fragile X tremor / ataxia syndrome (FXTAS), Arts syndrome, Christianson type X-linked mental retardation, X-linked sideroblastic anemia, idiopathic late-onset cerebellar ataxia, sporadic adult-onset ataxia of unknown origin (SAOA), transmissible mink encephalopathy, chronic wasting disease, feline spongiform encephalopathy, exotic ungulate encephalopathy, Kuru disease, variant Creutzfeldt-Jakob disease, Gerstmann-Scheinker syndrome, fatal familial insomnia, hereditary motor and sensory neuropathy with proximal predominance, wobbly hedgehog syndrome (WHS), progressive muscular atrophy (Duchenne-Aran muscular atrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorder (HAND), Parkinson's disease and scrapie. -Scheinker) syndrome, fatal familial insomnia, hereditary motor and sensory neuropathy with proximal predominance, wobbly hedgehog syndrome (WHS), progressive muscular atrophy (Duchenne-Aran muscular atrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorder (HAND), Parkinson's disease and scrapie.

[0419] In one embodiment, the spinocerebellar ataxia is infantile spinocerebellar ataxia, spinocerebellar ataxia (SCA) 1, spinocerebellar ataxia (SCA) 2, spinocerebellar ataxia (SCA) 3 (Machado-Joseph disease), spinocerebellar ataxia (SCA) 4, spinocerebellar ataxia (SCA) 5 (Lincoln ataxia), spinocerebellar ataxia (SCA) 6, spinocerebellar ataxia (SCA) 7, spinocerebellar ataxia (SCA) 8, spinocerebellar ataxia (SCA) 10, spinocerebellar ataxia (SCA) 11, spinocerebellar ataxia (SCA) 12, spinocerebellar ataxia (SCA) 13, spinocerebellar ataxia (SCA) 14, spinocerebellar ataxia (SCA) 15 / 16, spinocerebellar ataxia (SCA) 17, spinocerebellar ataxia (SCA) 18 (with ataxia sensory / motor neuropathy), spinocerebellar ataxia (SCA) 19 / 22, spinocerebellar ataxia (SCA) 20, spinocerebellar ataxia (SCA) 21, spinocerebellar ataxia (SCA) 23, spinocerebellar ataxia (SCA) 24, spinocerebellar ataxia (SCA) 25, spinocerebellar ataxia (SCA) 26, spinocerebellar ataxia (SCA) 27, spinocerebellar ataxia (SCA) 28 (spinocerebellar ataxia type 4 autosomal recessive (SCAR4); spinocerebellar ataxia with cystic involvement), spinocerebellar ataxia (SCA) 29, spinocerebellar ataxia (SCA) 30, spinocerebellar ataxia (SCA) 31, spinocerebellar ataxia (SCA) 32, spinocerebellar ataxia (SCA) 35, spinocerebellar ataxia (SCA) 36, X-linked spinocerebellar ataxia 1, X-linked spinocerebellar ataxia 2, X-linked spinocerebellar ataxia 3, X-linked spinocerebellar ataxia 4 or X-linked spinocerebellar ataxia 5.

[0420] In one embodiment, the neurodegenerative disease is cerebellar ataxia. In one embodiment, the neurodegenerative disease is Niemann-Pick disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is neuronal Gaucher's disease. In one embodiment, the neurodegenerative disease is Sandhoff disease. In one embodiment, the neurodegenerative disease is Louis-Barr syndrome. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is multiple system atrophy. In one embodiment, the neurodegenerative disease is frontotemporal dementia. In one embodiment, the neurodegenerative disease is lower limb Parkinsonism.

[0421] The main symptoms of Parkinson's disease (PD) are stiffness, tremors, and slowness of movement. These symptoms are also common in other diseases. These diseases, as well as PD itself, are within the scope of the umbrella term parkinsonism. PD can be referred to as primary parkinsonism. Other examples of parkinsonism include: multiple system atrophy, progressive supranuclear palsy, normal pressure hydrocephalus, and vascular or arteriosclerotic parkinsonism. Those diseases that can be classified as parkinsonism but are not PD can also be referred to as "Parkinson-Plus Syndrome". Unlike patients with PD, individuals with Parkinson-Plus Syndrome do not respond to LDopa. As used herein, the term "parkinsonism" can refer to a movement syndrome whose main symptoms are tremors at rest, stiffness, slowness of movement, and postural instability. Parkinsonian syndromes can be classified into four subtypes according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and parkinsonism-plus syndrome or multisystem degeneration.

[0422] In one embodiment, parkinsonism is parkinsonism-plus syndrome or multisystem degeneration. In one embodiment, parkinsonism is vascular parkinsonism (arteriosclerotic parkinsonism; lower body parkinsonism), multiple system atrophy with predominant parkinsonism (MSA-P), multiple system atrophy with cerebellar features (MSA-C; sporadic olivopontocerebellar atrophy (OPCA)), Shy–Drager syndrome, progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome), dementia with Lewy bodies, Pick's disease or frontotemporal dementia, and parkinsonism associated with chromosome 17.

[0423] As used herein, phrases such as "retarding the progression of LSD" mean retarding the onset of symptoms of LSD or markers associated with LSD in a subject, i.e., increasing the time of their appearance (compared to what is typically observed). It can include significantly slowing, preventing, or even completely preventing the onset of a disease or one or more symptoms and / or complications associated with the disease.

[0424] The phrase "retarding the progression of a neurodegenerative disease" or "retarding the progression of a neurodegenerative disease associated with a lysosomal storage defect" means retarding the onset of symptoms of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect or markers associated with a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect, i.e., increasing the time of their appearance (compared to what is typically observed). It can include significantly slowing, preventing, or even completely preventing the onset of a disease or one or more symptoms and / or complications associated with the disease.

[0425] Accordingly, delaying progression includes, but is not limited to, delaying or preventing symptoms and / or complications caused by or associated with, for example, LSD, neurodegenerative diseases, or neurodegenerative diseases associated with lysosomal storage defects. When provided prophylactically, N-acetyl-leucine is typically provided prior to the onset of symptoms of LSD, neurodegenerative diseases, or neurodegenerative diseases associated with lysosomal storage defects. Such prophylactic administration is generally for delaying or preventing the onset of symptoms of LSD, neurodegenerative diseases, or neurodegenerative diseases associated with lysosomal storage defects.

[0426] "Symptoms" of LSD include any clinical or laboratory manifestation associated with LSD and are not limited to those that can be felt or observed by a subject. Symptoms described herein include neurological symptoms. Examples of neurological symptoms include ataxia, dystonia, vertical and horizontal supranuclear saccadic / gaze palsy, and dementia. Also included are psychiatric symptoms such as depression or psychosis. Most LSDs can be diagnosed based on a subject's medical history, clinical findings, biochemical markers, and genetic testing.

[0427] "Symptoms" of a neurodegenerative disease optionally associated with a lysosomal storage defect include any clinical or laboratory manifestation associated with the neurodegenerative disease and are not limited to those that can be felt or observed by a subject. Symptoms described herein include neurological symptoms.

[0428] Progression is said to be delayed when the time to the appearance of symptoms of LSD or a biomarker associated with LSD or the time to the appearance of symptoms of a neurodegenerative disease is at least 5% longer than that typically observed in subjects with LSD or the neurodegenerative disease. In some embodiments, an increase in time is observed of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%.

[0429] One or more of the following can be used to evaluate disease treatment or progression: the Scale for the Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), the modified Disability Rating Scale (mDRS), the EuroQol 5Q-5D-5L (EQ-5D-5L), the Visual Analogue Scale (VAS), the Wechsler Adult Intelligence Scale Revised (WAIS-R), the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV), or the Montreal Cognitive Assessment (MoCA). For certain LSDs, such as NPC, specific scores have been developed and validated over the past few decades, such as the modified 6-domain NP-C disability scale (mDRS score). In this regard, certain scores in these tests are characteristic of symptomatic LSD or neurodegenerative subjects. Thus, "retarding the progression of LSD" or "retarding the progression of a neurodegenerative disease" can mean increasing the time (compared to what is typically observed) it takes for a subject to reach a SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, and / or MoCA score or other relevant test that is characteristic of a symptomatic LSD subject or a neurodegenerative subject.

[0430] "Treating a neurodegenerative disease", "treating a neurodegenerative disease associated with a lysosomal storage defect", or "treating an LSD" can be equivalent to improving the SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, and / or MoCA scores, or the results of another test suitable for characterizing a neurodegenerative disease or an LSD subject. In some embodiments, treatment will improve a score, such as from a value characteristic of a symptomatic subject to a value characteristic of an asymptomatic subject.

[0431] Any change in the progression of an LSD or a neurodegenerative disease (e.g., over time or through treatment) can be monitored by using one or more refined tests as further discussed herein at two or more time points and comparing the results.

[0432] Thus, to evaluate the overall neurological status, the mDRS (a four-domain scale (walking, manipulation, language, and swallowing)) can be applied. Cerebellar function can be evaluated using the following: SARA (an eight-item clinical rating scale (gait, stance, sitting, speech, fine motor function, and reflex movement; range 0 - 40, where 0 is the best neurological status and 40 is the worst)) and SCAFI, which includes an 8-minute walk time (8MW; performed by having the subject walk from one line to another twice as fast as possible without turning), the 9-hole peg test (9HPT), and the number of "PATA" repetitions in 10 seconds. Subjective impairment and quality of life can be evaluated using the EQ-5D-5L questionnaire and VAS. To evaluate ocular motor function, a 3-dimensional video oculography (EyeSeeCam) can be used to measure the peak velocity of saccades, the gain of smooth pursuit, the peak slow-phase velocity of gaze-evoked nystagmus (gaze holding function), the peak slow-phase velocity of optokinetic nystagmus, and the gain of the horizontal vestibulo-ocular reflex. To evaluate cognitive status, the WAIS-R or WISC-IV and the MoCA can be used, which evaluate different cognitive domains, including attention and concentration, executive function, memory, language, visual construction skills, conceptual thinking, calculation, and orientation, with a maximum score of 30 and a cut-off score of 26. A person skilled in the art will know how to perform such tests.

[0433] As used herein, the term "treating migraine" means reducing the frequency of migraine or one or more symptoms associated therewith, alleviating or eliminating migraine or one or more symptoms associated therewith.

[0434] As used herein, the term "preventing migraine" means preventing migraine or one or more symptoms associated therewith. The compounds of the present disclosure can be used prophylactically.

[0435] As used herein, the term "alleviating" means making migraine or one or more symptoms associated therewith less severe or intense than without treatment.

[0436] As used herein, the term "reducing the frequency of migraine" means decreasing the occurrence of migraine or one or more symptoms associated therewith relative to their occurrence without treatment within a specific time frame.

[0437] In one embodiment, the compounds of the present disclosure can reduce the frequency of, alleviate or eliminate one or more migraine symptoms selected from the following: headache, fatigue, aura, nausea, vomiting, light sensitivity, sound sensitivity, smell sensitivity, sweating, poor concentration, feeling hot or cold, abdominal pain, and diarrhea.

[0438] As used herein, symptoms associated with migraine include any clinical or laboratory manifestation associated with migraine and are not limited to those that a subject can feel or observe.

[0439] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or more preferably preventing aura (such as visual aura).

[0440] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing migraine associated with aura (e.g., "classical migraine").

[0441] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing migraine not associated with aura (e.g., "common migraine").

[0442] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing aura associated with migraine.

[0443] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing aura not associated with migraine.

[0444] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing hemiplegic migraine. For this embodiment, migraine typically includes headache and aura accompanied by motor weakness.

[0445] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing episodic hemiplegic migraine.

[0446] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing vestibular migraine. Vestibular migraine can be defined according to the diagnostic criteria established by the International Classification Committee of the Barany Society, and it typically has the following characteristics:

[0447] A. Moderate or severe vestibular symptoms (defined by the Barany Society's classification of vestibular symptoms) occur at least 5 times, each lasting from 5 minutes to 72 hours;

[0448] B. According to the International Classification of Headache Disorders (ICHD), there is a current or past history of migraine with or without aura;

[0449] C. At least 50% of the vestibular attacks have one or more of the following migraine characteristics:

[0450] 1. The headache has at least two of the following characteristics: unilateral location, pulsatile, moderate or severe pain intensity, aggravated by daily physical activity;

[0451] 2. Photophobia, phonophobia;

[0452] 3. Visual aura;

[0453] D. Cannot be better explained by another vestibular or ICHD diagnosis.

[0454] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing basilar migraine. For this embodiment, migraine typically includes headache and aura accompanied by one or more of the following symptoms: difficulty speaking, vertigo, tinnitus, and other brainstem-related symptoms.

[0455] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing retinal migraine. For this embodiment, retinal migraine typically includes headache accompanied by visual disturbances or transient blindness.

[0456] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing chronic migraine. As used herein, the term "chronic migraine" means that a subject has a headache for more than fifteen days per month for three months without medication (as defined by the International Headache Society), where more than eight days are migraines.

[0457] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing episodic migraine. As used herein, "episodic migraine" means that a subject has a headache for less than fifteen days per month for three months without medication (as defined by the International Headache Society).

[0458] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing acute migraine.

[0459] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing one or more prodromal symptoms associated with migraine. Preferably, the prodromal symptoms are selected from one or more of the following: mood changes, irritability, depression or euphoria, fatigue, craving for certain foods, muscle stiffness (especially in the neck), constipation, diarrhea, and sensitivity to odors and noises.

[0460] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing pain associated with migraine.

[0461] In another embodiment, the present disclosure provides a compound of the present disclosure for treating or preventing one or more postdromal symptoms associated with migraine. Preferably, the postdromal symptoms are selected from one or more of the following: pain in the area where the migraine is located, impaired thinking, tiredness, headache, cognitive difficulties, gastrointestinal symptoms, mood changes, and weakness.

[0462] In another embodiment, the present disclosure provides a compound of the present disclosure for reducing, alleviating, or eliminating migraine.

[0463] In another embodiment, the present disclosure provides a compound of the present disclosure that alleviates or eliminates aura.

[0464] In another embodiment, the present disclosure provides a compound of the present disclosure that reduces the frequency of one or more symptoms selected from the following, alleviates or eliminates these symptoms: visual problems or visual impairments, numbness or tingling, dizziness, balance problems, movement problems, speech difficulties, and loss of consciousness.

[0465] In another embodiment, the present disclosure provides a compound of the present disclosure that prevents the occurrence of aura, for example, by preventing the occurrence of one or more of the above symptoms.

[0466] In one embodiment, the present disclosure provides a compound of the present disclosure for use in a method of improving cognitive function, mobility, or both cognitive function and mobility in a subject.

[0467] In another embodiment, the present disclosure provides a compound of the present disclosure for use in a method of improving cognitive function in a subject.

[0468] In another embodiment, the present disclosure provides a compound of the present disclosure for use in a method of improving mobility in a subject.

[0469] In another embodiment, the subject is an elderly subject.

[0470] In another embodiment, the present disclosure provides a compound of the present disclosure for use in a method of improving mobility and / or cognitive function in an elderly subject.

[0471] In another embodiment, the present disclosure provides a method of improving mobility and / or cognitive function in an elderly subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0472] In another embodiment, cognitive function is one or more selected from the group consisting of perception, memory, image creation, consciousness, reasoning, thinking, and judgment ability.

[0473] According to the present disclosure, the compounds of the present disclosure can be used to treat age-related reduction in cognitive function and / or mobility.

[0474] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating restless legs syndrome.

[0475] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating vertigo.

[0476] "Mobility" refers to the ability of a subject to move. One or more simple tests can be used to evaluate the mobility of the elderly. For example, the "Get Up and Go" test is a simple test that can measure mobility. In this test, the speed of getting up from a sitting position, standing up, and walking to a target point is analyzed.

[0477] For example, the test can start with the subject sitting in a chair. At the start of the second, the subject should get up and walk to the target point without assistance. The target point can be 2 - 10 m away, optionally 4 - 6 m away. The second should stop when the subject reaches the target point. Any changes in mobility (e.g., over time or through treatment) can be monitored by using the "Get Up and Go" test at two or more time points and comparing the results. Other tests suitable for measuring mobility include those used in the Elderly Mobility Scale (EMS) (a 20 - point validated assessment tool for evaluating frail elderly subjects, which takes into account movement, balance, and changes in key positions).

[0478] As used herein, the phrase "improvement in mobility" means a positive change in the ability of a subject to move. Any of the above tests can be used at two or more time points to measure the positive change. For example, at a first time point, baseline mobility is measured, and at a second time point, mobility is measured after a period of time (during which a treatment may have been administered). The more confident the subject is due to improved stability (e.g., through treatment), the faster he or she will complete the test. Mobility is said to be improved when at least about a 5% increase in performance is observed between two time points in a relevant test. For example, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, at least about a 30%, at least about a 40%, at least about a 50%, at least about a 60%, at least about a 70%, at least about an 80%, at least about a 90%, or at least about a 100% increase in performance is observed between two time points in a relevant test. Additionally, for example, at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, or at least a 100% increase in performance is observed between two time points in a relevant test. The two time points can be one week apart, two weeks apart, three weeks apart, four weeks apart, two months apart, three months apart, four months apart, five months apart, or even six months apart. The treatment can be administered during the intervention. Thus, for example, "improvement in mobility" can mean that the subject will exhibit at least about a 5% increase in speed relative to the baseline measurement, as measured using the "Get Up and Go" test as defined herein. For example, the subject can exhibit at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, at least about a 30%, at least about a 40%, at least about a 50%, at least about a 60%, at least about a 70%, at least about an 80%, at least about a 90%, or at least about a 100% increase in speed in this test. Additionally, for example, the subject can exhibit at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, or at least a 100% increase in speed in this test.

[0479] In one embodiment, the subject has a movement disorder associated with aging.

[0480] As used herein, the term "aging-related movement disorder" refers to a movement impairment that is a direct consequence of the aging process; this is in contrast to movement impairments that are not a direct consequence of the aging process. The clinical manifestations between a subject with an aging-related movement disorder and a subject with a movement impairment that is not a direct consequence of the aging process (e.g., a subject with ataxia) may be different. Ataxia may manifest as the subject staggering while walking, while an aging-related movement disorder may manifest as an increased tendency to fall. Thus, for example, cerebellar ataxia is not an aging-related movement disorder.

[0481] In addition to the mobility assessments disclosed above, the motor ability of a subject with an aging-related movement disorder can be tested, for example, using a balance assessment and / or by monitoring the number of falls the subject experiences and / or using the "Get Up and Go" test.

[0482] In another embodiment, the present disclosure provides a compound of the present disclosure for improving balance in a subject, where the subject has balance impairment related to aging. According to the present disclosure, balance impairment related to aging is not vertigo.

[0483] According to the present disclosure, the subject may, for example, not have benign paroxysmal positional vertigo (BPPV); vestibular neuritis; vertigo associated with Meniere's disease, Wallenberg's syndrome, cerebellar ischemia, perilymphatic fistula, or acoustic neuroma; or recurrent vertigo of traumatic or toxic origin.

[0484] In another embodiment, the present disclosure provides a compound of the present disclosure for treating balance disorders related to aging.

[0485] In another embodiment, the present disclosure provides a compound of the present disclosure for increasing the stability of a subject, for example, when standing and / or walking, where the subject has reduced stability related to aging.

[0486] In another embodiment, the present disclosure provides a compound of the present disclosure for reducing the instability of a subject when walking, where the subject has increased instability related to aging.

[0487] In another embodiment, the present disclosure provides a compound of the present disclosure for treating a subject with impaired gait, where the impaired gait is related to aging. The subject may have an elderly gait disorder.

[0488] In another embodiment, the present disclosure provides a compound of the present disclosure for increasing the gait speed and / or rhythm of a subject, where the subject has impaired gait speed and / or rhythm related to aging.

[0489] In another embodiment, the present disclosure provides a compound of the present disclosure for treating a subject having a propensity to fall, wherein the propensity to fall is associated with aging.

[0490] "Cognitive function" can mean any mental process involving symbolic operations, such as the abilities of perception, memory, image creation, consciousness, reasoning, thinking, and judgment. Measurements of cognitive function include assessment tools designed to measure, for example: (a) general intelligence, (b) non-verbal intelligence, (c) achievement, (d) attention / executive function, (e) memory and learning, (f) visual-motor and motor function, and (g) language. Such assessment tools are well known in the art and include, for example, the Wechsler Adult Intelligence Scale and the Woodcock-Johnson III Tests of Cognitive Ability (both for assessing general intelligence), the Raven's Progressive Matrices (for assessing non-verbal intelligence), the Wide Range Achievement Test and the Woodcock-Johnson III Tests of Achievement (for assessing academic achievement), the Conners' Continuous Performance Test II (for assessing attention / executive function), the Wide Range Assessment of Memory and Learning (for assessing memory and learning), the Bender Visual-Motor Gestalt Test, the Halstead-Reitan Grip Strength Test, the Halstead-Reitan Finger Tapping Test, and the Lafayette Grooved Pegboard Task (all for assessing visual-motor and motor function), and the Peabody Picture Vocabulary Test (for assessing language).

[0491] Reaction speed and / or alertness tests (such as the Psychomotor Vigilance Task (e.g., as disclosed in the Examples)) can also be used to assess cognitive function. This test assesses components including fine motor skills; psychomotor speed; distraction; instability of alertness; and impulse caused by fatigue.

[0492] For example, the Psychomotor Vigilance Task (PVT) is a sustained attention reaction timing task used to measure the reaction speed of a subject to visual stimuli. The subject monitors the screen and presses the screen as quickly as possible when a visual stimulus appears. Then the visual stimulus will disappear and reappear (at irregular time intervals), for example, reappearing 10 times during the test, and the subject touches the screen as quickly as possible each time it reappears. Test performance is quantified according to, for example, the average of 10 reaction times. Any change in cognitive function (e.g., over time or through treatment) can be monitored by using one or more of these well-established tests at two or more time points and comparing the results.

[0493] As used herein, the phrase "improving cognitive function" means a positive change in the ability of a subject to perform symbolic operations (e.g., perception, memory, creation of mental images, clear thinking, consciousness, reasoning, thinking, or judgment). Any of the above tests can be used at two or more time points to measure the positive change. For example, a baseline cognitive function is measured at a first time point, and cognitive function is measured at a second time point after a period of time (during which a treatment may have been administered). Cognitive function is said to be improved when an improvement in performance of at least about 5% is observed between the two time points in a relevant test. For example, an improvement in performance of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% is observed between the two time points in a relevant test. Additionally, for example, an improvement in performance of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% is observed between the two time points in a relevant test. The two time points can be one week apart, two weeks apart, three weeks apart, four weeks apart, two months apart, three months apart, four months apart, five months apart, or even six months apart. The treatment can be administered during the intervention. Thus, as an example, "improving cognitive function" can mean that a subject will exhibit an improvement in performance of at least about 5% relative to a baseline measurement, as measured using the well - established Wechsler Adult Intelligence Scale. For example, a subject can exhibit an improvement in performance of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% in this test. Additionally, for example, a subject can exhibit an improvement in performance of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% in this test.

[0494] In another embodiment, the present disclosure provides a compound of the present disclosure for increasing reaction speed (e.g., the reaction speed of a subject to a visual stimulus).

[0495] In one embodiment, the subject has age - related decline in cognitive function.

[0496] As used herein, the term "aging-related cognitive decline" refers to a decline in cognitive function that is a direct consequence of the aging process; as contrasted with a decline in cognitive function that is not a direct consequence of the aging process. The clinical manifestations between subjects with aging-related cognitive decline and subjects with a decline in cognitive function that is not a direct consequence of the aging process may be different.

[0497] The term "improvement", when used to refer to mobility and / or cognitive function, may include treating and / or alleviating any impairment of mobility and / or cognitive decline in a subject. Accordingly, use of the compounds of the present disclosure as described herein may partially or completely reverse age-related decline in mobility and / or cognitive function.

[0498] As used herein, the term "restless legs syndrome" or "RLS" includes any form of RLS, including primary RLS and secondary RLS. In one embodiment, the RLS is primary RLS. In another embodiment, the RLS is secondary RLS. In another embodiment, the RLS is secondary to a disease or medical disorder. Examples of such diseases or medical disorders include iron deficiency, renal failure, uremia, peripheral neuropathy, varicose veins, neurodegenerative diseases, stress, sleep deprivation, fibromyalgia, hyperthyroidism or hypothyroidism, pregnancy, smoking, vitamin deficiency (e.g., vitamin B-12 deficiency), mineral deficiency (e.g., magnesium deficiency), amyloidosis, Lyme disease, spinal nerve injury, rheumatoid arthritis, and Sjogren's syndrome. In another embodiment, the RLS is secondary to a drug or substance. Examples of such drugs or substances include alcohol, caffeine, anticonvulsants (e.g., phenytoin), antidepressants (e.g., amitriptyline, paroxetine), hypertension medications (e.g., beta-blockers), antipsychotics, and withdrawal medications (e.g., vasodilators, sedatives, antidepressants). Examples of neurodegenerative diseases include Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. In one embodiment, the neurodegenerative disease is a motor neuron disease (e.g., progressive bulbar palsy (PBP), pseudobulbar palsy, primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), Huntington's disease, multiple sclerosis, Parkinson's disease, Canavan disease, frontotemporal degeneration, narcolepsy, Pelizaeus-Merzbacher disease, and spinal muscular atrophy). In one embodiment, the neurodegenerative disease is Parkinsonism, including primary or idiopathic, secondary or acquired, hereditary Parkinsonism, and Parkinson-plus syndromes or multisystem degenerations. In another embodiment, the disease or medical disorder is associated with dopaminergic system dysfunction (such as dopaminergic cell loss).

[0499] Symptoms related to RLS include any clinical or laboratory manifestations related to RLS. Symptoms of RLS are generally but not necessarily manifestations related to a disease that a subject can feel or observe. Symptoms related to RLS include but are not limited to calf sensations, periodic limb movements during sleep (PLMS), uncomfortable leg sensations, motor urges, restlessness, sleep disorders, excessive daytime sleepiness, etc.

[0500] In another embodiment, the compounds of the present disclosure are used in a method for reducing, inhibiting or eliminating one or more symptoms related to RLS in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of the compounds of the present disclosure.

[0501] In another embodiment, the one or more symptoms are selected from any one or any combination of the following: calf sensations, periodic leg movements during sleep, uncomfortable leg sensations, motor urges, restlessness, excessive daytime sleepiness, and sleep disorders.

[0502] The severity of RLS or one or more symptoms of RLS can be evaluated, for example, using known scales, indices, assessments or scores. For example, a scale, index, assessment, score or other suitable test can correspond to the severity of RLS in general or to the severity of one or more symptoms related to RLS. In one embodiment, the treatment described herein improves this assessment from the value or degree characteristic of a symptomatic subject to the value or degree characteristic of an asymptomatic subject.

[0503] In one embodiment, the treatment described herein improves this assessment compared to a baseline. The baseline can be, for example, the condition of the subject before starting any RLS treatment or before starting treatment of RLS with the compounds of the present disclosure. Optionally, the baseline can be, for example, the condition of the subject after treating RLS for a period of time.

[0504] In one embodiment, treatment with the compounds of the present disclosure reduces the International Restless Legs Syndrome Study Group Rating Scale ("IRLS") of the subject compared to a baseline. In one embodiment, the IRLS is reduced by at least 10%, at least 20%, at least 30%, at least 40% or at least 50% compared to a baseline. In one embodiment, the IRLS is reduced by at least 60%, at least 70%, at least 80%, at least 90% or 100%.

[0505] As used herein, the term "vertigo" includes any form of vertigo, including, for example, benign paroxysmal positional vertigo (BPPV), vestibular neuritis; vertigo associated with Meniere's disease, Wallenberg syndrome, cerebellar ischemia, perilymphatic fistula or acoustic neuroma; or recurrent vertigo of traumatic or toxic origin.

[0506] The symptoms of dizziness include any clinical or laboratory manifestation associated with dizziness. The symptoms of dizziness include, but are not limited to, feeling nauseous, vomiting, abnormal eye movements or twitching (nystagmus), headache, sweating, tinnitus, and / or hearing loss.

[0507] In the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure, which is typically formulated according to pharmaceutical practice, is administered to a subject in need thereof (e.g., a human). Whether such treatment is needed depends on the individual situation and requires a medical evaluation (diagnosis), taking into account the signs, symptoms, and / or dysfunctions present, the risk of developing specific signs, symptoms, and / or dysfunctions, and other factors.

[0508] The compounds of the present disclosure can be administered by any suitable route, such as orally, buccally, by inhalation, sublingually, rectally, vaginally, intracisternally or intrathecally by lumbar puncture, transurethrally, transnasally, by percutaneous puncture (i.e., transdermally) or parenterally (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intra-articular, intrathecal, retrobulbar, intralung injection, and / or surgical implantation at a specific site). Parenteral administration can be accomplished using a needle and syringe or using high-pressure techniques.

[0509] Pharmaceutical compositions include those in which a compound of the present disclosure is administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage are determined by the individual physician based on the diagnosed disorder or disease. The dosage and interval can be adjusted individually to provide a level of the compound of the present disclosure sufficient to maintain the therapeutic effect.

[0510] The toxicity and therapeutic efficacy of the compounds of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of the compound (which is defined as the highest dose that does not cause toxicity in the animal). The dose ratio between the MTD and the therapeutic effect (e.g., delaying the progression of LSD or neurodegenerative diseases) is the therapeutic index. The dose can vary within this range depending on the dosage form employed and the route of administration used. Determining the therapeutically effective amount is entirely within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0511] The therapeutically effective amount of the compounds of the present disclosure for treatment varies with the nature of the disorder being treated, the duration of desired activity, and the age and disorder of the subject, and is ultimately determined by the attending physician. The dosage and interval can be adjusted individually to provide a plasma level sufficient to maintain the desired therapeutic effect. The required dosage can be conveniently administered as a single dose or in multiple doses at appropriate intervals, such as one, two, three, four or more sub-doses per day. Multiple doses are often desirable or necessary. For example, the compounds of the present disclosure can be administered at the following frequencies: four doses, one dose delivered per day, with a four-day interval (q4d x 4); four doses, one dose delivered per day, with a three-day interval (q3d x 4); one dose delivered per day, with a five-day interval (qd x 5); one dose delivered per week for three weeks (qwk3); five doses per day, with a two-day break, followed by five doses per day (5 / 2 / 5); or, any dosage regimen determined to be suitable for the situation. In cases where long-term treatment is required, multiple doses can be administered to the patient daily over a long period of time (e.g., about 3 months, about 6 months, about 1 year, about 2 years, about 3 years, about 5 years, about 10 years or longer).

[0512] The compounds of the present disclosure used in the methods of the present disclosure can be administered in an amount of about 1 to about 2,000 milligrams (mg) per dose, about 100 to about 1,000 mg per dose, or about 250 to about 750 mg per dose. For example, the compounds of the present disclosure can be administered in an amount of about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1,000 mg per dose (including all doses between 1 and 1000 mg).

[0513] The compounds of the present disclosure used in the methods of the present disclosure can be administered to a subject in an amount of 250 to 15,000 mg per day, 500 to 10,000 mg per day, 1,000 to 5,000 mg per day, or 1,500 to 2,500 mg per day. For example, the compounds of the present disclosure can be administered to a subject in an amount of about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, about 3,000 mg, about 3,500 mg, about 4,000 mg, about 4,500 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, about 8,000 mg, about 9,000 mg, about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg or about 15,000 mg per day.

[0514] The total daily dose can be distributed over multiple administrations, i.e., it may be necessary to administer the compound twice or more times a day to achieve the desired dose. For example, the number of tablets required to provide the total daily dose of the compounds of the present disclosure can be divided into two administrations (e.g., in the morning and in the evening) or three administrations (e.g., in the morning, at noon, and in the evening).

[0515] The dose of the composition containing the compound of the present disclosure or the composition containing it can be from about 1 ng / kg to about 200 mg / kg, from about 1 μg / kg to about 100 mg / kg, or from about 1 mg / kg to about 50 mg / kg. The dose of the composition can be any dose, including but not limited to about 1 μg / kg. The dose of the composition can be any dose, including but not limited to about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or greater. The above doses are examples of general cases, but in individual cases, there should be higher or lower doses, which are within the scope of the present disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for the individual subject, which can vary with the age, weight, and response of the particular subject.

[0516] Medicine box

[0517] In another embodiment, the present disclosure provides a kit comprising a compound of the present disclosure (or a composition comprising a compound of the present disclosure), the kit being packaged in a manner that facilitates their use in practicing the methods of the present disclosure. In one embodiment, the kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure) packaged in a container (such as a sealed bottle or vessel), and a label (and / or instructions) affixed to the container or included in the kit that describes the use of the compound or composition to practice the methods of the present disclosure. In one embodiment, the compound or composition is packaged in unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration.

[0518] The term "container" means any container piece and closure that is suitable for storing, transporting, dispensing, and / or handling a pharmaceutical product.

[0519] The term "insert" means the information that accompanies a pharmaceutical product, which provides a description of how to administer the product, as well as the safety and efficacy data needed to allow physicians, pharmacists, and subjects to make informed decisions regarding the use of the product. A package insert is generally considered to be the "label" of a pharmaceutical product.

[0520] Personalized medicine

[0521] In another embodiment, the present disclosure provides a personalized medicine program for a subject having an LSD or a neurodegenerative disease, migraine, restless legs syndrome, or vertigo and associated symptoms, or for a subject in need of improving mobility and / or cognitive function, and includes selecting a treatment option having the highest likelihood of a successful outcome for an individual subject having an LSD or a neurodegenerative disease, migraine, restless legs syndrome, or vertigo and associated symptoms, or for a subject in need of improving mobility and / or cognitive function. In another aspect, the present disclosure relates to using an assay to predict treatment outcome, such as the likelihood of a favorable response or treatment success, in a subject having an LSD or a neurodegenerative disease, migraine, restless legs syndrome, or vertigo and associated symptoms, or for a subject in need of improving mobility and / or cognitive function.

[0522] In another embodiment, the present disclosure provides a method of selecting a subject (e.g., a human subject) for treatment of LSD or a neurodegenerative disease with a compound of the present disclosure, the method comprising obtaining a biological sample (e.g., blood cells or cerebrospinal fluid) from the subject, testing for the presence of an LSD-related biomarker or a neurodegenerative-disease-related biomarker in the biological sample from the subject, and selecting the subject for treatment if the biological sample contains a biomarker, such as an abnormal level of a biomarker in a body fluid, such as an accumulation or elevated level of a biomarker in a body fluid or a depletion or reduced level of a biomarker in a body fluid. In another embodiment, if the biological sample contains a biomarker, the method further comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure. In another embodiment, the same method can be applied to a subject to treat migraine, restless legs syndrome or vertigo and related symptoms, or to improve mobility and / or cognitive function.

[0523] In another embodiment, the present disclosure provides a method for predicting a treatment outcome in a subject having LSD or a neurodegenerative disease, the method comprising obtaining a biological sample from the subject, testing for the presence of an LSD-related biomarker or a neurodegenerative-disease-related biomarker in the biological sample from the subject, wherein detection of the biomarker indicates that the subject will respond favorably to administration of a therapeutically effective amount of a compound of the present disclosure. Favorable responses include, but are not limited to, delaying the onset of symptoms normally expected in a subject having LSD or a neurodegenerative disease. In another embodiment, the same method for predicting a treatment outcome in a subject can be applied to a subject having migraine, restless legs syndrome or vertigo and related symptoms, or to a subject in need of improving mobility and / or cognitive function.

[0524] In another embodiment, the present disclosure provides a method of treating LSD or a neurodegenerative disease, the method comprising administering to a subject (e.g., a human subject) having LSD or a neurodegenerative disease a therapeutically effective amount of a compound of the present disclosure, wherein the cells of the subject contain an LSD-related biomarker or a neurodegenerative-disease-related biomarker. In one embodiment, the subject is selected for treatment with a compound of the present disclosure after determining that the cells of the subject contain a biomarker (e.g., an elevated level of an LSD-related biomarker or a neurodegenerative-disease-related biomarker or a reduced level of an LSD-related biomarker or a neurodegenerative-disease-related biomarker). In another embodiment, the same method can be applied to a subject to treat migraine, restless legs syndrome or vertigo and related symptoms, or to improve mobility and / or cognitive function.

[0525] In another embodiment, a method of treating a subject having an LSD or a neurodegenerative disease includes obtaining a biological sample from the subject, determining whether the biological sample contains elevated levels of an LSD-related biomarker or a neurodegenerative disease-related biomarker or reduced levels of an LSD-related biomarker or a neurodegenerative disease-related biomarker, and, if the biological sample contains elevated or reduced levels of a biomarker, administering to the subject a therapeutically effective amount of a compound of the present disclosure. In another embodiment, the same method can be applied to a subject to treat a subject having migraine, restless legs syndrome or vertigo and associated symptoms, or to improve the mobility and / or cognitive function of the subject.

[0526] As used herein, the term "biomarker" refers to any biological compound that can be detected and / or quantified in a subject or in a biological sample obtained from a subject, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc. Additionally, a biomarker can be an entire intact molecule, or it can be a portion or fragment thereof. In one embodiment, the expression level of a biomarker is measured. The expression level of a biomarker can be measured, for example, by detecting the protein or RNA (e.g., mRNA) level of the biomarker. A biomarker can also be measured by HPLC-MS / MS. In some embodiments, a portion or fragment of a biomarker can be detected or measured, for example, by an antibody or other specific binding agent. In some embodiments, a measurable aspect of a biomarker is related to a given state of the subject, such as a particular stage of an LSD. For a biomarker detected at the protein or RNA level, such measurable aspects can include, for example, the presence, absence or concentration (i.e., expression level) of the biomarker in the subject or in a biological sample obtained from the subject. For a biomarker detected at the nucleic acid level, such measurable aspects can include, for example, the allelic form of the biomarker or the type, rate and / or extent of a mutation of the biomarker, also referred to herein as the mutation state.

[0527] As used herein, the term "LSD-related biomarker" refers to any biological compound, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc., that accumulates or decreases in a subject due to a pathological enzyme defect or due to a cytopathological process associated with an LSD. Examples of LSD-related biomarkers include, but are not limited to, globotriaosylceramide (Gb3), lyso-globotriaosylceramide (LysoGb3), LysoGb3 analogs or methylated / non-methylated Gb3 subtypes associated with Fabry disease; glucosylceramide, chitotriosidase (ChT), pulmonary and activation-regulated chemokine (CCL18 / PARC), macrophage inflammatory protein 1-α and 1-β (MIP-1α and MIP-1β), cathepsin K, ganglioside, GM3 / monosialodihexosylganglioside, glucosylsphingosine or osteopontin associated with Gaucher disease; galactosylceramide, galactosylsphingosine / emetine associated with Krabbe disease; dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin 6-sulfate, chondroitin 4,6-sulfate, hyaluronic acid, glycosaminoglycan fragment, β-galactosidase, collagen Iα, fatty acid-binding protein 5, nestin-1, cartilage oligomeric matrix protein, insulin-like growth factor-binding protein 7 or protein HEG1 associated with mucopolysaccharidosis; sphingomyelin, free cholesterol (in fibroblasts), lysosphingomyelin (Lyso-SPM), cholestane-3β,5α,6β-triol (C-triol), 7-ketocholesterol (7-KC), 24(S)-hydroxycholesterol, NPCBA1 (3β-hydroxy, 7β-N-acetylglucosaminyl-5-cholenoic acid), NPCBA2 (possibly 3β,5α,6β-trihydroxy-cholanoic acid-glycine), calbindin D, lysosphingomyelin-509 associated with Niemann-Pick disease; and / or glycogen, tetraglucose (Glc4), myostatin or insulin-like growth factor-I (IGF-I) associated with Pompe disease. See, e.g., Labato et al., Diseases 4:40 (2016); Aerts et al., J Inherit Metab Dis 34:605–619 (2011); and Giese et al., Orphanet Journal of Rare Diseases 10:78 (2015) for LSD-related biomarkers.

[0528] As used herein, the term "neurodegenerative disease-related biomarker" refers to any biological compound, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc., that accumulates in a subject due to a neurodegenerative disease.

[0529] As used herein, the term "migraine-related biomarker" refers to any biological compound, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc., that accumulates or decreases in a subject due to migraine.

[0530] As used herein, the term "mobility-related biomarker" refers to any biological compound, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc., that accumulates or decreases in a subject due to decreased mobility.

[0531] As used herein, the term "cognitive function-related biomarker" refers to any biological compound, such as a protein, protein fragment, peptide, polypeptide, nucleic acid, etc., that accumulates or decreases in a subject due to decreased or altered cognitive function.

[0532] In certain aspects of the present disclosure, a biomarker is present differently in one phenotypic state (e.g., a subject with an LSD) compared to another phenotypic state (e.g., a normal, non-diseased subject).

[0533] In addition to individual biological compounds, as used herein, the term "biomarker" is intended to include a group or set of multiple biological compounds. For example, a combination of lyso-SM-509 and lyso-Gb3 can constitute a biomarker. Thus, a "biomarker" can comprise one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, or more biological compounds.

[0534] Any one of many methods known in the art (e.g., using HPLC-MS / MS or techniques) can be used to determine the plasma level of a biomarker in a subject. Any method known in the art for quantifying a specific LSD-related biomarker in a subject or biological sample can be used in the methods of the present disclosure.

[0535] As used herein, the term "biological sample" refers to any tissue or fluid from a subject that is suitable for detecting a biomarker (such as the plasma level of lyso-SM-509). Examples of useful biological samples include, but are not limited to, biopsy tissue and / or cells, such as solid tumors, lymph nodes, inflamed tissue, tissue and / or cells associated with a disorder or disease, blood, plasma, serum, cerebrospinal fluid, saliva, urine, lymph fluid, cerebrospinal fluid, etc. Those of ordinary skill in the relevant art will be familiar with other suitable biological samples. Any technique known in the art can be used to analyze the biomarker expression and / or mutation of a biological sample, and techniques within the ordinary knowledge of a clinical practitioner can be used to obtain a biological sample. In one embodiment of the present disclosure, the biological sample comprises blood cells.

[0536] The present disclosure provides the following specific embodiments for personalized medicine for subjects suffering from LSD:

[0537] Embodiment I: A method of treating a subject suffering from LSD, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the cells of the subject contain an elevated or reduced concentration of an LSD-related biomarker.

[0538] Embodiment II: A method of treating a subject suffering from LSD, the method comprising:

[0539] (a) determining the concentration of an LSD-related biomarker in a biological sample from the subject, and when the determined concentration is higher or lower than the concentration of a control sample (e.g., a sample from a normal, non-diseased subject); and

[0540] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0541] Embodiment III: A method of treating LSD in a subject having an elevated or reduced concentration of an LSD-related biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0542] The present disclosure provides the following specific embodiments for personalized medicine for subjects suffering from neurodegenerative diseases:

[0543] Embodiment I: A method of treating a subject suffering from a neurodegenerative disease, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the cells of the subject contain an elevated or reduced concentration of a neurodegenerative-disease-related biomarker.

[0544] Embodiment II: A method of treating a subject suffering from LSD, the method comprising:

[0545] (a) determining the concentration of a neurodegenerative-disease-related biomarker in a biological sample from the subject, and when the determined concentration is higher or lower than the concentration of a control sample (e.g., a sample from a normal, non-diseased subject); and

[0546] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0547] Embodiment III: A method of treating a neurodegenerative disease in a subject having an elevated or reduced concentration of a neurodegenerative-disease-related biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0548] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects suffering from migraine and related symptoms:

[0549] Embodiment I: A method of treating a subject suffering from migraine and related symptoms, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the subject's cells contain an elevated or reduced concentration of a migraine-related biomarker.

[0550] Embodiment II: A method of treating a subject suffering from migraine and related symptoms, the method comprising:

[0551] (a) determining the concentration of a migraine-related biomarker in a biological sample from the subject, and when the determined concentration is higher or lower than the concentration of a control sample (e.g., a sample from a normal, non-diseased subject); and

[0552] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0553] Embodiment III: A method for treating migraine and related symptoms in a subject having an elevated or reduced concentration of a migraine-related biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0554] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects in need of improved mobility:

[0555] Embodiment I: A method of treating a subject in need of improved mobility, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the subject's cells contain an elevated or reduced concentration of a mobility-related biomarker.

[0556] Embodiment II: A method of treating a subject in need of improved mobility, the method comprising:

[0557] (a) determining the concentration of a mobility-related biomarker in a biological sample from the subject, and when the determined concentration is higher or lower than the concentration of a control sample (e.g., a sample from a normal, non-diseased subject); and

[0558] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0559] Embodiment III: A method for improving the mobility of a subject having an elevated or reduced concentration of a mobility-related biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0560] The present disclosure provides the following specific embodiments regarding personalized medicine for a subject in need of improved cognitive function:

[0561] Embodiment I: A method of treating a subject in need of improved cognitive function, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein the cells of the subject contain an elevated or reduced concentration of a biomarker associated with cognitive function.

[0562] Embodiment II: A method of treating a subject in need of improved cognitive function, the method comprising:

[0563] (a) determining the concentration of a biomarker associated with cognitive function in a biological sample from the subject and when the determined concentration is higher or lower than the concentration of a control sample (e.g., a sample from a normal, non-diseased subject); and

[0564] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0565] Embodiment III: A method of improving cognitive function in a subject having an elevated or reduced concentration of a biomarker associated with cognitive function, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0566] Examples

[0567] Example 1

[0568] General Preparation of Deuterated N-Acetyl-Leucine

[0569] (D-enantiomer, L-enantiomer, and D,L-mixture)

[0570] A variety of methods can be used to selectively replace one or more hydrogen atoms in leucine with deuterium (“D” or “2H”). Such compounds can be prepared where, at each position, D has an isotope enrichment of 90% or more. A general method involves deuterated leucine, which is then converted to the N-acetyl form. In some cases, the N-acetyl form can be directly deuterated (e.g., “labeled”). Unless otherwise specified, these methods are general for D-, L-, and D,L-mixtures. See, for example, Yamauchi et al., Biosci. Biotechnol. Biochem. 70:276–278 (2006); Kelly et al., Nat. Prod. Rep. 14:205–219 (1997); August et al., Tetrahedron Lett. 33:4617–4620 (1992); Oba et al., Tetrahedron Lett. 39:1595–1598 (1998); Hill et al., Can. J. Chem. 72:110–113 (1994); Kelly et al., Tetrahedron Lett. 36:8315–8318 (1995); and Fletcher et al., J. Chem. Soc., Perkin Trans. I, 43–52 (2000).

[0571] Example 2

[0572] Preparation of Compounds Based on D-Leucine

[0573] The synthesis of D-leucine and its labeled analogues can be achieved via reductive amination of 2-oxo-4-methylpentanoic acid with D-amino acid dehydrogenase (DAADH).

[0574] A reaction mixture (1 mL) containing 100 mM glycine-KOH (pH 10.5), 5.0 mM NADPH, 70 mM NH4Cl, 5.0 mM 2-oxo acid (sodium salt), and 2.9 mg DAADH was incubated at 50 °C for 1 h while maintaining the pH at 10.5 by adding 1.0 M KOH solution. The pH value was measured using a pH meter. The reaction was terminated by adding trichloroacetic acid to a final concentration of 10%. After clarifying the mixture by centrifugation and filtration, the resulting D-leucine can be separated and purified on a reverse-phase column and detected using a fluorescence detector (excitation at 350 nm and detection at 450 nm). Optionally, a regeneration system using NADPH with glucose dehydrogenase (GDH) can be used in a reaction mixture (1 mL) containing 100 mM glycine-KOH (pH 10.5), 1.0 mM NADPH or NADP+, 20 mM glucose, 70 mM NH4Cl, 5.0 mM 2-oxo acid, 2.9 mg DAADH, and 0.32 mg GDH was incubated at 50 °C for 1 h while maintaining the pH at 10.5 by adding 1.0 M KOH solution. D-Leucine was separated and purified as described above. The above reaction can be carried out in deuterium oxide to incorporate D into the α-carbon. DAADH catalyzes the production of D-amino acids from the corresponding 2-oxo acids in the presence of ammonia and gives excellent yields (>99%) and high enantioselectivities (>99%). (Akita et al., Biotechnol Lett 34:1693 (2012) and Akita et al., Biotechnol Lett 36:2245 (2014)).

[0575] Example 3

[0576] Method for converting racemic leucine into the L-enantiomer

[0577] Racemic amino acids can be resolved into their L- and D-enantiomers by enzymatic or chemical procedures. A general method for converting racemic amino acids into homochiral products using an oxidase-amino transferase coupling system has been reported (Shah et al., Tetrahedron Lett. 35:29 - 32 (1994)). This method can be used to produce L-leucine from the racemate using D-amino acid oxidase (EC 1.4.3.3), catalase (EC 1.11.1.6), leucine dehydrogenase (EC 1.4.1.9), and formate dehydrogenase (EC 1.2.1.2) in the presence of oxygen, NAD +In the enzymatic system with ammonium formate, D-leucine is completely converted in situ to the L-enantiomer via the achiral intermediate α-oxo-γ-methylthio-butyrate. In the presence of NAD+, leucine dehydrogenase catalyzes the reversible deamination of various aliphatic L-amino acids, including methionine, to their α-oxo analogues. This reaction is favorable for reductive amination accelerated by combination with the formate dehydrogenase reaction. Formate dehydrogenase catalyzes the irreversible oxidation of formic acid to CO2 while reducing NAD+ to NADH. The α-oxo acid is spontaneously decarboxylated by oxidation with H2O2.

[0578] The reaction mixture contained DL-leucine (100 μmol), NADH (1 μmol), ammonium chloride (25 μmol), sodium formate (500 μmol), Tris-HCl buffer (pH 8.5; 100 μmol), D-amino acid oxidase from Sigma (5 units), catalase from Sigma (2 units), leucine dehydrogenase from Clostridium thermoaceticum AN28-4 (10 units), and formate dehydrogenase from Boehringer (2 units) in a final volume of 1 mL at 37 °C and pH 8.0 - 8.5. After incubation for 10 h, HCl was added to the reaction mixture to a final concentration of 1.0 M. The solution was applied to a Dowex 50(H + ) column (1 x 10 cm), and L-leucine was eluted with 1 M NH4OH. The fractions containing L-leucine were combined and concentrated to a small volume and then evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of 80% hot ethanol, and L-leucine was crystallized at 4 °C. Using this method, DL-leucine (0.1 M) could be converted to the L-enantiomer (yield 95%; ee 99% in 2 h) based on separation by enantioselective HPLC using a Daicel Crown-packed column (0.4 i.d. x 50 cm) (Nakajima et al., J. Chem. Soc., Chem. Commun. 13:947 - 948 (1990)).

[0579] Example 4

[0580] Preparation of the N-acetylated form of deuterated leucine analogues

[0581] Methods for the N-acetylation of amines and α-amino acids, including leucine, have been widely reported. The deuterated leucine analogs synthesized by the methods reported above were not N-acetylated according to the said methods, and the resulting deuterated leucine analogs will be N-acetylated by one of the following methods. In one of the described methods, the acetylating agent is acetic acid carried out as follows: (CH3CO)2O + H2N-CH(R)-COOH → CH3CONH-CH(R)-COOH + CH3COOH. This reaction is carried out in an acetic acid environment or in a mixture of water and pyridine. The acetylation of L-leucine and D-leucine by acetic anhydride proceeds effectively in an aqueous solution of the starting compound when the reaction mixture is heated from 50 °C to 70 °C. The optimal molar ratio of the amino acid to acetic anhydride is 1.25 - 1.5. The acetylated product can be crystallized from the aqueous solution upon cooling to form a monohydrate with a yield of 75 - 80%. Distilled water (760 mL) was placed in a glass reactor equipped with a stirrer and a thermometer, and L-leucine (14.0 mol) was added in batches while stirring and heating to 50 - 55 °C, and the mixture was stirred until completely dissolved. Acetic anhydride (1980 mL, 21.0 mol) was added via a dropping funnel over 2.0 - 2.5 hours. The acetic anhydride was added at a rate such that the temperature of the mixture did not exceed 70 °C. The reaction was then heated to 70 °C and maintained for 0.5 hour, and crystallization occurred upon cooling. The reaction mixture was mixed for 40 minutes, and then hydrochloric acid (1060 ml, 37%) was added dropwise to adjust the pH to 2.0 - 2.5. The resulting precipitate was collected by filtration, washed successively with ice water and alcohol on the filter, dried at 50 - 60 °C, and then dried in air at 25 - 30 °C. An anhydrous product was obtained by drying to constant weight in vacuo at 85 °C. An additional 360 g of product was obtained by evaporating the aqueous acetic acid from the mother liquor in a rotary evaporator at a bath temperature of 70 °C.

[0582] Example 5

[0583] Preparation of compounds deuterated on the α-carbon (C-2)

[0584] A preparation for labeling the α-position of amino acids starting from commercially available amino acids has been reported. This preparation is rapid, inexpensive, and generally applicable, and has been shown to be effective for leucine (Upson and Hruby, J. Org. Chem. 42:2329–2330 (1977)). In this method, leucine is refluxed in acetic acid and acetic anhydride to give racemic N-acetyl leucine. A solution of Ac2O in AcOD is obtained using a mixture of excess acetic anhydride and D2O. The amino acid is treated with this solution under reflux for a few minutes, resulting in acylation, racemization, and exchange at this α-position. Then, N-acetyl-leucine is the starting compound for enzymatic resolution using porcine kidney acylase, carboxypeptidase, or other enzymes capable of selectively cleaving the acetyl group from one stereoisomer without significantly cleaving the enantiomeric compound. To achieve a high level of exchange, a higher 2H / 1H ratio is required. This condition can be approached in several ways: (a) acetic acid-d in a high molar excess relative to the amino acid can be used; (b) the labile hydrogens of the amino acid can be pre-exchanged; (c) the exchange reaction can be repeated. One treatment results in 83% exchange, and a second treatment raises the exchange level to 91%.

[0585] DL-Leucine (0.01 mol) was shaken with 3.7 mL of D2O to exchange the labile protons. The mixture was frozen and lyophilized. Immediately, 21.7 mL of Ac2O and 2.5 mL of D2O were added to the resulting powder, and the flask was placed in a 170 °C bath. The solution was refluxed for 2 minutes, then cooled (dry tube), and 2 mL of D2O was added to destroy the remaining Ac2O and convert any azlactone back to N-acetyl leucine. The solvent was removed by rotary evaporation. The α-hydrogen could be detected by proton nuclear magnetic resonance spectroscopy in 80% yield.

[0586] In another example, leucine dehydrogenase can be used to catalyze the exchange of α-protons, so that when the reaction is carried out in 2 H2O, L-[2- 2 H]leucine can be prepared. By pre-exchanging the α-keto acid in 2 H2O-base prior to the enzymatic conversion, deuteration is also extended to the β-position. This method can synthesize various isotopically labeled α-amino acids, including gram amounts of [2,3,3- 2H3]Leucine. The formate dehydrogenase (FDH) catalytic system can be used to recycle NADH for the preparation of leucine from its α-keto acid and leucine dehydrogenase. Formate dehydrogenase catalyzes the oxidation of formate ions to carbon dioxide and releases a hydride anion that reacts with NAD+, thus driving the reversible reductive amination reaction in the desired direction. Additionally, a general method for converting racemic amino acids to homochiral products using an oxidase - aminotransferase coupled system has been reported. (Kelly et al., Tetrahedron Lett. 37:1517 - 1520 (1996) and Kelly et al., Nat. Prod. Rep. 14:205 - 219 (1997)).

[0587] In another method, enzyme - catalyzed transformations have been shown to be valuable for the preparation of a series of α - deuterated L - amino acids, including leucine (Kelly et al., Tetrahedron Lett. 37:1517 - 1520 (1996)). This method involves incubating the unlabeled L - amino acid in D2O with freeze - dried Escherichia coli B / It7 - A cells enriched in tryptophanase. The relatively broad substrate specificity enables the preparation of a series of α - deuterated L - amino acids, including leucine, in reasonable yields (43 - 95%).

[0588] In another method, racemic [2 - 2 H] amino acids are prepared by heating the corresponding amino acid with 0.05 equivalents of benzaldehyde in deuterated acetic acid (Kelly et al., Tetrahedron Lett. 37:1517 - 1520 (1996)). The acid is converted to the methyl ester, followed by alkaline protease - catalyzed resolution to give the homochiral amino acid with deuterium incorporation >99%.

[0589] In another method, for the synthesis of α - deuterated α - amino acids, chiral auxiliaries and templates are used (Rose et al., J. Chem. Soc., Perkin Trans. 1, 157 - 165 (1995)). Specifically, base - catalyzed deuteration of bis - lactam ethers, (3R)- or (3S)-3 - isopropyl - 2,5 - dimethoxy - 3,6 - dihydropyrazine is carried out in refluxing MeO 2 H - 2 H2O to give the [6 - H2] isotope 9 without disturbing the stereocenter at C - 3. 2 H2] isotope 9 without disturbing the stereocenter at C - 3.

[0590] Chatterjee et al., Org. Lett. 18:5892–5895 (2016) have demonstrated ruthenium-catalyzed selective α-deuteration of amino acids. High deuterium incorporation, selectivity of the α-CH2 protons for the amine functional group, and low catalyst loading make this protocol attractive and advantageous for both laboratory and large-scale amino acid preparation. Complex 1 can be used for efficient labeling of amino acids, including leucine. A series of amino acids are catalyzed using deuterium oxide (including leucine). See Table 3 of Chatterjee et al., Org. Lett. 18:5892–5895 (2016).

[0591] Example 6

[0592] Preparation of Compounds Deuterated at the β-Carbon (C-3)

[0593] The aminotransferase-catalyzed exchange of α-protons with deuterium described in the above section can also be used to incorporate deuterium into the β-position by pre-exchanging α-keto acids in 2 H20-base as described by Kelly et al., Tetrahedron Lett. 37:1517-1520 (1996). In another method, certain prochiral β-methylene groups can be exchanged using the enzyme cystathionine γ-synthase, which is suitable for the preparation of several grams of enantiopure deuterated L-leucine (Homer et al., Anal Biochem. 215:211-215 (1993)). The reaction is carried out in a buffer (pH 7.2) of 33 mM Na2HPO4, 17 mM KH2PO4, 1 mM EDTA, and 0.2 mM pyridoxal phosphate in 2 H2O. After pre-exchanging the solvent-exchangeable protons in 2 H2O, L-leucine (20 mg / mL) is incubated with cystathionine γ-synthase at 37 °C in the dark for three days. The product [2S,3R- 2 H2]leucine is then isolated by standard procedures. For stereoselective labeling of the prochiral β-methylene group of L-leucine, a combined chemoenzymatic method can be used as described for the synthesis of L-threo- and L-erythro-[1- 13 C,2,3- 2Variations of the reported methods for amino acids (including leucine) (Oba et al., Tetrahedron Lett. 39:1595 - 1598 (1998); Oba et al., J. Chem. Soc., Perkin Trans. 1, 1603 - 1609 (1995)). The stereoselective incorporation of deuterium into the α,β-positions of protected amino acids is accomplished by the following process: catalytic deuteration of a dehydro amino acid derivative followed by resolution with an acylase to give L-threo-[2,3- 2 H2] amino acids in good yield. For the L-erythro isomer, it is necessary to racemize the remaining D-threo isomer (from the initial resolution) and then perform further resolution. This method can be extended to the stereospecific labeling with combinations of deuterium of β-methylene and prochiral δ-methyl groups.

[0594] Example 7

[0595] Preparation of compounds deuterated at the γ-carbon (C-4)

[0596] This chemoenzymatic method for deuterating the δ-carbon of L-leucine, described in detail below (Fletcher et al., J. Chem. Soc., Perkin Trans. 1, 43 - 51 2000), can be used to synthesize leucine analogues bearing deuterium at the γ-carbon (C-4). This can be achieved by using 2 H] sodium acetate as the isotopic labeling source. For example, treatment of [2- 2 H] sodium acetate with pivaloyl chloride gives a mixed anhydride which reacts with the lithium salt of 1 to give the acylated product 12 in 70% yield, which is a precursor of [4- 2 H]-L-leucine.

[0597] Example 8

[0598] Preparation of compounds deuterated at the δ-carbon (C-5)

[0599] Strategies for the stereoselective synthesis of leucine and valine with deuterium-labeled methyl groups have been reported.

[0600] In one method (Hill et al., Canadian Journal of Chemistry 72:10 - 113 (1994)), (R)-pulegone 1 was converted to (R)-citronellic acid 2 (R = H) according to the published procedure. See Scheme 1. Reduction of the methyl ester 2 (R = CH3) with lithium aluminum deuteride gave citronellol-1,1-d2 3, which was oxidized to citronellal-1-d 4 by pyridinium chlorochromate. The acidic hydrogen at C-2 was exchanged for deuterium by multiple exchanges with Na2CO3 in D2O - CH3OD to give citronellal-1,2,2-d3 5. Decarbonylation of the aldehyde was effected with Wilkinson's catalyst to give (6S)-[7,7,7- 2 H3]-2,6-dimethyl-2-heptene 6, in which the key asymmetric center containing a methyl and a tri-deuterated methyl was introduced, with a defined configuration and maintaining the enantiomeric purity of pulegone. Oxidation of the double bond of 6 to (4s)-[5,5,5-2~3]-4-methylpentanoic acid 7 was carried out by the Lemieux - Rudloff procedure (10). An amino group was introduced in a conventional manner by α-bromination followed by ammonolysis, and the amino acid was resolved by hydrolysis of the N-acetyl derivative 9 catalyzed by porcine kidney acylase. The reaction gave the (2S,4S) diastereomer 10 of leucine-5-d3, and acid hydrolysis of the recovered amide 11 gave the (2R,4S) diastereomer 12.

[0601] Scheme 1

[0602]

[0603] Scheme 2. Conversion of (R)-pulegone to leucine-d3.

[0604]

[0605] Figure 1 . Fischer projection formula of labeled leucine.

[0606] Example 9

[0607] Synthesis of acetyl-leucine-2,3,3,4-d4 and acetyl-L-leucine-2,3,3,4-d4

[0608] Scheme 2

[0609]

[0610] Step 1: 3-methylbutanal-2,3-d2 (3).

[0611] At room temperature, 3-methylbut-2-enal 2 (10.0 g, 11.5 mL, 1 Eq, 119 mmol) was added to a mixture of palladium on carbon (1 g, 0.08 Eq, 9 mmol) in deuterium oxide (50 mL). The apparatus was evacuated twice and filled with D2 gas using a deuterium-filled balloon. The reaction mixture was stirred at room temperature while the conversion was monitored by GC-MS. After 7 days, GC-MS showed that the starting material was almost completely consumed (remaining <2%). The Pd / C was removed by filtration through Celite. The flask and the filter were washed with D2O (3 x 4 mL). The combined filtrate and washings, a solution of 3-methylbutanal-2,3-d2 (3) in D2O, was used as such in the next step. The structure of (3) was confirmed by 1 1H-NMR and GC-MS.

[0612] Step 2: 3-methylbutanal-2,3,3-d3 (4).

[0613] The crude 3-methylbutanal-2,3-d2 (3) (119 mmol) in D2O (29861-24) was poured into a pressure tube. Pyridine (941 mg, 0.96 mL, 0.1 Eq, 11.9 mmol) was added and the mixture was heated overnight at 130 °C in a closed pressure tube. 1 1H-NMR analysis showed partial H / D exchange. The mixture was heated for another 5 days and then complete deuterium incorporation was observed. The resulting solution of 3-methylbutanal-2,3,3-d3 (4) in D2O / pyridine was used as such in the next step. The structure of (4) was confirmed by 1 1H NMR.

[0614] Step 3: 2-hydroxy-4-methylpentanenitrile-3,3,4-d3 (5).

[0615] The crude solution of 3-methylbutanal-2,3,3-d3 (4) (in D2O, containing 0.1 eq pyridine) was cooled to 10 °C and sodium metabisulfite (11.73 g, 61.69 mmol) was added in small portions. After almost all of the solid had dissolved, the mixture was cooled to 4-5 °C and potassium cyanide (7.305 g, 1 Eq, 112.2 mmol) was added in portions. The mixture was stirred at room temperature for 2 h. The product was extracted with ethyl acetate (3 x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give 2-hydroxy-4-methylpentanenitrile-3,3,4-d3 (5) as an orange oil (4.8 g, 41 mmol). This material contained impurities but was used as such in the next step. The structure of (5) was confirmed by 1 1H NMR.

[0616] Step 4: 5-(2-Methylpropyl-1,1,2-d3)imidazolidine-2,4-dione (6).

[0617] Ammonium carbonate, fine powder (9.3 g, 2.33 Eq, 96 mmol) was added to deuterium oxide (15 mL) and stirred until almost all of the solid had dissolved. The crude 2-hydroxy-4-methylpentanenitrile-3,3,4-d3 (5) (4.8 g, 1 Eq, 41 mmol) was transferred into the reaction mixture by means of THF (15 mL). The mixture was heated overnight at 100 °C in a sealed tube. Volatiles (THF) were removed in vacuo, leaving a suspension in deuterium oxide. The solid, consisting mainly of the desired hydantoin 6 (2.6 g), was separated by filtration. The solid was triturated in DCM (10 mL) to give 1.5 g of 6 as a pale yellow solid containing impurities. Based on 1 1H-NMR spectroscopy, the incorporation rate of deuterium at the α-position of the carbonyl was 60%.

[0618] Step 5: Acetyl-leucine-2,3,3,4-d4 (1-rac)

[0619] 5-(2-Methylpropyl-1,1,2-d3)imidazolidine-2,4-dione (6) (1.5 g, 1 Eq, 9.4 mmol) was suspended in a solution of 40% sodium deuteroxide in D2O (21 g, 15 mL, 1 Eq, 9.4 mmol) and heated at reflux for 72 h. The mixture was neutralized with DCl (20% solution in D2O). Acetic anhydride (3.8 g, 3.6 mL, 4 Eq, 38 mmol) was added to the neutralized mixture and the reaction mixture was stirred overnight at room temperature. The solid was filtered off and the product was extracted with THF to give 220 mg of product containing impurities. The aqueous filtrate was extracted with THF to give 900 mg of product. The remaining aqueous phase was concentrated to dryness and the residue was extracted with THF to give an additional 120 mg of product. All product batches were combined and precipitated from EtOAc to give 330 mg of product containing some inorganic impurities. The mother liquor was treated with dichloromethane to give an additional 300 mg of product. The two precipitated product fractions were combined to give 630 mg of material which was rinsed on a small silica plug with a DCM solution of MeOH to remove inorganic impurities. This gave 430 mg (9.4 mmol, 29%) of rac-acetyl-leucine-2,3,3,4-d4 (1-rac), purity >98% (ELSD). The structure of (1-rac) was confirmed by 1 1H NMR and LCMS.

[0620] Step 6: Acetyl-L-leucine-2,3,3,4-d4 (1)

[0621] Chiral resolution of acetyl-leucine-2,3,3,4-d4 (1-rac) was carried out using chiral preparative HPLC. The concentrated fractions from this separation contained the ammonium salt of acetyl-L-leucine-2,3,3,4-d4. This salt was removed by lyophilization. Both acetyl-L-leucine-2,3,3,4-d4 (320 mg) and acetyl-D-leucine-2,3,3,4-d4 (340 mg) were isolated from 1.0 g of 1-rac. The purity of acetyl-L-leucine-2,3,3,4-d4 (1) was 99.6% (ELSD), and the optical purity was 97% ee.

[0622] Example 10

[0623] Synthesis of acetyl-leucine-2,3,3-d3 and acetyl-L-leucine-2,3,3-d3

[0624]

[0625] Acetyl-leucine-2,3,3-d3 and acetyl-L-leucine-2,3,3-d3 can be prepared using the method described in Example 9.

[0626] Example 11

[0627] Measurement of lysosomal volume using flow cytometry

[0628] The techniques applied in this study are described in te Vruchte et al., J. Clin. Invest. 3:1320 - 1328 (2014). Briefly, human fibroblasts from patients with the AB variant of Tay - Sachs disease were purchased from the NINDS Human Genetic Mutant Cell Repository, Coriell Institute for Medical Research, 403 Haddon Avenue, Camden, NJ 08103, USA. Fibroblasts or Chinese hamster ovary cells were grown in T75 flasks, treated with the compound for 7 days, trypsinized, centrifuged (180 g, 5 minutes), washed twice with 1x PBS, centrifuged again, and stained with 1 ml of a PBS solution of 100 nM LysoTracker - green DND - 26 (Invitrogen) (10 minutes, in the dark). After incubation, the cells were centrifuged (800 g, 5 minutes), resuspended in 0.5 ml of FACS buffer (1x PBS solution with 0.1% BSA, 0.02 M NaN3), and placed on ice for up to 1 hour before flow cytometry analysis (BD Biosciences FACSCanto II or Accuri C6 Plus). The Cytometer Setup and Tracking beads (BD) were used to calibrate the hemocytometer, and compensation was performed using BD FACSDiva software (BD) or BD Accuri C6 Plus software (BD) with Lysotracker - or propidium iodide - stained cells.

[0629] Acetyl - leucine - 2,3,3,4 - d4 (referred to as rac - N - acetyl - leucine - d4) showed significantly better effects than acetyl - leucine (referred to as N - acetyl - DL - leucine). For example, compared to 1 mM acetyl - leucine, 1 mM acetyl - leucine - 2,3,3,4 - d4 showed a significant decrease in LysoTracker fluorescence levels. This effect was observed in both the NPC CHO cell line and the Tay - Sachs AB variant human fibroblast cell line. The results are shown in Figure 1 and Figure 2 are shown.

[0630] Example 12

[0631] Pharmacokinetic studies

[0632] Acetyl - leucine, acetyl - L - leucine, acetyl - leucine - 2,3,3,4 - d4 (1 - rac), and acetyl - L - leucine - 2,3,3,4 - d4 (1) were administered to male BALB / c mice via the oral (po) route. Plasma and tissue samples were collected at predetermined time points and analyzed using HR / MS. The plasma concentration - time curves are shown in Figures 3 - 6presented in

[0633] After oral administration of acetyl-leucine at a nominal dose of 100 mg / kg, the C of acetyl-D-leucine was reached at 0.25 hours after dosing max , which was 86,100 ng / ml, where AUC last was 57,800 h*ng / ml; the C of acetyl-L-leucine was reached at 0.25 hours after dosing max , which was 3,410 ng / ml, where AUC last was 2,600 h*ng / ml. Therefore, the L-form / D-form ratio was 0.04 for both C max and AUC last . See Figure 3 .

[0634] After oral administration of acetyl-leucine-2,3,3,4-d4(1-rac) at a nominal dose of 100 mg / kg, the C of acetyl-D-leucine-2,3,3,4-d4 was reached at 0.50 hours after dosing max , which was 50,600 ng / ml, where AUC last was 99,600 h*ng / ml; the C of acetyl-L-leucine-2,3,3,4-d4(1) was reached at 0.25 hours after dosing max , which was 3,880 ng / ml, where AUC last was 3,430 h*ng / ml. Therefore, the L-form / D-form ratio was 0.08 for C max and 0.03 for AUC last . See Figure 4 .

[0635] After oral administration of acetyl-L-leucine at a nominal dose of 100 mg / kg, the C of acetyl-D-leucine was reached at 0.25 hours after dosing max , which was 436 ng / ml, where AUC last was 573 h*ng / ml; the C of acetyl-L-leucine was reached at 0.25 hours after dosing max , which was 16,800 ng / ml, where AUC last was 11,400 h*ng / ml. Therefore, the L-form / D-form ratio was 38.5 for C max and 19.8 for AUC last . See Figure 5 .

[0636] After oral administration of acetyl-L-leucine-2,3,3,4-d4 (1) at a nominal dose of 100 mg / kg, the C of acetyl-D-leucine-2,3,3,4-d4 reached 3,230 ng / ml at 0.25 hours after dosing, where the AUC max was 3,150 h*ng / ml; the C of acetyl-L-leucine-2,3,3,4-d4 (1) reached 29,300 ng / ml at 0.25 hours after dosing, where the AUC last was 18,200 h*ng / ml. The L-form / D-form ratio was 9.08 for C max and 5.78 for AUC last . See max . last Figure 6 .

[0637] These data indicate that when deuterated or non-deuterated acetyl-leucine is administered, the ratios of acetyl-D-leucine-2,3,3,4-d4 / acetyl-D-leucine for C max and AUC last are 0.59 and 1.72, respectively. The ratios of acetyl-L-leucine-2,3,3,4-d4 (1) / acetyl-L-leucine for C max and AUC last are 1.14 and 1.32, respectively.

[0638] These data also indicate that when deuterated or non-deuterated acetyl-L-leucine is administered, the ratios of acetyl-D-leucine-2,3,3,4-d4 / acetyl-D-leucine for C max and AUC last are 7.40 and 5.50, respectively. The ratios of acetyl-L-leucine-2,3,3,4-d4 (1) / acetyl-L-leucine for C max and AUC last are 1.75 and 1.61, respectively.

[0639] The methods, compounds, and compositions herein have now been fully described, and those skilled in the art will understand that the same operations can be carried out within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any of their embodiments. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.​

Claims

1. A compound having the formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is hydrogen; R 2 is methyl; R 3 is hydrogen or deuterium; R 4 is hydrogen or deuterium; R 5 is hydrogen or deuterium; R 6 is hydrogen or deuterium; and R 7 、R 8 、R 9 、R 10 、R 11 、R 12 and R 13 are hydrogen, wherein R 3 , R 4 , R 5 and R 6 any two or more of which are deuterium, and the compound is not:

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein, The compound having formula I is optically active.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 3 、R 4 、R 5 and R 6 Any three or more of them are deuterium.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein, R 3 、R 4 、R 5 and R 6 are deuterium.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, the compound being:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

7. Use of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for treating lysosomal storage diseases or delaying the progression of lysosomal storage diseases, treating neurodegenerative diseases or delaying the progression of neurodegenerative diseases, treating or preventing migraine, treating or preventing restless legs syndrome, treating or preventing dizziness, or improving mobility and / or cognitive function.

8. Use according to claim 7, wherein, The medicament is used for treating lysosomal storage diseases or delaying the progression of lysosomal storage diseases in a subject in need thereof.

9. Use according to claim 8, wherein, The medicament is used for treating Niemann-Pick disease, type C (NPC), Tay-Sachs disease, Sandhoff disease, GM1-gangliosidosis or Fabry disease, or delaying the progression of Niemann-Pick disease, type C (NPC), Tay-Sachs disease, Sandhoff disease, GM1-gangliosidosis or Fabry disease.

10. Use according to claim 7, wherein, The medicament is used for treating neurodegenerative diseases or delaying the progression of neurodegenerative diseases in a subject in need thereof.

11. Use according to claim 10, wherein, The medicament is used for treating neurodegenerative diseases associated with lysosomal storage defects or delaying the progression of neurodegenerative diseases associated with lysosomal storage defects in a subject in need thereof.

12. The use according to claim 7, wherein, The medicament is used for treating or preventing migraine.

13. The use according to claim 7, wherein, The medicament is used for treating or preventing restless legs syndrome.

14. The use according to claim 7, wherein, The medicament is used for treating or preventing dizziness.

15. The use according to claim 7, wherein, The medicament is used for improving mobility and / or cognitive function.

16. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for providing neuroprotection in a subject suffering from a lysosomal disorder.

17. A kit comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound to a subject for treating a lysosomal storage disorder or delaying the progression of a lysosomal storage disorder, treating a neurodegenerative disease or delaying the progression of a neurodegenerative disease, treating or preventing migraine, treating or preventing restless legs syndrome, treating or preventing dizziness, or improving mobility and cognitive function.

18. A kit comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound to provide neuroprotection in a subject suffering from a lysosomal disorder.

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