Deuterated analogs of acetyl-leucine

Abstract

The present disclosure provides compounds represented by formula I: I, and pharmaceutically acceptable salts and 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 As defined in this specification, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The deuterium enrichment of any one or more of is about 15% or more. The present disclosure also provides a compound having Formula I for treating a lysosomal storage disease or a neurodegenerative disease in a subject or delaying the progression of the disease, providing neuroprotection in a subject with a lysosomal disorder, treating or preventing migraine and symptoms associated therewith in a subject, or improving the mobility and / or cognitive function of a subject.

Description

Background of the Invention Technical Field

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

[0004] 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 often associated with lysosomal storage defects. This includes neurodegenerative lysosomal storage diseases 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 a broad neuroprotective effect are generally applicable to neurodegenerative diseases, including diseases caused by underlying lysosomal storage diseases and diseases caused by other processes.

[0005] Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by defects in lysosomal homeostasis. LSDs encompass more than 70 disorders with an overall clinical frequency of 1:5000 live births. These disorders can be divided into two major categories: primary storage diseases caused by direct defects in degradation pathways (usually lysosomal enzyme deficiencies) and secondary storage diseases caused by dysfunction of downstream lysosomal proteins. Different LSDs caused by inactivation of different lysosomal proteins often share similar pathology. In most cases, multiple organs and tissues are involved. Most of these diseases are characterized by region-specific neurodegeneration.

[0006] Migraines are characterized by recurring moderate to severe headaches. Typically, the headaches affect half of the head, are throbbing in nature, and last between 2 and 72 hours. Symptoms of a migraine include nausea, vomiting, and sensitivity to light, sound, or smells. Physical activity often worsens the pain. About 15% of the world's population is affected by migraines.

[0007] Changes that occur as we age can cause problems with a person's ability to get around. Mobility problems can include unsteadiness when walking, difficulty getting in and out of a chair, or falls. Muscle weakness, joint problems, pain, illness, and neurological (brain and nervous system) problems (common in older people) can all cause mobility problems. Sometimes several minor problems occur at once and combine to seriously affect mobility.

[0008] In addition to potential mobility problems, all older adults will experience some degree of cognitive decline, with symptoms often including forgetfulness, decreased ability to maintain attention, decreased problem-solving skills, and / or decreased spatial awareness. Symptoms may progress to more serious conditions such as dementia and depression or even Alzheimer's disease.

[0009] Many factors are thought to contribute to age-related cognitive decline, including oxidative stress and free radical damage, decreased hormone levels (such as estrogen, testosterone, DHEA, and pregnenolone), arterial intima (endothelial) dysfunction, insulin resistance, excess weight, inadequate nutrition, loneliness, lack of social networks, and stress.

[0010] Current treatments for neurodegenerative diseases, LSDs, and migraines, as well as for 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 an inhibitor of sphingolipid (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 disease type C (NPC) (showing improved ataxia). See Schniepp, R. et al., Cerebellum & Ataxias 3:8 (2016); Bremova, T. et al., Neurology 85:1368 (2015).

[0011] Despite the beneficial effects of N-acetyl leucine, there is still a need for improved treatments of LSDs. There is also a need to develop improved treatments for neurodegenerative diseases, neurodegenerative diseases associated with lysosomal storage defects, migraine, 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

[0012] In one aspect, the present disclosure provides deuterated N-acetylleucine analogs represented by any one of the following Formula IV and pharmaceutically acceptable salts and solvates thereof, as well as deuterated N-acetylleucine alkyl ester analogs and pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "compounds of the present disclosure". The compounds of the present disclosure are enriched with at least one deuterium atom, the abundance of which is at least 1000 times greater than the natural abundance of deuterium.

[0013] In another aspect, the present disclosure provides a method of treating LSD or slowing the progression of LSD, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0014] In another aspect, the present disclosure provides a method of providing neuroprotection in a subject suffering from LSD, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0015] In another aspect, the present disclosure provides a method of treating or slowing progression of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect, 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 of treating or preventing migraine and symptoms associated therewith, 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 of 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.

[0018] In another aspect, the present disclosure provides a method of treating or preventing restless legs syndrome and symptoms associated therewith, 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 method of treating or preventing vertigo and symptoms associated therewith, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[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.

[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 treating LSD in a subject or delaying the progression of 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 providing neuroprotection in a subject suffering from LSD.

[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 a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect in a subject or delaying the progression of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect.

[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 treating or preventing migraine and symptoms associated therewith 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 improving the mobility and / or cognitive function of 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 restless legs syndrome and symptoms associated therewith in a subject.

[0027] 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 vertigo and symptoms associated therewith in a subject.

[0028] In another aspect, the present disclosure provides a compound of the present disclosure for use in treating LSD or delaying the progression of LSD in a subject.

[0029] In another aspect, the present disclosure provides a compound of the present disclosure for use in providing neuroprotection in a subject suffering from LSD.

[0030] In another aspect, the present disclosure provides a compound of the present disclosure for use in treating or delaying progression of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect in a subject.

[0031] In another aspect, the present disclosure provides a compound of the present disclosure for use in treating or preventing migraine and symptoms associated therewith in a subject.

[0032] In another aspect, the present disclosure provides a compound of the present disclosure for use in improving mobility and / or cognitive function in a subject.

[0033] In another aspect, the present disclosure provides a compound of the present disclosure for use in treating or preventing restless legs syndrome and symptoms associated therewith in a subject.

[0034] In another aspect, the present disclosure provides a compound of the present disclosure for use in treating or preventing vertigo and symptoms associated therewith in a subject.

[0035] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating LSD or delaying the progression of LSD in a subject.

[0036] 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 suffering from a LSD.

[0037] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or delaying progression of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect in a subject.

[0038] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing migraine and symptoms associated therewith in a subject.

[0039] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for improving mobility and / or cognitive function in a subject.

[0040] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing restless legs syndrome and symptoms associated therewith in a subject.

[0041] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing vertigo and symptoms associated therewith in a subject.

[0042] In another aspect, the disclosure provides kits comprising a compound of the disclosure and, optionally, a package insert comprising instructions for use, for treating a LSD, a neurodegenerative disease, or a neurodegenerative disease associated with a lysosomal storage defect in a patient.

[0043] In another aspect, the disclosure provides kits comprising a compound of the disclosure and, optionally, a package insert comprising instructions for use, for treating or preventing migraine and symptoms associated therewith in a subject.

[0044] In another aspect, the disclosure provides kits comprising a compound of the disclosure and, optionally, a package insert comprising instructions for use, for improving mobility and / or cognitive function in a subject.

[0045] In another aspect, the disclosure provides kits comprising a compound of the disclosure and, optionally, a package insert comprising instructions for use, for treating or preventing restless legs syndrome and symptoms associated therewith in a subject.

[0046] In another aspect, the disclosure provides kits comprising a compound of the disclosure and, optionally, a package insert comprising instructions for use, for treating or preventing vertigo and symptoms associated therewith in a subject.

[0047] In another embodiment, the present disclosure provides a personalized medical program for a subject suffering from an LSD or a neurodegenerative disease and includes selecting a treatment option with the highest likelihood of a successful outcome for the individual LSD or neurodegenerative subject.

[0048] In another embodiment, the present disclosure provides a personalized medical program for a subject suffering from migraine and symptoms associated therewith, and includes selecting a treatment option with the highest likelihood of a successful outcome for treating or preventing the subject's migraine and symptoms associated therewith.

[0049] In another embodiment, the present disclosure provides a personalized medical program 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 in improving the subject's mobility and / or cognitive function.

[0050] In another aspect, the present disclosure provides methods of preparing the compounds of the present disclosure.

[0051] Other embodiments and advantages of the present disclosure will be explained in part in the following description and will be revealed from the description, or can be learned through the practice of the present disclosure. The embodiments and advantages of the present disclosure will be realized and achieved by means of the elements and combinations particularly pointed out in the appended claims.

[0052] 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 invention, as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 is a line graph showing the effect of acetyl-leucine (referred to as IB1000) and acetyl-leucine-2,3,3,4-d4 (referred to as DIB1000) in NPC cell phenotype assays. 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. 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.

[0054] Figure 2 is a bar graph showing the effect of acetyl-leucine (referred to as IB1000) and acetyl-leucine-2,3,3,4-d4 (referred to as DIB1000) in the Tay-Sachs AB human fibroblast assay. Fibroblasts derived from patients with the AB variant of Tay-Sachs 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.

[0055] Figure 3 is a line graph showing the plasma concentration versus time curve of acetyl-D-leucine (referred to as N-acetyl-D-leucine) and acetyl-L-leucine (referred to as N-acetyl-L-leucine) after oral administration of acetyl-leucine (referred to as N-acetyl-DL-leucine) in saline solution at a dose of 100 mg / kg to male BALB / c mice.

[0056] Figure 4is a line graph showing the plasma concentration versus time curve of acetyl-D-leucine-2,3,3,4-d4 (referred to as N-acetyl-D-leucine-d4) and acetyl-L-leucine-2,3,3,4-d4(1) (referred to as N-acetyl-L-leucine-d4) after oral administration of acetyl-leucine-2,3,3,4-d4(1-rac) (referred to as N-acetyl-DL-leucine-d4) in saline solution at a dose of 100 mg / kg to male BALB / c mice.

[0057] Figure 5 is a line graph showing the plasma concentration versus time curve of acetyl-D-leucine (referred to as N-acetyl-D-leucine) and acetyl-L-leucine after oral administration of acetyl-L-leucine (referred to as N-acetyl-L-leucine) in saline solution at a dose of 100 mg / kg to male BALB / c mice.

[0058] Figure 6 is a line graph showing the plasma concentration versus time curve of acetyl-D-leucine-2,3,3,4-d4 (referred to as N-acetyl-D-leucine-d4) and acetyl-L-leucine-2,3,3,4-d4 (1) (referred to as N-acetyl-L-leucine-d4) after oral administration of acetyl-L-leucine-2,3,3,4-d4 (1) in saline solution at a dose of 100 mg / kg to male BALB / c mice. DETAILED DESCRIPTION

[0059] 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 a lysosomal storage defect in a subject or delay the progression of a neurodegenerative disease associated with a lysosomal storage defect, treat or prevent migraine and symptoms associated therewith in a subject, treat or prevent restless legs syndrome and symptoms associated therewith in a subject, treat or prevent vertigo and symptoms associated therewith in a subject, or improve mobility and / or cognitive function in a subject.

[0060] In one embodiment, the compound of the present disclosure is a compound having Formula I:

[0061]

[0062] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0063] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0064] R 2 C 1-6 Alkyl; and

[0065] 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,

[0066] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The deuterium enrichment of any one or more of is about 15% or more.

[0067] In another embodiment, the compound of the present disclosure is a compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0068] (a) When R 13 When it is hydrogen, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 At least one of is hydrogen; and

[0069] (b) and the compound is not:

[0070]

[0071]

[0072] In another embodiment, the compound of the present disclosure is an optically inactive compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, ie, the compound is racemic.

[0073] In another embodiment, the compound of the present disclosure is an optically active compound having Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0074] In another embodiment, the compound of the present disclosure is a compound having Formula II:

[0075]

[0076] 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 conjunction with Formula I.

[0077] In another embodiment, the compound of the present disclosure is a compound having Formula III:

[0078]

[0079] 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 conjunction with Formula I.

[0080] In another embodiment, the compound of the present disclosure is a compound having Formula IV:

[0081]

[0082] 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 , R10 , R 11 , R 12 and R 13 As defined in conjunction with Formula I.

[0083] In another embodiment, the compound of the present disclosure is a compound having Formula V:

[0084]

[0085] 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 conjunction with Formula I.

[0086] In another embodiment, the compound of the present disclosure is a compound of any one of Formula IV, 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%.

[0087] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 For hydrogen.

[0088] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is methyl.

[0089] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 For hydrogen.

[0090] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, 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 two or more of is about 15% or more.

[0091] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, 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 is about 15% or more.

[0092] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, 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 is about 15% or more.

[0093] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, 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 the is about 15% or more.

[0094] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 , R4 , 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 the is about 15% or more.

[0095] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, 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 seven or more of the is about 15% or more.

[0096] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Any eight or more of the above have a deuterium enrichment of about 15% or more.

[0097] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0098] R 7 The deuterium enrichment is about 15% or more;

[0099] R 10 The deuterium enrichment is about 15% or more; and

[0100] R 6 , R 8 , R 9 , R 11 and R 12 For hydrogen.

[0101] In another embodiment, the compound of the present disclosure is a compound having any one of Formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0102] R 7 and R 8 The deuterium enrichment is about 15% or more;

[0103] R 10 and R 11 The deuterium enrichment is about 15% or more; and

[0104] R 9 and R 12 For hydrogen.

[0105] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of:

[0106]

[0107]

[0108] or a pharmaceutically acceptable salt or solvate thereof.

[0109] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of:

[0110]

[0111] or a pharmaceutically acceptable salt or solvate thereof.

[0112] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of:

[0113]

[0114] or a pharmaceutically acceptable salt or solvate thereof.

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

[0116]

[0117] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of:

[0118]

[0119] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of:

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

[0128]

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

[0130]

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

[0132]

[0133] The term "N-acetyl-L-leucine" or "acetyl-L-leucine" refers to the compound having the following structure:

[0134]

[0135] As used herein, the term “C 1-6 "Alkyl" refers to a straight or branched aliphatic hydrocarbon containing one to six carbon atoms. In another embodiment, the alkyl group is selected from a straight chain C 1-6 In another embodiment, the alkyl group is selected from branched C 3-6 In another embodiment, the alkyl group is selected from a linear C 1-4 In another embodiment, the alkyl group is selected from branched C 3-4 Alkyl group. Term C 1-6 The alkyl group includes at least one deuterium analog in place of hydrogen, the abundance of which is at least about 1000 times greater than the natural abundance of deuterium. Non-limiting exemplary C 1-6Alkyl groups include methyl, -CH2D, -CHD2, -CD3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl and hexyl.

[0136] When a position in any of Formula IV is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen at its natural abundance isotopic composition.

[0137] When a position in any of Formula IV is specifically designated as "D" or "" deuterium, that position is understood to have deuterium in an abundance at least about 1000 times greater than the natural abundance of deuterium, which is about 0.015%.

[0138] As used herein, the term "deuterium enrichment" refers to the percentage of deuterium being incorporated at a given position of any one of Formula IV to replace the hydrogen at that position. In one embodiment, deuterium enrichment is about 15% or more, i.e., at least about 1000 times greater than the natural abundance of deuterium. In another embodiment, 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, 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.

[0139] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds that have more than one chiral center and are not mirror images of each other (diastereomers).

[0140] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0141] The terms "enantiomer" and "enantiomeric" refer to molecules that are not superimposable on their mirror images and therefore optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0142] The term "racemic" refers to a mixture of equal parts of enantiomers and the mixture is optically inactive.

[0143] The term "absolute configuration" refers to the spatial arrangement of atoms of a chiral molecular entity (or group) and its stereochemical description, eg, R or S.

[0144] Unless otherwise noted, stereochemical terminology and conventions used in the specification are intended to be consistent with those described in Pure & Appl. Chem 68:2193 (1996).

[0145] The term "enantiomeric excess" or "ee" refers to a measure of how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |RS|*100, where R and S are the respective mole 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 percent enantiomeric excess is defined as ([α] obs / [α] max )*100, where [α] obs is the optical rotation of the enantiomeric mixture, [α] max is the optical rotation of the pure enantiomer. Enantiomeric excess can be determined using a variety of analytical techniques including NMR spectroscopy, chiral column chromatography, or optical polarimetry.

[0146] Salts and solvates (eg, hydrates) of the disclosed compounds may also be used in the methods disclosed herein.

[0147] The present disclosure encompasses the preparation and use of salts of compounds of the present disclosure. As used herein, "pharmaceutically acceptable salts" refers to salts or zwitterionic forms of compounds of the present disclosure. Salts of compounds of the present disclosure can be prepared during the final separation and purification of the compound, or prepared separately by reacting the compound with an acid having a suitable cation. Pharmaceutically acceptable salts of compounds of the present 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 compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, edisylate, benzenesulfonate, and p-toluenesulfonate. In addition, available amino groups present in the compounds of the present disclosure may be quaternized with methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference to the compounds of the present disclosure appearing herein is intended to include the compounds of the present disclosure and pharmaceutically acceptable salts, hydrates or solvates thereof.

[0148] The present disclosure encompasses the preparation and use of solvates of compounds of the present disclosure. Solvates generally do not significantly change the physiological activity or toxicity of the compound, and therefore can act as pharmacological equivalents. As used herein, the term "solvate" is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate, wherein the ratio of the solvent molecule to the compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, solvates can be separated, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Therefore, "solvate" includes a solution phase and a separable solvate. The compounds of the present disclosure may exist in a solvated form with a pharmaceutically acceptable solvent (such as water, methanol and ethanol), and the present disclosure is intended to include solvated and non-solvated forms of the compounds of the present disclosure.

[0149] A solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally act as pharmacological equivalents. 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 solvates 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 AL Bingham et al., Chem. Commun. 603-604 (2001). A typical non-limiting process for preparing a solvate will involve dissolving the 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 separating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in solvate crystals.

[0150] Unless otherwise stated, in the context of describing the present disclosure (especially in the context of the claims), the use of the terms "one", "a", "the" and similar references should be interpreted as covering both the singular and the plural. Unless otherwise stated herein, references to a range of values ​​herein are intended only to serve as a shorthand method of individually referring to each individual value within the range, and each individual value is incorporated into the specification as if it were individually cited 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 rather than to limit the scope of the present disclosure. Any language in the specification should not be interpreted as indicating any unclaimed element as being necessary to practice the present disclosure.

[0151] Pharmaceutical composition

[0152] 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.

[0153] The compounds of the present disclosure are generally administered in admixture with a pharmaceutical excipient selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the compounds of the present disclosure.

[0154] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee manufacturing, emulsification, encapsulation, embedding or lyophilization processes. Appropriate formulations depend on the selected route of administration. When a therapeutically effective amount of the compounds of the present disclosure is administered orally, the composition is typically in the form of tablets, capsules, powders, solutions or elixirs. When administered in tablet form, the composition may additionally contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules and powders contain about 0.01% to about 95% (e.g., about 1% to about 50%) of the compounds of the present disclosure. When administered in liquid form, a liquid carrier may be added, such as water, petroleum or oils of animal or plant origin. The liquid form of the composition may further contain physiological saline solution, dextrose or other sugar solutions or glycols. When administered in liquid form, the composition contains about 0.1% to about 90% (e.g., about 1% to about 50%) of the compounds of the present disclosure by weight.

[0155] 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 parenteral acceptable aqueous solution. The preparation of such parenteral acceptable solutions with appropriate consideration of pH, isotonicity, stability, etc. is within the skill of the art. Compositions for intravenous, cutaneous or subcutaneous injection typically contain an isotonic vehicle.

[0156] 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 edition. 1995. Such carriers enable the active agent to be formulated 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 following process: adding the compounds of the present disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable auxiliaries (if necessary) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, a disintegrant can be added.

[0157] The compounds of the present disclosure may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). The preparations for injection may be present in unit dosage form, such as in ampoules or in multidose containers, together with an added preservative. The composition may be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain preparatants, such as suspending agents, stabilizers, and / or dispersants.

[0158] Pharmaceutical compositions for parenteral administration include aqueous solutions of active agents in water-soluble form. In addition, suspensions of 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 increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the composition of the present invention can be in powder form, to be reconstituted with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0159] 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 preparations described previously, compounds of the present disclosure can also be formulated into long-acting preparations. Such long-acting preparations can be applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, 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.

[0160] 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 mixed with excipients or in the form of elixirs or suspensions containing flavorings 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 injected parenterally, such as intravenous, intramuscular, subcutaneous or intracoronary injection. For parenteral administration, the compounds of the present disclosure are generally used in the form of sterile aqueous solutions, which may contain other substances, such as salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.

[0161] In one embodiment, the pharmaceutically acceptable carrier is a solid, and the composition is in the form of a powder or tablet. A solid pharmaceutically acceptable carrier may include one or more substances, which may also serve as flavoring agents, buffers, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings or tablet disintegrants. The carrier may also be an encapsulating material. In a powder, the carrier is a finely divided solid mixed with a finely divided active agent according to the present invention. In a tablet, the active agent may be mixed with a carrier having the necessary compression properties in a suitable ratio and pressed into a desired shape and size. Powders and tablets may 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, polyvinyl pyrrolidine, low melting point waxes and ion exchange resins. In another embodiment, the pharmaceutically acceptable carrier may be a gel, and the composition may be in the form of an ointment or the like.

[0162] The carrier may include one or more excipients or diluents. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc.

[0163] In another embodiment, the pharmaceutically acceptable carrier is a liquid, and the pharmaceutical composition is in the form of a solution. The liquid carrier is used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds disclosed herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier (such as water, an organic solvent, a mixture of the two) or in 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, thickeners, colorants, viscosity modifiers, stabilizers or osmotic pressure regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohol (including monohydric alcohols and polyols, such as diols) and derivatives thereof, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be a grease, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers can be used for sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0164] 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 using sterile water, saline or other suitable sterile injectable media when administered.

[0165] The compounds of the present disclosure and compositions thereof can be orally administered in the form of sterile solutions or suspensions containing other solutes or suspending agents (e.g., saline or glucose sufficient to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 (oleate copolymerized with sorbitol and its anhydride and ethylene oxide), and the like.

[0166] The compounds of the present disclosure and compositions thereof can also be orally administered 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 that can be used for parenteral administration include sterile solutions, emulsions and suspensions.

[0167] The compounds of the present disclosure and compositions thereof may alternatively be administered by inhalation (e.g., intranasally). The compositions may also be formulated for topical use. For example, a cream or ointment may be applied to the skin.

[0168] The compounds of the present disclosure and compositions thereof can be incorporated into slow or delayed 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 may be particularly advantageous when long-term treatment with the compounds of the present disclosure is required and frequent administration (e.g., at least daily administration) is generally required.

[0169] In another embodiment, the pharmaceutical composition is in the form of a tablet suitable for oral administration. In the tablet, the compound of the present disclosure can be mixed with a vehicle having the necessary compression properties in a suitable ratio and compressed into a desired shape and size. The tablet can contain up to 99% by weight of the compound of the present disclosure.

[0170] Pharmaceutical preparations in solid oral dosage forms, such as tablets, can be prepared by any method known in the pharmaceutical art. Pharmaceutical preparations are generally prepared by mixing a compound of the present disclosure or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier, diluent or excipient.

[0171] How to use

[0172] In another embodiment, the present disclosure provides a method of treating or slowing the progression of a lysosomal storage disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0173] In another embodiment, the present disclosure provides a method of providing neuroprotection in a subject suffering from a lysosomal storage disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0174] In another embodiment, the present disclosure provides a method of treating a neurodegenerative disease or slowing the progression of a neurodegenerative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0175] In another embodiment, the present disclosure provides a method of treating or slowing the progression of a neurodegenerative disease associated with a lysosomal storage defect, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0176] In another embodiment, the present disclosure provides a method of treating or preventing migraine and symptoms associated therewith, 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 of 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.

[0178] In another aspect, the present disclosure provides a method of 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.

[0179] In another aspect, the present disclosure provides a method of treating or preventing vertigo, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0180] The present invention also provides the following specific embodiments.

[0181] Embodiment 1. A method of treating or delaying the progression of a 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:

[0182] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0183] R 2 C 1-6 Alkyl; and

[0184] 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,

[0185] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The deuterium enrichment of any one or more of is about 15% or more.

[0186] Embodiment II. A method of providing neuroprotection, treating or slowing the progression of a neurodegenerative disease, or treating or slowing the progression of a neurodegenerative disease associated with a lysosomal storage defect, treating or preventing migraine and symptoms associated therewith, treating or preventing restless legs syndrome and symptoms associated therewith, treating or preventing vertigo and symptoms associated therewith, or improving mobility and / or cognitive function in a subject with a lysosomal storage disease, 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:

[0187] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0188] R 2 C 1-6 Alkyl; and

[0189] 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,

[0190] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The deuterium enrichment of any one or more of is about 15% or more.

[0191] Embodiment III. The method of Embodiment I or II, wherein the compound of Formula I is optically active.

[0192] Embodiment IV. The method of Embodiment III, wherein the optically active compound of Formula I is a compound of Formula II (see above).

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

[0194] Embodiment VI. The method of Embodiment III, wherein the compound of Formula I is a compound of Formula IV (see above).

[0195] Embodiment VII. The method of Embodiment III, wherein the compound of Formula I is a compound of Formula V (see above).

[0196] Embodiment VIII. A method as described in any one of embodiments I-VII, wherein R 1 For hydrogen.

[0197] Embodiment IX. The method of any one of embodiments I-VIII, wherein:

[0198] R 2 For-CR 2a R 2b R 2c ;and

[0199] R 2a , R 2b and R 2c independently selected from the group consisting of hydrogen and deuterium,

[0200] Where R 2a , R 2b and R 2c In another embodiment, the deuterium enrichment of any one or more of R is about 15% or more. 2a , R 2b and R 2c Each is hydrogen, that is, R 2 It is methyl.

[0201] Embodiment X. A method as described in any one of embodiments I-IX, wherein R 13 For hydrogen.

[0202] Embodiment XI. A method as described in any one of Embodiments IX, 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 two or more of is about 15% or more.

[0203] Embodiment XII. A method as described in Embodiment XI, wherein R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The deuterium enrichment of any three or more of is about 15% or more.

[0204] Embodiment XIII. A method as described in Embodiment XII, 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 is about 15% or more.

[0205] Embodiment XIV. A method as described in Embodiment XIII, 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 the is about 15% or more.

[0206] Embodiment XV. A method as described in Embodiment XIV, 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 the is about 15% or more.

[0207] Embodiment XVI. A method as described in 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 the is about 15% or more.

[0208] Embodiment XVII. A method as described in Embodiment XVI, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Any eight or more of the above have a deuterium enrichment of about 15% or more.

[0209] Embodiment XVIII. The method of embodiment XI, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0210] R 7 The deuterium enrichment is about 15% or more;

[0211] R 10 The deuterium enrichment is about 15% or more; and

[0212] R 6 , R 8 , R 9 , R 11 and R 12 For hydrogen.

[0213] Embodiment XIX. The method of embodiment XIII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0214] R 7 and R 8 The deuterium enrichment is about 15% or more;

[0215] R 10 and R 11 The deuterium enrichment is about 15% or more; and

[0216] R 9 and R 12 For hydrogen.

[0217] Embodiment XX. The method of Embodiment I or II, wherein the compound having Formula I is selected from the group consisting of:

[0218]

[0219]

[0220] Embodiment XXI. The method of Embodiment III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0221]

[0222] Embodiment XXII. The method of Embodiment III, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0223]

[0224]

[0225] Embodiment XXIII. A compound of the present disclosure having Formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0226] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0227] R 2 C 1-6 Alkyl; and

[0228] 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,

[0229] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Any one or more of the deuterium enrichment is about 15% or more,

[0230] The compound or a pharmaceutically acceptable salt or solvate thereof is used in a method for treating a lysosomal storage disease or delaying the progression of a lysosomal storage disease.

[0231] Embodiment XXIV. A compound of the present disclosure having Formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0232] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0233] R 2 C 1-6 Alkyl; and

[0234] 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,

[0235] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Any one or more of the deuterium enrichment is about 15% or more,

[0236] The compounds or pharmaceutically acceptable salts or solvates thereof are used to provide neuroprotection in subjects with lysosomal disorders, treat neurodegenerative diseases or slow the progression of neurodegenerative diseases, treat neurodegenerative diseases associated with lysosomal storage defects or slow the progression of neurodegenerative diseases associated with lysosomal storage defects, treat or prevent migraine and symptoms associated therewith, treat or prevent restless legs syndrome and symptoms associated therewith, treat or prevent vertigo and symptoms associated therewith, or improve mobility and / or cognitive function.

[0237] Embodiment XXV. A compound as used in Embodiment XXIII or XXIV, wherein the compound of formula I is optically active.

[0238] Embodiment XXVI. The compound as used in Embodiment XXV, wherein the optically active compound of formula I is a compound of formula II (see above).

[0239] Embodiment XXVII. The compound as used in Embodiment XXV, wherein the compound of formula I is a compound of formula III (see above).

[0240] Embodiment XXVIII. The compound as used in Embodiment XXV, wherein the compound of formula I is a compound of formula IV (see above).

[0241] Embodiment XXIX. The compound as used in Embodiment XXV, wherein the compound of formula I is a compound of formula V (see above).

[0242] Embodiment XXX. A compound as used in any one of Embodiments XXIII-XXIX, wherein R 1 For hydrogen.

[0243] Embodiment XXXI. A compound as used in any one of Embodiments XXIII-XXX, wherein:

[0244] R 2 For-CR 2a R 2b R 2c ;and

[0245] R 2a , R 2b and R 2c independently selected from the group consisting of hydrogen and deuterium,

[0246] Where R 2a , R 2b and R 2c In another embodiment, the deuterium enrichment of any one or more of R is about 15% or more. 2a , R 2b and R 2c Each is hydrogen, that is, R 2 It is methyl.

[0247] Embodiment XXXII. A compound as used in any one of Embodiments XXIII-XXXI, wherein R 13 For hydrogen.

[0248] Embodiment XXXIII. A compound as used in any one of Embodiments XXIII-XXXII, 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 two or more of is about 15% or more.

[0249] Embodiment XXXIV. Compounds as used in Embodiment XXXIII, 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 is about 15% or more.

[0250] Embodiment XXXV. Compounds 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 The deuterium enrichment of any four or more of is about 15% or more.

[0251] 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 The deuterium enrichment of any five or more of the is about 15% or more.

[0252] Embodiment XXXVII. Compounds 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 The deuterium enrichment of any six or more of the is about 15% or more.

[0253] Embodiment XXXVIII. Compounds as used in Embodiment XXXVII, wherein R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The deuterium enrichment of any seven or more of the is about 15% or more.

[0254] Embodiment XXXIX. Compounds 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 Any eight or more of the above have a deuterium enrichment of about 15% or more.

[0255] Embodiment XL. A compound as used in Embodiment XXXIII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0256] R 7 The deuterium enrichment is about 15% or more;

[0257] R 10 The deuterium enrichment is about 15% or more; and

[0258] R 6 , R 8 , R 9 , R 11 and R 12 For hydrogen.

[0259] Embodiment XLI. A compound as used in Embodiment XXXV, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0260] R 7 and R 8 The deuterium enrichment is about 15% or more;

[0261] R 10 and R 11 The deuterium enrichment is about 15% or more; and

[0262] R 9 and R 12 For hydrogen.

[0263] Embodiment XLII. As used in embodiments XXIII or XXIV, the compound wherein the compound of formula I is selected from the group consisting of:

[0264]

[0265]

[0266] Embodiment XLIII. A compound as used in Embodiment XXV, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0267]

[0268] Embodiment XLIV. A compound as used in Embodiment XXV, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0269]

[0270]

[0271] Embodiment XLV. 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 treating or delaying the progression of a lysosomal storage disease, wherein:

[0272] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0273] R 2 C 1-6 Alkyl; and

[0274] 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,

[0275] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 and R 13 The deuterium enrichment of any one or more of is about 15% or more.

[0276] 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 symptoms associated therewith, treating or preventing restless legs syndrome and symptoms associated therewith, treating or preventing vertigo and symptoms associated therewith, or improving mobility and cognitive function in a subject with a lysosomal disorder, wherein:

[0277] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0278] R 2 C 1-6 Alkyl; and

[0279] 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,

[0280] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The deuterium enrichment of any one or more of is about 15% or more.

[0281] Embodiment XLVII. The use according to Embodiment XLV or XLVI, wherein the compound of Formula I is optically active.

[0282] Embodiment XLVIII. The use according to embodiment XLVII, wherein the optically active compound of formula I is a compound of formula II (see above).

[0283] Embodiment XLIX. The use according to embodiment XLVII, wherein the compound of formula I is a compound of formula III (see above).

[0284] Embodiment L. The use according to Embodiment XLVII, wherein the compound of formula I is a compound of formula IV (see above).

[0285] Embodiment LI. The use according to embodiment XLVII, wherein the compound of formula I is a compound of formula V (see above).

[0286] Embodiment LII. The use according to any one of embodiments XLV-LI, wherein R 1 For hydrogen.

[0287] Embodiment LIII. The use according to any one of embodiments XLV-LII, wherein:

[0288] R 2 For-CR 2a R 2b R 2c ;and

[0289] R 2a , R 2b and R 2c independently selected from the group consisting of hydrogen and deuterium,

[0290] Where R 2a , R 2b and R 2c In another embodiment, the deuterium enrichment of any one or more of R is about 15% or more. 2a , R 2b and R 2c Each is hydrogen, that is, R 2 It is methyl.

[0291] Embodiment LIV. The use as described in any one of embodiments XLV-LIII, wherein R 13 For hydrogen.

[0292] Embodiment LV. The use according to any one of embodiments XLV-LIV, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , R 10 , R 11 and R 12 The deuterium enrichment of any two or more of is about 15% or more.

[0293] Embodiment LVI. The use according to embodiment LV, 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 is about 15% or more.

[0294] Embodiment LVII. The use according to embodiment LVI, 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 is about 15% or more.

[0295] Embodiment LVIII. The use according to embodiment LVII, 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 the is about 15% or more.

[0296] Embodiment LIX. The use according to embodiment LVIII, 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 the is about 15% or more.

[0297] Embodiment LX. The use according to embodiment LIX, 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 seven or more of the is about 15% or more.

[0298] Embodiment LXI. The use according to embodiment LX, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Any eight or more of the above have a deuterium enrichment of about 15% or more.

[0299] Embodiment LXII. The use according to embodiment LV, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0300] R 7 The deuterium enrichment is about 15% or more;

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

[0302] R 6 , R 8 , R 9 , R 11 and R 12 For hydrogen.

[0303] Embodiment LXIII. The use according to embodiment LVII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0304] R 7 and R 8 The deuterium enrichment is about 15% or more;

[0305] R 10 and R 11 The deuterium enrichment is about 15% or more; and

[0306] R 9 and R 12 For hydrogen.

[0307] Embodiment LXIV. The use according to embodiment XLV or XLVI, wherein the compound of formula I is selected from the group consisting of:

[0308]

[0309] Embodiment LXV. The use according to Embodiment XLVII, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0310]

[0311] Embodiment LXVI. The use according to Embodiment XLVII, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0312]

[0313] Embodiment LXVII. A pharmaceutical composition comprising a compound of the present disclosure having Formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0314] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0315] R 2 C 1-6 Alkyl; and

[0316] 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,

[0317] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Any one or more of the deuterium enrichment is about 15% or more,

[0318] The pharmaceutical composition is used in a method for treating a lysosomal storage disease or delaying the progression of a lysosomal storage disease.

[0319] 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:

[0320] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0321] R 2 C 1-6 Alkyl; and

[0322] 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,

[0323] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Any one or more of the deuterium enrichment is about 15% or more,

[0324] The pharmaceutical composition is used to provide neuroprotection in a subject with a lysosomal disorder, treat a neurodegenerative disease or slow the progression of a neurodegenerative disease, treat a neurodegenerative disease associated with a lysosomal storage defect or slow the progression of a neurodegenerative disease associated with a lysosomal storage defect, treat or prevent migraine and symptoms associated therewith, treat or prevent restless legs syndrome and symptoms associated therewith, treat or prevent vertigo and symptoms associated therewith, or improve mobility and / or cognitive function.

[0325] Embodiment LXIX. A pharmaceutical composition according to Embodiment LXVII or LXVIII, wherein the compound of Formula I is optically active.

[0326] Embodiment LXX. A pharmaceutical composition according to Embodiment LXIX, wherein the optically active compound of Formula I is a compound of Formula II (see above).

[0327] Embodiment LXXI. A pharmaceutical composition according to Embodiment LXIX, wherein the compound of Formula I is a compound of Formula III (see above).

[0328] Embodiment LXXII. A pharmaceutical composition according to Embodiment LXIX, wherein the compound of Formula I is a compound of Formula IV (see above).

[0329] Embodiment LXXIII. A pharmaceutical composition according to Embodiment LXIX, wherein the compound of Formula I is a compound of Formula V (see above).

[0330] Embodiment LXXIV. A pharmaceutical composition as described in any one of Embodiments LXVII-LXXIII, wherein R 1 For hydrogen.

[0331] Embodiment LXXV. A pharmaceutical composition according to any one of embodiments LXVII-LXXIV, wherein:

[0332] R 2 For-CR 2a R 2b R 2c ;and

[0333] R 2a , R 2b and R 2c independently selected from the group consisting of hydrogen and deuterium,

[0334] Where R 2a , R 2b and R 2c In another embodiment, the deuterium enrichment of any one or more of R is about 15% or more. 2a , R 2b and R 2c Each is hydrogen, that is, R 2 It is methyl.

[0335] Embodiment LXXVI. A pharmaceutical composition as described in any one of embodiments LXVII-LXXV, wherein R 13 For hydrogen.

[0336] Embodiment LXXVII. A pharmaceutical composition as described in any one of Embodiments LXVII-LXXVI, wherein R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The deuterium enrichment of any two or more of is about 15% or more.

[0337] Embodiment LXXVIII. A pharmaceutical composition according to 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 is about 15% or more.

[0338] 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 is about 15% or more.

[0339] Embodiment LXXX. A pharmaceutical composition according to 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 the is about 15% or more.

[0340] Embodiment LXXXI. A pharmaceutical composition according to embodiment LXXX, 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 six or more of the is about 15% or more.

[0341] Embodiment LXXXII. A pharmaceutical composition according to embodiment LXXXI, 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 seven or more of the is about 15% or more.

[0342] Embodiment LXXXIII. A pharmaceutical composition according to embodiment LXXXII, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Any eight or more of the above have a deuterium enrichment of about 15% or more.

[0343] Embodiment LXXXIV. A pharmaceutical composition according to embodiment LXXVII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0344] R 7 The deuterium enrichment is about 15% or more;

[0345] R 10 The deuterium enrichment is about 15% or more; and

[0346] R 6 , R 8 , R 9 , R 11 and R 12 For hydrogen.

[0347] Embodiment LXXXV. A pharmaceutical composition according to Embodiment LXXIX, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0348] R 7 and R 8 The deuterium enrichment is about 15% or more;

[0349] R 10 and R 11 The deuterium enrichment is about 15% or more; and

[0350] R 9 and R 12 For hydrogen.

[0351] Embodiment LXXXVI. A pharmaceutical composition according to embodiment LXVII or LXVIII, wherein the compound having formula I is selected from the group consisting of:

[0352]

[0353] Embodiment LXXXVII. A pharmaceutical composition according to Embodiment LXIX, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0354]

[0355] Embodiment LXXXVIII. A pharmaceutical composition according to Embodiment LXIX, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0356]

[0357] Embodiment LXXXIX. A kit comprising a compound of the present disclosure having Formula I (see above), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0358] R 1 Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0359] R 2 C 1-6 Alkyl; and

[0360] 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,

[0361] Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 , R 12 and R 13 The invention relates to a composition comprising a compound comprising a lysosomal storage disorder and a lysosomal storage disorder, wherein the compound has a deuterium enrichment of about 15% or more, and instructions for administering the compound to a subject to treat or slow the progression of a lysosomal storage disorder, or to provide neuroprotection in a subject with a lysosomal disorder, or to treat or slow the progression of a neurodegenerative disease, to treat or slow the progression of a neurodegenerative disease associated with a lysosomal storage defect, to treat or prevent migraine and symptoms associated therewith, to treat or prevent restless legs syndrome and symptoms associated therewith, to treat or prevent vertigo and symptoms associated therewith, or to improve mobility and / or cognitive function.

[0362] Embodiment XC. The kit of Embodiment LXXXIX, wherein the compound of Formula I is optically active.

[0363] Embodiment XCI. A kit according to Embodiment XC, wherein the optically active compound of Formula I is a compound of Formula II (see above).

[0364] Embodiment XCII. The kit of Embodiment XC, wherein the compound of Formula I is a compound of Formula III (see above).

[0365] Embodiment XCIII. The kit of Embodiment XC, wherein the compound of Formula I is a compound of Formula IV (see above).

[0366] Embodiment XCIV. The kit of Embodiment XC, wherein the compound of Formula I is a compound of Formula V (see above).

[0367] Embodiment XCV. A kit as described in any one of Embodiments LXXXIX-XCIV, wherein R 1 For hydrogen.

[0368] Embodiment XCVI. A kit according to any one of embodiments LXXXIX-XCV, wherein:

[0369] R 2 For-CR 2a R 2b R 2c ;and

[0370] R 2a , R 2b and R 2c independently selected from the group consisting of hydrogen and deuterium,

[0371] Where R 2a , R 2b and R 2c In another embodiment, the deuterium enrichment of any one or more of R is about 15% or more. 2a , R 2b and R 2c Each is hydrogen, that is, R 2 It is methyl.

[0372] Embodiment XCVII. A kit as described in any one of embodiments LXXXIX-XCVI, wherein R 13 For hydrogen.

[0373] Embodiment XCVIII: A kit according to any one of Embodiments LXXXIX to XCVII, 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 two or more of is about 15% or more.

[0374] Embodiment XCIX. A kit as described in Embodiment XCVIII, 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 is about 15% or more.

[0375] Embodiment C. A kit according to embodiment XCIX, 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 is about 15% or more.

[0376] Embodiment CI. A kit as described in Embodiment C, wherein R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The deuterium enrichment of any five or more of the is about 15% or more.

[0377] 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 The deuterium enrichment of any six or more of the is about 15% or more.

[0378] Embodiment CIII. A kit according to embodiment CII, 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 seven or more of the is about 15% or more.

[0379] 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 Any eight or more of the above have a deuterium enrichment of about 15% or more.

[0380] Embodiment CV. A kit according to embodiment XCVIII, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0381] R 7 The deuterium enrichment is about 15% or more;

[0382] R 10 The deuterium enrichment is about 15% or more; and

[0383] R6 , R 8 , R 9 , R 11 and R 12 For hydrogen.

[0384] Embodiment CVI. A kit as described in Embodiment C, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0385] R 7 and R 8 The deuterium enrichment is about 15% or more;

[0386] R 10 and R 11 The deuterium enrichment is about 15% or more; and

[0387] R 9 and R 12 For hydrogen.

[0388] Embodiment CVII. A kit according to Embodiment LXXXIX, wherein the compound having Formula I is selected from the group consisting of:

[0389]

[0390] Embodiment CVIII. A kit according to Embodiment XC, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0391]

[0392] Embodiment CIX. The kit of Embodiment XC, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound having Formula I is selected from the group consisting of:

[0393]

[0394] In another embodiment, the compounds of the present disclosure are administered in combination with a second therapeutic agent that can be used to treat LSD, neurodegenerative diseases or migraine, restless legs syndrome or vertigo, or can be used to improve 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. In addition, the compounds of the present disclosure and the second therapeutic agent can be administered by a single composition or two separate compositions.

[0395] The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. The effective dosage range of 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 a determined range.

[0396] 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, or 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.

[0397] 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, cattle, 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.

[0398] Unless otherwise indicated, the term "treat" as used herein refers to eliminating, alleviating or ameliorating a disease or disorder and / or symptoms associated therewith. Although not excluded, treating a disease or disorder does not require complete elimination of the disease, disorder or symptoms associated therewith. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. Treatment can be directed to symptoms, for example, suppressing symptoms. It can work in the short term, for the medium term, or can be a long-term treatment, for example in the context of maintenance therapy.

[0399] As used herein, the term "prevention" refers to a method of preventing the onset of a disease or disorder and / or its associated symptoms or preventing a subject from developing a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its associated symptoms and reducing the risk of a subject developing a disease. The term "prevention" may include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or disorder or recurrence of a previously controlled disease or disorder in a subject who does not have a disease or disorder or a recurrence of a disease or disorder, but is at risk of recurrence of a disease or disorder or a recurrence of a disease or disorder, or is susceptible to recurrence of a disease or disorder or a recurrence of a disease or disorder.

[0400] As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of a compound of the present disclosure that, when administered by the methods of the present disclosure, is sufficient to deliver a compound for treating the disorder or disease of interest to a subject in need thereof and produce the desired effect in the subject. In the case of LSD or neurodegenerative diseases, a therapeutically effective amount of a compound of the present disclosure can, for example, delay the time to the onset of symptoms of LSD or markers associated with LSD or delay the time to the onset of symptoms of a neurodegenerative disease.

[0401] As used herein, the term "lysosomal storage disease" or "LSD" refers to any disorder involving dysfunction or disruption of the secondary endosomal / lysosomal system. LSD may involve an increase in the volume and / or pH of the endosomal / lysosomal system. LSD may also involve increased lipid or non-lipid storage.

[0402] LSDs may be defects of primary lysosomal hydrolases, defects in post-translational processing of lysosomal enzymes, defects in trafficking of lysosomal enzymes, defects in protection of lysosomal enzymes, defects in soluble nonenzymatic lysosomal proteins, defects in transmembrane (nonenzymatic) proteins, or unclassified defects.

[0403] Primary lysosomal hydrolase deficiencies include, but are not limited to, Gaucher disease (glucosylceramidase 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 type A and B (sphingomyelinase deficiency), metachromatic leukodystrophy (arylsulfatase A deficiency), MPS IH (Hurler syndrome; α-iduronidase deficiency), MPS IS (Scheie syndrome; α-iduronidase deficiency), MPS IH-S (Hurler-Scheie syndrome; α-iduronidase deficiency), MPS II (Hunter syndrome; iduronic acid sulfatase deficiency), MPS MPS IIIA (Sanfilippo A syndrome; heparan sulfamidase deficiency), MPS IIIB (Sanfilippo B syndrome; acetyl-α-glucosaminidase deficiency), MPS IIIC (Sanfilippo C syndrome; acetyl-CoA:α-glucosamine N-acetyltransferase deficiency), MPS IIID (Sanfilippo D syndrome; N-acetylglucosamine-6-sulfatase deficiency), MPS IV A (Morquio A disease; acetylgalactosamine-6-sulfatase deficiency), MPS IVB (Morquio B disease; β-galactosidase deficiency), MPS V (renamed MPS IS), MPS VI (Maroteaux Lamy syndrome; 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, Gaucher disease type 1 (non-neuronopathic), Gaucher disease type 2 / 3 (neuronopathic), ML1 (MLI;Sialidosis (alpha-N-acetylneuraminidase (sialidase) deficiency), ML2 (MLII, I-cell disease; N-acetylglucosamine phosphoryltransferase deficiency), ML3 (MLIII, pseudo-Hurler dystrophy; N-acetylglucosamine phosphoryltransferase deficiency), ML4 (MLIV, mucolipidase 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 - late infantile form of Turkey (CLN8), neuronal ceroid lipofuscinosis type 9 - late infantile form of Germany / Serbia (CLN9), neuronal ceroid lipofuscinosis type 10 (CLN10; congenital cathepsin D deficiency), pycnodystrophy (cathepsin K deficiency), infantile Pompe disease, late-onset Pompe disease, and cholesterol ester storage disease. ;

[0404] Defects in post-translational processing of lysosomal enzymes include, but are not limited to, mucosulfate deposition disease (MSD; multiple sulfatase deficiency).

[0405] Defects in the transport of lysosomal enzymes include, but are not limited to, mucolipidosis type II (I-cell disease; N-acetylglucosamine phosphoryltransferase deficiency), mucolipidosis type IDA (pseudo-Hurlary dystrophy; N-acetylglucosamine phosphoryltransferase deficiency), and mucolipidosis type IIIC.

[0406] Lysosomal enzyme protection defects include, but are not limited to, galactosialidase (protective protein cathepsin A (PPCA) deficiency), β-galactosidase deficiency, and neuraminidase deficiency. Soluble non-enzymatic lysosomal protein defects include, but are not limited to, GM2 activator protein deficiency (variant AB), sphingolipid activator protein (SAP) deficiency, and neuronal ceroid lipofuscinosis (NCL) (CLN5).

[0407] Transmembrane (non-enzyme) protein defects include, but are not limited to, Danon disease (lysosomal associated membrane protein 2 (LAMP2) defect), NPC (NPC1 and / or NPC2 defect), cystinosis (cystine transporter defect), infantile free sialic acid storage disease (ISSD; sialic acid transporter defect), sialic acid storage diseases (free sialic acid storage; sialic acid transporter defect), juvenile neuronal ceroid lipofuscinosis (CLN3, Batten disease), neuronal ceroid lipofuscinosis (NCL) (CLN6 and CLN8), and mucolipidosis type IV (mucolipin defects).

[0408] Unclassified defects include, but are not limited to, neuronal ceroid lipofuscinosis (NCL) (CLN4 and CLN7).

[0409] The LSD to be treated, delayed or ameliorated by the compounds, compositions and methods of the present disclosure is any of the following: NPC (NPC1 and / or NPC2 deficiency, primary or secondary), Smith-Lemli-Opitz syndrome (SLOS), inborn errors of cholesterol synthesis, 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 thioesterase deficiency.

[0410] In some embodiments, LSDs with significant central nervous system (CNS) involvement, such as, for example, NPC, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, or Fabry disease, are treated or delayed by the compounds of the present disclosure, as well as the compositions and methods described herein.

[0411] Niemann-Pick diseases are a heterogeneous group of autosomal recessive LSDs. Common cellular features include abnormal sphingomyelin (SM) storage in mononuclear phagocytes and parenchyma, and (hepato)splenomegaly. Of the three major subgroups (AC), NPC (formerly classified as NPC and NPD, now considered a single disease) is classified as a fatal neurovisceral LSD caused by the accumulation of unesterified cholesterol in secondary endosomal / lysosomal compartments induced by abnormal intracellular cholesterol transport.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] GM1 gangliosidosis is caused by a deficiency of the enzyme β-galactosidase, which results in the accumulation of GM1 ganglioside (monosialyl ganglioside 1) in lysosomes.

[0417] Fabry disease is caused by a deficiency of alpha-galactosidase, which results in the accumulation of ceramide trihexosylation in lysosomes.

[0418] As used herein, the term "neurodegenerative disease" refers to any disorder that affects neurons and involves the progressive loss of neuronal structure, the progressive loss of neuronal function, or the progressive death of neuronal cells.

[0419] 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 lobar degeneration, Gaucher disease, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, Lewy body dementia, lysosomal storage diseases, neuroborreliosis, Machado-Joseph disease, disease), multiple system atrophy, multiple sclerosis, multiple sulfatase deficiency, mucolipidosis, narcolepsy, Niemann-Pick disease type C, Niemann-Pick disease, Parkinson's disease, lower limb parkinsonism, Pelvic Illness, Pick's disease, Pompe disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjogren-Battenberg disease 5tten), cerebellar ataxia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, familial Tay-Sachs morbidity, dentate-rubral-pallidular Lewy body atrophy, paroxysmal ataxia (EA) 1, paroxysmal ataxia (EA) 2, paroxysmal ataxia (EA) 3, paroxysmal ataxia (EA) 4, paroxysmal Ataxia (EA) 5, paroxysmal ataxia (EA) 6, paroxysmal ataxia (EA) 7, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), autosomal recessive cerebellar ataxia type 1 (Beauce recessive ataxia (RAB)), autosomal recessive cerebellar ataxia type 2 (autosomal recessive spinocerebellar ataxia 9,SCAR9), ataxia with oculomotor ataxia type 1 (AOA1), ataxia with oculomotor ataxia type 2 (AOA2), ataxia with vitamin E deficiency (AVED), Friedreich's 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 fragmented red fibers (MERRF), neurogenic myopathy Asthenia, ataxia, and retinitis pigmentosa (NARP), Kearns-Sayre disease (KSS), fragile X tremor / ataxia syndrome (FXTAS), Arts syndrome, Christianson type X-linked syndrome mental retardation, X-linked sideroblastic anemia, idiopathic tardive cerebellar ataxia, sporadic adult-onset ataxia of unknown cause (SAOA), transmissible mink encephalopathy, chronic wasting disease, feline spongiform encephalopathy, exotic cloven-hoofed encephalopathy, Kuru, variant Creutzfeldt-Jakob disease, Gerstmann-Schmidt-Jakob disease, -Scheinker syndrome, fatal familial insomnia, hereditary motor and sensory neuropathy with proximal dominance, wiggly hedgehog syndrome (WHS), progressive muscular atrophy (Duchenne-Aran muscular dystrophy), progressive bulbar palsy, pseudobulbar palsy, HIV-associated neurocognitive disorder (HAND), Parkinson's disease, and scrapie.

[0420] 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 (Lincoln ataxia), spinocerebellar ataxia (SCA) 9 (Lincoln ataxia), spinocerebellar ataxia (SCA) 10 (Lincoln ataxia), spinocerebellar ataxia (SCA) 11 (Lincoln ataxia), spinocerebellar ataxia (SCA) 12 (Lincoln ataxia), spinocerebellar ataxia (SCA) 13 (Lincoln ataxia), spinocerebellar ataxia (SCA) 14 (Lincoln ataxia), spinocerebellar ataxia (SCA) 15 (Lincoln ataxia), spinocerebellar ataxia (SCA) 16 (Lincoln ataxia), spinocerebellar ataxia (SCA) 17 (Lincoln ataxia), spinocerebellar ataxia (SCA) 18 (Lincoln ataxia), spinocerebellar ataxia (SCA) 19 (Lincoln ataxia), spinocerebellar ataxia (SCA) 20 (Lincoln ataxia), spinocerebellar ataxia (SCA) 21 (Lincoln ataxia), spinocerebellar a 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), Spinal Ataxia (SCA) 19 / 22, Spinocerebellar Ataxia (SCA) 20, Spinocerebellar Ataxia (SCA) 21, Spinocerebellar Ataxia (SCA) 23, Spinocerebellar Ataxia 5 (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); with cystic involvement of the spinal cord cerebral ataxia), 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.

[0421] 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 neuropathic Gaucher disease. In one embodiment, the neurodegenerative disease is Sandhof 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.

[0422] The main symptoms of Parkinson's disease (PD) are stiffness, tremor and slow movement. These symptoms are also common in other diseases. These diseases and PD itself are all within the scope of the inclusive term Parkinson's disease. PD can be called primary Parkinson's disease. Other examples of Parkinson's disease include: multiple system atrophy, progressive supranuclear palsy, normal pressure hydrocephalus and vascular or arteriosclerotic Parkinson's disease. Those diseases that can be classified as Parkinson's disease but not PD are also called "Parkinson's superposition syndrome (Parkinson-Plus Syndrome)". Unlike PD patients, individuals with Parkinson's superposition syndrome do not respond to LDopa. As used herein, the term "Parkinson's disease" can refer to a movement syndrome whose main symptoms are tremor, stiffness, slow movement and unstable posture when at rest. Parkinson's syndrome can be divided into four subtypes according to its origin: primary or idiopathic, secondary or acquired, hereditary Parkinson's disease and Parkinson's superposition syndrome or multi-system degeneration.

[0423] In one embodiment, Parkinson's disease is Parkinson's plus syndrome or multisystem degeneration. In one embodiment, Parkinson's disease is vascular Parkinson's disease (arteriosclerotic Parkinson's disease; lower limb parkinsonism), multiple system atrophy with comparative parkinsonism (MSA-P), multiple system atrophy with cerebellar features (MSA-C; sporadic olivopontocerebellar atrophy (OPCA)), Shy-Drager syndrome, progressive supranuclear palsy (S-Lee-O'S syndrome), Lewy body dementia, Pick's disease or frontotemporal dementia, and Parkinson's disease associated with chromosome 17.

[0424] As used herein, the phrase "delaying the progression of LSD" and the like means delaying the onset of symptoms of LSD or markers associated with LSD in a subject, i.e., increasing the time of their appearance (compared to that normally observed). It may 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] The phrase "delaying the progression of a neurodegenerative disease" or "delaying the progression of a neurodegenerative disease associated with a lysosomal storage defect" refers to delaying the onset of a symptom of a neurodegenerative disease or a neurodegenerative disease associated with a lysosomal storage defect, or a marker 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 that normally observed). It may 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.

[0426] Thus, delaying progression includes, but is not limited to, delaying or preventing symptoms and / or complications caused by or associated with, for example, a LSD, a neurodegenerative disease, or a neurodegenerative disease associated with a lysosomal storage defect. When provided prophylactically, acetyl-leucine is generally provided prior to the onset of symptoms of the LSD, neurodegenerative disease, or a neurodegenerative disease associated with a lysosomal storage defect. Such prophylactic administration is generally to delay or prevent the onset of symptoms of a LSD, a neurodegenerative disease, or a neurodegenerative disease associated with a lysosomal storage defect.

[0427] "Symptoms" of LSD include any clinical or laboratory manifestations associated with LSD, and are not limited to what the subject can feel or observe. Symptoms described herein include neurological symptoms. Examples of neurological symptoms include ataxia, muscle tension disorders, vertical and horizontal supranuclear saccades / gaze palsies, and dementia. Also included are psychiatric symptoms, such as depression or psychosis. Most LSDs can be diagnosed based on subject history, clinical findings, biochemical markers, and genetic testing.

[0428] "Symptoms" of a neurodegenerative disease, optionally associated with a lysosomal storage defect, include any clinical or laboratory manifestation associated with a neurodegenerative disease, and are not limited to what a subject can feel or observe. Symptoms described herein include neurological symptoms.

[0429] Progression is said to be slowed when the time for LSD symptoms or LSD-related markers to appear or the time for symptoms of a neurodegenerative disease to appear is at least 5% longer than the time typically observed in subjects with an LSD or neurodegenerative disease. In some embodiments, the time observed is increased by 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%.

[0430] Disease treatment or progression can be assessed using one or more of the following: Scale for Assessment and Rating of Ataxia (SARA), Spinocerebellar Ataxia Functional Index (SCAFI), Modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L (EQ-5D-5L), Visual Analog Scale (VAS), Wechsler Adult Intelligence Scale-Revised (WAIS-R), Wechsler Intelligence Scale for Children, Version IV (WISC-IV), or Montreal Cognitive Assessment (MoCA). For some LSDs, such as NPC, specific scores have been developed and validated over the past several decades, such as the modified 6-domain NP-C Disability Scale (mDRS score). In this regard, some of the scores in these tests are characteristic of symptomatic LSD or neurodegenerative subjects. Thus, "delaying the progression of a LSD" or "delaying the progression of a neurodegenerative disease" can mean increasing the time required 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 symptomatic LSD subjects or neurodegenerative subjects (compared to that typically observed).

[0431] "Treating a neurodegenerative disease," "treating a neurodegenerative disease associated with a lysosomal storage defect," or "treating a LSD" can be equivalent to improving the results of SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, and / or MoCA scores, or another test suitable for characterizing a subject with a neurodegenerative disease or LSD. In some embodiments, treatment improves, for example, a score from a value characteristic of a symptomatic subject to a value characteristic of an asymptomatic subject.

[0432] Any changes in the progression of an LSD or neurodegenerative disease (e.g., over time or with treatment) can be monitored by using one or more well-established tests as further discussed herein at two or more time points and comparing the results.

[0433] Therefore, to assess the overall neurological status, the mDRS, a four-domain scale (walking, maneuvering, speech, and swallowing), can be applied. Cerebellar function can be assessed using the SARA, an eight-item clinical rating scale (gait, stance, sitting, speech, fine motor function, and reflex movements; range 0-40, where 0 is the best neurological status and 40 is the worst) and the SCAFI, which includes an 8-minute walk time (8MW; performed by asking the subject to walk from one line to another twice as quickly 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 assessed using the EQ-5D-5L questionnaire and the VAS. To assess oculomotor function, a 3-dimensional video-oculogram (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 assess cognitive status, the WAIS-R or WISC-IV and MoCA can be used, which assess 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. The technician will know how to conduct such tests.

[0434] As used herein, the term "treating migraine" means reducing the frequency of, alleviating or eliminating migraine headaches or one or more symptoms associated therewith.

[0435] As used herein, the term "preventing migraine" refers to preventing a migraine or one or more symptoms associated therewith. The compounds of the present disclosure may be used prophylactically.

[0436] As used herein, the term "relieve" means to make the migraine headache or one or more symptoms associated therewith less severe or less intense than when not undergoing treatment.

[0437] As used herein, the term "reducing the frequency of migraine headaches" means reducing the occurrence of migraine headaches or one or more symptoms associated therewith within a specified time frame relative to their occurrence in the absence of treatment.

[0438] In one embodiment, the compounds of the present disclosure may reduce the frequency, alleviate or eliminate one or more migraine symptoms selected from the group consisting of headache, tiredness, aura, nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smell, sweating, poor concentration, sensation of heat or cold, abdominal pain and diarrhea.

[0439] As used herein, symptoms associated with migraine include any clinical or laboratory manifestation associated with migraine and are not limited to what a subject can feel or observe.

[0440] In another embodiment, the present disclosure provides a compound of the present disclosure for use in the treatment or, more preferably, prevention of aura (eg, visual aura).

[0441] In another embodiment, the disclosure provides a compound of the disclosure for use in treating or preventing migraine associated with aura (eg, "classic migraine").

[0442] In another embodiment, the disclosure provides a compound of the disclosure for use in the treatment or prevention of migraine not associated with aura (eg, "common migraine").

[0443] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing aura associated with migraine.

[0444] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing aura not associated with migraine.

[0445] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing hemiplegic migraine. For this embodiment, migraine typically includes headache with motor weakness and aura.

[0446] In another embodiment, the present disclosure provides a compound of the present disclosure for use in the treatment or prevention of episodic hemiplegic migraine.

[0447] In another embodiment, the present disclosure provides a compound of the present disclosure for use in 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, which generally has the following characteristics:

[0448] A. At least 5 episodes of moderate or severe vestibular symptoms (defined by the Barany Society Vestibular Symptom Classification), each lasting 5 minutes to 72 hours;

[0449] B. Current or past history of migraine with or without aura according to the International Classification of Headache Disorders (ICHD);

[0450] C. At least 50% of vestibular attacks have one or more of the following migraine features:

[0451] 1. The headache has at least two of the following characteristics: unilateral location, pulsating nature, moderate or severe pain intensity, and aggravated by daily physical activities;

[0452] 2. Fear of light and sound;

[0453] 3. Visual aura;

[0454] D. Not better explained by another vestibular or ICHD diagnosis.

[0455] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing basilar migraine. For this embodiment, migraine typically includes headache and aura with one or more of the following symptoms: difficulty speaking, dizziness, tinnitus, and other brainstem-related symptoms.

[0456] In another embodiment, the disclosure provides a compound of the disclosure for use in treating or preventing retinal migraine. For this embodiment, retinal migraine typically includes headaches accompanied by visual disturbances or transient blindness.

[0457] In another embodiment, the disclosure provides a compound of the disclosure for use in the treatment or prevention of chronic migraine. As used herein, the term "chronic migraine" refers to a subject suffering from headaches for more than fifteen days per month over a three-month period without medication (as defined by the International Headache Society), of which more than eight days are migraines.

[0458] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing episodic migraine. As used herein, "episodic migraine" refers to a subject suffering from headaches less than fifteen days per month over a three-month period without drug treatment (as defined by the International Headache Society).

[0459] In another embodiment, the present disclosure provides a compound of the present disclosure for use in the treatment or prevention of acute migraine.

[0460] In another embodiment, the present disclosure provides a compound of the present disclosure for use in 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, cravings for certain foods, muscle stiffness (especially in the neck), constipation, diarrhea, and sensitivity to smells and noises.

[0461] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing pain associated with migraine.

[0462] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing one or more post-drome symptoms associated with migraine. Preferably, the post-drome symptoms are selected from one or more of the following: pain in the area where the migraine is located, impaired thinking, fatigue, headache, cognitive difficulties, gastrointestinal symptoms, mood changes and weakness.

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

[0464] In another embodiment, the present disclosure provides a compound of the present disclosure that reduces or eliminates aura.

[0465] In another embodiment, the disclosure provides a compound of the disclosure that reduces the frequency, alleviates or eliminates one or more symptoms selected from the group consisting of vision problems or visual disturbances, numbness or tingling, dizziness, balance problems, movement problems, speech difficulties and loss of consciousness.

[0466] In another embodiment, the disclosure provides a compound of the disclosure for preventing the occurrence of an aura, for example by preventing one or more of the above symptoms from occurring.

[0467] In one embodiment, the disclosure provides a compound of the disclosure for use in a method of improving cognitive function, mobility, or both cognitive function and mobility in a subject.

[0468] 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.

[0469] In another embodiment, the present disclosure provides a compound of the present disclosure for use in a method of improving mobility in a subject.

[0470] In another embodiment, the subject is an elderly subject.

[0471] 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.

[0472] 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.

[0473] In another embodiment, the cognitive function is one or more selected from the group consisting of perception, memory, image creation, consciousness, reasoning, thinking and judgment ability.

[0474] According to the present disclosure, the compounds of the present disclosure can be used to treat age-related decreases in cognitive function and / or mobility.

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

[0476] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating vertigo.

[0477] "Mobility" refers to a subject's ability to move. One or more simple tests can be used to assess mobility in older adults. For example, the "up and go" test is a simple test that measures mobility. In this test, the speed of going from sit to stand and walking to a target point is analyzed.

[0478] For example, the test can start with the subject sitting in a chair. At the beginning of the second, the subject should get up and walk to the target point without help. The target point can be 2-10m away, optionally 4-6m away. The second should stop when the subject reaches the target point. Any change in mobility (for example, over time or by treatment) can be monitored by using the "get up and walk" test and comparing the results at two or more time points. Other tests suitable for measuring mobility include those tests used for the Elderly Mobility Scale (EMS) (a 20-point validated assessment tool for assessing frail elderly subjects, taking into account movement, balance and key position changes).

[0479] As referred to herein, the phrase "improving mobility" means that there is a positive change in the subject's ability to move. Any of the above tests can be used to measure positive changes at two or more occasions, for example, the first occasion measures baseline mobility, and the second occasion measures the mobility after a period of time (wherein treatment may have been applied). The more confident the subject is due to improved stability (such as by treatment), the faster he or she completes the test. When performance is observed to improve by at least about 5% between two time points in a related test, it can be said that mobility is improved. For example, performance is observed to improve by 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% between two time points in a related test. In addition, for example, between two time points in a relevant test, it is observed that performance improves by 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%. Two time points can be separated by one week, two weeks, three weeks, four weeks, two months, three months, four months, five months or even six months. Treatment can be applied during the intervention period. Therefore, for example, "improving activity ability" can mean that the subject will show an increase in speed of at least about 5% relative to a baseline measurement, as measured using a "get up and walk" test as defined herein. For example, a subject may exhibit 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% increase in velocity in the test. In addition, for example, a subject may exhibit 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% increase in velocity in the test.

[0480] In one embodiment, the subject suffers from a movement disorder associated with aging.

[0481] As used herein, the term "movement disorder associated with aging" refers to a motor impairment that is a direct consequence of the aging process; this is in contrast to a motor impairment that is not a direct consequence of the aging process. The clinical presentation may differ between a subject with a movement disorder associated with aging and a subject with a motor impairment that is not a direct consequence of the aging process (e.g., a subject with ataxia). Ataxia may manifest as a subject stumbling when walking, while a movement disorder associated with aging may manifest as an increased tendency to fall. Thus, for example, cerebellar ataxia is not a movement disorder associated with aging.

[0482] In addition to the mobility assessments disclosed above, the motor ability of subjects with aging-related movement disorders can also be tested, for example, using balance assessments and / or by monitoring the number of falls experienced by the subject and / or using a "get-up-and-go" test.

[0483] In another embodiment, the present disclosure provides a compound of the present disclosure for use in improving balance in a subject, wherein the subject has impaired balance associated with aging. According to the present disclosure, the impaired balance associated with aging is not vertigo.

[0484] According to the present disclosure, a 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.

[0485] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating a balance disorder associated with aging.

[0486] In another embodiment, the disclosure provides a compound of the disclosure for use in increasing stability in a subject, for example while standing and / or walking, wherein the subject has decreased stability associated with aging.

[0487] In another embodiment, the present disclosure provides a compound of the present disclosure for use in reducing instability in a subject while walking, wherein the subject has increased instability associated with aging.

[0488] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating a subject with impaired gait, wherein the impaired gait is associated with aging.The subject may suffer from an elderly gait disorder.

[0489] In another embodiment, the present disclosure provides a compound of the present disclosure for use in increasing gait speed and / or cadence in a subject, wherein the subject has aging-related impairment of gait speed and / or cadence.

[0490] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating a subject with a tendency to fall, wherein the tendency to fall is associated with aging.

[0491] "Cognitive function" can refer to any mental process involving symbolic manipulation, such as perception, memory, image creation, consciousness, reasoning, thinking, and judgment. Measures of cognitive function include assessment tools designed to measure, for example: (a) general intelligence, (b) nonverbal 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 Test of Cognitive Abilities (both used to assess general intelligence), the Raven's Progressive Matrices (used to assess non-verbal intelligence), the Broad Achievement Test and the Woodcock-Johnson III Test of Achievement (used to assess academic achievement), the Connors Continuous Performance Test II (used to assess attention / executive function), the Broad Memory and Learning Assessment (used to assess memory and learning), the Bender Visuomotor Gestalt Test, the Halstead-Rattan Grip Strength Test, the Halstead-Rattan Finger Tapping Test, and the Lafayette Grooved Pegboard Task (all used to assess visual-motor and motor function), and the Peabody Picture Vocabulary Test (used to assess language).

[0492] Cognitive function can also be assessed using reaction speed and / or vigilance tests such as the psychomotor vigilance task (e.g., as disclosed in the Examples). This test assesses components including fine motor skills; psychomotor speed; distractibility; vigilance instability; and fatigue-induced impulsivity.

[0493] For example, the psychomotor vigilance task (PVT) is a sustained attention reaction timing task that measures the subject's reaction speed to visual stimuli. The subject monitors the screen and presses the screen as quickly as possible when the visual stimulus appears. The visual stimulus will then disappear and reappear (at irregular 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 based on, for example, the average of 10 reaction times. Any changes in cognitive function (e.g., over time or by treatment) can be monitored by using one or more of these well-established tests at two or more time points and comparing the results.

[0494] As referred to herein, the phrase "improving cognitive function" means that the subject's ability to perform symbolic operations (e.g., perception, memory, creating mental images, clear thinking, consciousness, reasoning, thinking or judgment) changes positively. Any of the above tests can be used to measure positive changes at two or more times, for example, the first time measures baseline cognitive function, and the second time measures cognitive function after a period of time (wherein treatment may have been administered). When performance is observed to improve by at least about 5% between two time points in a related test, it can be said that cognitive function is improved. For example, performance is observed to improve by 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% between two time points in a related test. In addition, for example, between two time points in a relevant test, performance is observed to improve by 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%. Two time points can be separated by one week, two weeks, three weeks, four weeks, two months, three months, four months, five months or even six months. Treatment can be applied during the intervention period. Therefore, as an example, "improving cognitive function" can mean that the subject will show a performance improvement of at least about 5% relative to a baseline measurement, as measured using a perfect Wei's Adult Intelligence Scale. For example, a subject may exhibit 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% improvement in performance in the test. In addition, for example, a subject may exhibit 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% improvement in performance in the test.

[0495] In another embodiment, the disclosure provides a compound of the disclosure for use in increasing a reaction speed (eg, a subject's reaction speed to a visual stimulus).

[0496] In one embodiment, the subject has cognitive decline associated with aging.

[0497] As used herein, the term "aging-related cognitive decline" refers to cognitive decline that is a direct consequence of the aging process; in contrast to cognitive decline that is not a direct consequence of the aging process. The clinical presentation may differ between a subject with aging-related cognitive decline and a subject with cognitive decline that is not a direct consequence of the aging process.

[0498] The term "improvement" when used to refer to mobility and / or cognitive function can include treating and / or alleviating any impairment of mobility and / or cognitive decline in a subject. Thus, use of the compounds of the present disclosure as described herein can partially or completely reverse age-related decline in mobility and / or cognitive function.

[0499] As used herein, the term "restless legs syndrome" or "RLS" includes any form of RLS, including primary RLS and secondary RLS. In one embodiment, RLS is primary RLS. In another embodiment, RLS is secondary RLS. In another embodiment, RLS is secondary to a disease or medical condition. Examples of such diseases or medical conditions 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 Sjögren's syndrome. In another embodiment, 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), high blood pressure 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 paraparesis, 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 lobar degeneration, narcolepsy, Pelvic floor disease, and spinal muscular atrophy). In one embodiment, the neurodegenerative disease is Parkinson's disease, including primary or idiopathic, secondary or acquired, hereditary Parkinson's disease and Parkinson's plus syndrome or multisystem degeneration. In another embodiment, the disease or medical condition is associated with dopaminergic system dysfunction (such as dopaminergic cell loss).

[0500] Symptoms associated with RLS include any clinical or laboratory manifestations associated with RLS. Symptoms of RLS are usually, but not necessarily, manifestations associated with the disease that can be felt or observed by the subject. Symptoms associated with RLS include, but are not limited to, calf sensations, periodic limb movements during sleep (PLMS), leg discomfort, movement urges, restlessness, sleep disorders, excessive daytime sleepiness, etc.

[0501] In another embodiment, the compounds of the present disclosure are used in a method of reducing, inhibiting or eliminating one or more symptoms associated with RLS in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0502] In another embodiment, the one or more symptoms are selected from any one or any combination of: calf sensation, periodic leg movements during sleep, leg discomfort, urge to move, restlessness, excessive daytime sleepiness, and sleep disturbances.

[0503] The severity of RLS or one or more symptoms of RLS can be assessed, for example, using a known scale, index, assessment or score. For example, a scale, index, assessment, score or other suitable test can correspond to the overall severity of RLS or to the severity of one or more symptoms associated with RLS. In one embodiment, the treatment described herein improves this assessment from a value or degree characteristic of a symptomatic subject to a value or degree characteristic of an asymptomatic subject.

[0504] In one embodiment, the treatment described herein improves this assessment compared to the baseline. The baseline can be, for example, the subject's condition before starting any RLS treatment or before starting to treat RLS with a compound of the present disclosure. Alternatively, the baseline can be, for example, the subject's condition after treating RLS for a period of time.

[0505] In one embodiment, treatment with a compound of the present disclosure reduces the subject's International Restless Legs Syndrome Research Group Rating Scale ("IRLS") compared to 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 baseline. In one embodiment, the IRLS is reduced by at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0506] 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.

[0507] Symptoms of vertigo include any clinical or laboratory manifestations associated with vertigo. Symptoms of vertigo include, but are not limited to, feeling sick, vomiting, abnormal eye movements or twitching (nystagmus), headache, sweating, tinnitus, and / or hearing loss.

[0508] In the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure, typically formulated in accordance with pharmaceutical practice, is administered to a subject in need thereof (e.g., a human being). Whether such treatment is necessary depends on the individual situation and requires a medical evaluation (diagnosis), which takes into account the presence of signs, symptoms, and / or dysfunction, the risk of developing specific signs, symptoms, and / or dysfunction, and other factors.

[0509] The compounds of the present disclosure can be administered by any suitable route, for example, by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal administration by lumbar puncture, transurethral, ​​transnasal, percutaneous puncture (i.e., percutaneous) or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation of a specific site). Parenteral administration can be accomplished using a needle and syringe or using high pressure techniques.

[0510] Pharmaceutical compositions include those in which the compounds of the present disclosure are administered in effective amounts to achieve their intended purpose. The exact formulation, route of administration, and dosage are determined by individual physicians based on the diagnosed illness or disease. Dosages and intervals may be adjusted individually to provide levels of the compounds of the present disclosure sufficient to maintain the therapeutic effect.

[0511] 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, for example, for determining the maximum tolerated dose (MTD) of a compound, which defines the highest dose that does not cause toxicity in an animal. The dose ratio between the maximum tolerated dose and the therapeutic effect (e.g., delaying the progression of an LSD or neurodegenerative disease) is the therapeutic index. The dose can vary within this range depending on the dosage form employed and the route of administration used. Determining a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0512] The therapeutically effective amount of the compound of the present disclosure for treatment varies with the nature of the disease being treated, the duration of the desired activity, and the age and disease of the subject, and is ultimately determined by the attending physician. The dose and interval can be adjusted individually to provide a plasma level sufficient to maintain the desired therapeutic effect. The desired dose can be conveniently administered in 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 desired or required. For example, the compound of the present disclosure can be administered at the following frequency: four doses, one dose delivered per day, four days apart (q4d x 4); four doses, one dose delivered per day, three days apart (q3d x 4); one dose delivered per day, five days apart (qd x 5); one dose delivered per week for three weeks (qwk3); five doses per day, two days off, and five doses per day (5 / 2 / 5); or, determine any dosage regimen suitable for the situation. Where long-term treatment is desired, the patient may be administered multiple doses 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 more).

[0513] 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 (including all doses between 1 and 1000 mg) per dose.

[0514] The compounds of the disclosure used in the methods of the disclosure may 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, a compound 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.

[0515] The total daily dose may be distributed over multiple administrations, i.e., two or more administrations may be required a day to achieve the desired dose. For example, the number of tablets required to provide the total daily dose of a compound of the present disclosure may be divided into two administrations (e.g., morning and evening) or three administrations (e.g., morning, noon, and evening).

[0516] The dosage of the composition containing the compound of the present disclosure or the composition containing it can be about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of the composition can be any dosage, including but not limited to about 1 μg / kg. The dosage of the composition can be any dosage, 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 g, 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 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45mg / kg, about 50mg / kg, about 60mg / kg, about 70mg / kg, about 80mg / kg, about 90mg / kg, about 100mg / kg, about 125mg / kg, about 150mg / kg, about 175mg / kg, about 200mg / kg or larger. The above dosage is an example of the general situation, but in individual cases, there should be higher or lower dosage, which is within the scope of the present disclosure. In practice, the doctor determines the actual dosage regimen that is most suitable for individual subjects, which can vary with the age, body weight and reaction of specific subjects.

[0517] Pill Box

[0518] In another embodiment, the disclosure provides a medicine box comprising a compound of the disclosure (or a composition comprising a compound of the disclosure), which is packaged in a manner that is conducive to them for practicing the method of the disclosure. In one embodiment, the medicine box includes a compound of the disclosure (or a composition comprising a compound of the disclosure) packaged in a container (such as a sealed bottle or a vessel), and a label (and / or instructions) affixed to the container or included in the medicine box describing the use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in unit dosage form. The medicine box can also include a device suitable for administering the composition according to the intended route of administration.

[0519] The term "container" means any container means and closure means suitable for storing, transporting, dispensing and / or handling a pharmaceutical product thereby.

[0520] The term "insert" means the information that accompanies a drug product and provides a description of how to administer the product, as well as the safety and effectiveness data needed to allow physicians, pharmacists, and subjects to make informed decisions about the product's use. The package insert is often considered the "label" for a drug product.

[0521] Personalized medicine

[0522] In another embodiment, the present disclosure provides a personalized medical program for subjects with LSD or neurodegenerative diseases, migraine, restless legs syndrome or vertigo and symptoms associated therewith, or subjects in need of improved mobility and / or cognitive function, and includes selecting treatment options with the highest likelihood of a successful outcome for individual subjects with LSD or neurodegenerative diseases, migraine, restless legs syndrome or vertigo and symptoms associated therewith, or subjects in need of improved mobility and / or cognitive function. In another aspect, the present disclosure relates to the use of assays to predict treatment outcomes, such as the likelihood of a favorable response or treatment success, in subjects with LSD or neurodegenerative diseases, migraine, restless legs syndrome or vertigo and symptoms associated therewith, or for subjects in need of improved mobility and / or cognitive function.

[0523] In another embodiment, the present disclosure provides a method of selecting a subject (e.g., a human subject) to treat 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 the biological sample from the subject for the presence of LSD-related biomarkers or neurodegenerative disease-related biomarkers, and selecting the subject for treatment if the biological sample contains the biomarker, e.g., an abnormal level of the biomarker in a body fluid, such as an accumulation or elevated level of the biomarker in the body fluid or a depletion or decreased level of the biomarker in the body fluid. In another embodiment, if the biological sample contains the biomarker, the method further comprises administering a therapeutically effective amount of a compound of the present disclosure to the subject. In another embodiment, the same method can be applied to a subject to treat migraine, restless legs syndrome, or vertigo and symptoms associated therewith, or to improve mobility and / or cognitive function.

[0524] In another embodiment, the present disclosure provides a method for predicting treatment outcomes in a subject with LSD or a neurodegenerative disease, the method comprising obtaining a biological sample from the subject, testing the biological sample from the subject for the presence of LSD-related biomarkers or neurodegenerative disease-related biomarkers, wherein the detection of the biomarkers indicates that the subject will respond favorably to the 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 typically expected in a subject with LSD or a neurodegenerative disease. In another embodiment, the same method for predicting treatment outcomes in a subject can be applied to a subject with migraine, restless legs syndrome, or vertigo and symptoms associated therewith, or to a subject in need of improved mobility and / or cognitive function.

[0525] In another embodiment, the present disclosure provides a method for treating LSD or a neurodegenerative disease, the method comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject (e.g., a human subject) suffering from LSD or a neurodegenerative disease, wherein the subject's cells contain LSD-related biomarkers or neurodegenerative disease-related biomarkers. In one embodiment, after determining that the subject's cells contain biomarkers (e.g., elevated levels of LSD-related biomarkers or neurodegenerative disease-related biomarkers or reduced levels of LSD-related biomarkers or neurodegenerative disease-related biomarkers), the subject is selected for treatment with 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 symptoms associated therewith, or to improve mobility and / or cognitive function.

[0526] In another embodiment, a method of treating a subject suffering from LSD or a neurodegenerative disease comprises obtaining a biological sample from the subject, determining whether the biological sample contains elevated levels of LSD-related biomarkers or neurodegenerative disease-related biomarkers or decreased levels of LSD-related biomarkers or neurodegenerative disease-related biomarkers, and administering to the subject a therapeutically effective amount of a compound of the present disclosure if the biological sample contains elevated levels or decreased levels of the biomarkers. In another embodiment, the same method can be applied to a subject to treat a subject suffering from migraine, restless legs syndrome, or vertigo and symptoms associated therewith, or to improve the subject's mobility and / or cognitive function.

[0527] 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, a protein fragment, a peptide, a polypeptide, a nucleic acid, etc. In addition, a biomarker can be a whole intact molecule, or it can be a part or a 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. Biomarkers can also be measured by HPLC-MS / MS. In some embodiments, a part or fragment of a biomarker can be detected or measured, for example, by an antibody or other specific binding agent. In some embodiments, the measurable aspects of a biomarker are related to a given state of a subject (such as a specific stage of LSD). For biomarkers detected at the protein or RNA level, such measurable aspects may include, for example, the presence, absence, or concentration (i.e., expression level) of a biomarker in a subject or a biological sample obtained from a subject. For biomarkers detected at the nucleic acid level, such measurable aspects may include, for example, the allele form of a biomarker or the mutation type, rate, and / or degree of a biomarker, also referred to herein as a mutation state.

[0528] As used herein, the term "LSD-associated 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 cellular pathological process associated with LSD. Examples of biomarkers associated with LSD include, but are not limited to, ceramide hexatriosylceramide (Gb3), lysoGb3, LysoGb3 analogs, or methylated / unmethylated Gb3 isoforms associated with Fabry disease; glucosylceramide, chitotriosidase (ChT), lung and activation-regulated chemokine (CCL18 / PARC), macrophage inflammatory protein 1-alpha and 1-beta (MIP-1α and MIP-1β), cathepsin K, ganglioside, GM3 / monosialyldihexosylganglioside, glucosylceramide, or osteopontin associated with Gaucher disease; galactosylceramide, galactosylceramide / togecin associated with Krabbe disease; dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin-6 sulfate, chondroitin-4,6 sulfate, hyaluronic acid, glycosaminoglycans associated with mucopolysaccharidoses. β-galactosidase, collagen Iα, fatty acid binding protein 5, nidogen-1, cartilage oligomeric matrix protein, insulin-like growth factor binding protein 7, or HEG1 associated with Niemann-Pick disease; sphingomyelin, free cholesterol (in fibroblasts), lyso-sphingomyelin (Lyso-SPM), cholestane-3β,5α,6βtriol (C-triol), 7-keto-cholesterol (7-KC), 24(S)-hydroxycholesterol, NPCBA1 (3β-hydroxy, 7β-N-acetylglucosaminyl-5-cholenic acid), NPCBA2 (probably 3β,5α,6β-trihydroxycholine-glycine), calcium binding protein D, lyso-sphingomyelin-509 associated with Pompe disease; and / or glycogen, tetrasaccharide glucose (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-associated biomarkers.

[0529] As used herein, the term "neurodegenerative disease-associated 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.

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

[0531] As used herein, the term "activity-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 activity.

[0532] As used herein, the term "cognitive function-related biomarker" refers to any biological compound, such as protein, protein fragment, peptide, polypeptide, nucleic acid, etc., which accumulates or decreases in a subject due to a decline or change in cognitive function.

[0533] In certain aspects of the disclosure, a biomarker is differentially present in one phenotypic state (eg, a subject with a LSD) compared to another phenotypic state (eg, a normal non-diseased subject).

[0534] 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, lyso-Gb3 can constitute a biomarker. Therefore, a "biomarker" can include one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty or more biological compounds.

[0535] Any of a number of methods known in the art can be used (e.g., using HPLC-MS / MS or Techniques) are used to determine the plasma levels of biomarkers 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.

[0536] As used herein, the term "biological sample" refers to any tissue or fluid suitable for detecting biomarkers (such as lyso-SM-509 plasma levels) from a subject. Examples of useful biological samples include, but are not limited to, biopsy tissue and / or cells, such as solid tumors, lymph nodes, inflammatory tissues, tissues and / or cells, blood, plasma, serous fluid, cerebrospinal fluid, saliva, urine, lymph, cerebrospinal fluid, etc. relevant to an illness or disease. Those of ordinary skill in the relevant art will be familiar with other suitable biological samples. Any technology known in the art can be used to analyze biomarker expression and / or mutations of biological samples, and technology within the common knowledge of clinical practitioners can be used to obtain biological samples. In one embodiment of the present disclosure, the biological sample includes hemocytes.

[0537] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects with LSD:

[0538] 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 cells of the subject contain elevated or decreased concentrations of LSD-associated biomarkers.

[0539] Embodiment II: A method of treating a subject suffering from LSD, the method comprising:

[0540] (a) determining the concentration of a LSD-associated biomarker in a biological sample from a subject, and when the concentration is determined to be higher than the concentration in a control sample (e.g., a sample from a normal non-diseased subject) or lower than the concentration in a control sample; and

[0541] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0542] Embodiment III: A method for treating LSD in a subject having elevated or decreased concentrations of LSD-associated biomarkers, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0543] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects with neurodegenerative diseases:

[0544] Embodiment I: A method of treating a subject having a neurodegenerative disease, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein cells of the subject contain elevated or decreased concentrations of biomarkers associated with the neurodegenerative disease.

[0545] Embodiment II: A method of treating a subject suffering from LSD, the method comprising:

[0546] (a) determining the concentration of a biomarker associated with a neurodegenerative disease in a biological sample from a subject, and when the concentration is determined to be higher than the concentration in a control sample (e.g., a sample from a normal non-diseased subject) or lower than the concentration in a control sample; and

[0547] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0548] Embodiment III: A method for treating a neurodegenerative disease in a subject having an elevated or decreased concentration of a neurodegenerative disease-associated biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0549] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects suffering from migraine and symptoms associated therewith:

[0550] Embodiment I: A method of treating a subject suffering from migraine and symptoms associated therewith, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, wherein cells of the subject contain elevated or decreased concentrations of migraine-associated biomarkers.

[0551] Embodiment II: A method of treating a subject suffering from migraine and symptoms associated therewith, the method comprising:

[0552] (a) determining the concentration of a migraine-associated biomarker in a biological sample from a subject, and when the concentration is determined to be higher than the concentration in a control sample (e.g., a sample from a normal non-diseased subject) or lower than the concentration in a control sample; and

[0553] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0554] Embodiment III: A method for treating migraine and symptoms associated therewith in a subject having elevated or decreased concentrations of a migraine-associated biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0555] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects in need of improved mobility:

[0556] 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 cells of the subject contain elevated or decreased concentrations of a mobility-related biomarker.

[0557] Embodiment II: A method of treating a subject in need of improved mobility, the method comprising:

[0558] (a) determining the concentration of a biomarker associated with motility in a biological sample from a subject, and when the concentration is determined to be higher than the concentration in a control sample (e.g., a sample from a normal non-diseased subject) or lower than the concentration in a control sample; and

[0559] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0560] Embodiment III: A method for improving mobility in a subject having an elevated or decreased concentration of a mobility-related biomarker, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0561] The present disclosure provides the following specific embodiments regarding personalized medicine for subjects in need of improved cognitive function:

[0562] 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 cells of the subject contain elevated or decreased concentrations of biomarkers associated with cognitive function.

[0563] Embodiment II: A method of treating a subject in need of improved cognitive function, the method comprising:

[0564] (a) determining the concentration of a biomarker associated with cognitive function in a biological sample from a subject, and when the concentration is determined to be higher than the concentration in a control sample (e.g., a sample from a normal non-diseased subject) or lower than the concentration in a control sample; and

[0565] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0566] Embodiment III: A method for improving cognitive function in a subject having elevated or decreased concentrations 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.

[0567] Example

[0568] Example 1

[0569] General preparation of deuterated N-acetyl-leucine

[0570] (D-enantiomer, L-enantiomer and D,L-mixture)

[0571] 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 in which D has an isotopic enrichment of 90% or more at each position. 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, e.g., 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).

[0572] Example 2

[0573] Preparation of D-leucine-based compounds

[0574] The synthesis of D-leucine and its labeled analogs can be achieved via the reductive amination of 2-oxo-4-methylpentanoic acid with D-amino acid dehydrogenase (DAADH).

[0575] The 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 hour 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 the mixture was clarified by centrifugation and filtration, the D-leucine produced could be separated and purified on a reverse phase column and detected using a fluorescence detector (350 nm excitation and 450 nm detection). Alternatively, a regeneration system using NADPH together 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 is incubated at 50° C. for 1 hour while maintaining the pH at 10.5 by adding 1.0 M KOH solution. D-leucine is separated and purified as described above. The above reaction can be carried out in deuterium dioxide to incorporate D on the α carbon. DAADH catalyzes the production of D-amino acids from the corresponding 2-oxo acid in the presence of ammonia and obtains excellent yields (> 99%) and high enantioselectivity (> 99%). (Akita et al., Biotechnol Lett 34: 1693 (2012) and Akita et al., Biotechnol Lett 36: 2245 (2014)).

[0576] Example 3

[0577] Method for converting racemic leucine into L-enantiomer

[0578] 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-aminotransferase coupled 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 with the aid of 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 an 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 analogs. This reaction is advantageous for reductive amination that is accelerated by combining with the formate dehydrogenase reaction. Formate dehydrogenase catalyzes the irreversible oxidation of formate to CO2 while reducing NAD+ to NADH. The α-oxo acids are spontaneously decarboxylated by oxidation with H2O2.

[0579] 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 hours, 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 (1x10cm) and L-leucine was eluted with 1M 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 (0.1M) can be converted to the L-enantiomer (yield 95%; ee 99% in 2 hours) based on separation using enantioselective HPLC with a Daicel Crown packed column (0.4idx 50cm) (Nakajima et al., J.Chem.Soc., Chem.Commun.13:947-948 (1990)).

[0580] Example 4

[0581] Preparation of N-acetylated forms of deuterated leucine analogs

[0582] Methods for N-acetylation of amines and α-amino acids, including leucine, have been widely reported. Deuterated leucine analogs synthesized by the methods reported above are not N-acetylated according to the methods described, and the resulting deuterated leucine analogs are N-acetylated by one of the following methods. In one of the methods described, the acetylating agent is acetic acid which is carried out as follows: (CH3CO)2O+H2N-CH(R)-COOH→CH3CONH-CH(R)-COOH+CH3COOH. The 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 is effectively carried out 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 amino acids to acetic anhydride is 1.25-1.5. The acetylated product can be crystallized from an 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 through 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 for 0.5 hours and crystallized while cooling. The reaction mixture was mixed for 40 minutes, and then hydrochloric acid (1060 ml, 37%) was added dropwise to a pH of 2.0-2.5. The resulting precipitate was collected by filtration, washed on the filter with ice water and alcohol successively, dried at 50-60°C, and then dried in air at 25-30°C. The anhydrous product was obtained by drying to constant weight in a vacuum at 85°C. Another 360 g of product was obtained after evaporating the acetic acid aqueous solution from the mother liquor in a rotary evaporator at a bath temperature of 70°C.

[0583] Example 5

[0584] Preparation of deuterated compounds at the α carbon (C-2)

[0585] A preparation for labeling the α position of amino acids starting from commercially available amino acids has been reported that 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 obtain racemic N-acetyleucine. A mixture of excess acetic anhydride and D2O is used to obtain a solution of Ac2O in AcOD. The amino acid is treated with this solution at reflux for several minutes, resulting in acylation, racemization, and exchange at the α position. N-acetyl-leucine is then the starting compound for enzymatic resolution using porcine kidney acylase, carboxypeptidase, or other enzymes that can selectively cleave the acetyl group from one stereoisomer without significantly cleaving enantiomeric compounds. In order to achieve high levels of exchange, a high 2H / 1H ratio is required. Such conditions can be approached in several ways: (a) a high molar excess of acetic acid-d relative to the amino acid can be used; (b) the labile hydrogen of the amino acid can be pre-exchanged; (c) the exchange reaction can be repeated. One treatment resulted in 83% exchange, and a second treatment increased the exchange level to 91%.

[0586] Full leucine (0.01 mol) was shaken with 3.7 mL of D2O to exchange unstable protons. The mixture was frozen and lyophilized. 21.7 mL of Ac2O and 2.5 mL of D2O were immediately added to the resulting powder and the flask was placed in a 170 ° C bath. The solution was refluxed for 2 minutes, then cooled (drying 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. Alpha hydrogens were detected by proton NMR spectroscopy with a yield of 80%.

[0587] In another example, leucine dehydrogenase can be used to catalyze the exchange of the α-proton, so that when the reaction is 2 When carried out in H2O, L-[2- 2 H] leucine. 2 The α-keto acid is pre-exchanged in H2O-base, and the deuteration effect is also extended to the β position. This method can synthesize various isotopically labeled α-amino acids, including gram quantities of [2,3,3- 2H3] Leucine. The formate dehydrogenase (FDH) catalytic system can be used to recycle NADH to prepare leucine from its α-keto acid and leucine dehydrogenase. Formate dehydrogenase catalyzes the oxidation of formate ions into carbon dioxide and releases hydride ions that react with NAD+, thereby promoting reversible reductive amination reactions in the desired direction. In addition, a general method for converting racemic amino acids into homochiral products using an oxidase-aminotransferase coupling system has been reported. (Kelly et al., Tetrahedron Lett. 37: 1517-1520 (1996) and Kelly et al., Nat. Prod. Rep. 14: 205-219 (1997)).

[0588] In another approach, enzyme-based conversion has proven valuable for the preparation of a range of α-deuterated L-amino acids, including leucine (Kelly et al., Tetrahedron Lett. 37: 1517-1520 (1996)). The method involves incubating unlabeled L-amino acids in D20 with lyophilized E. coli B / It7-A cells enriched with tryptophanase. The relatively broad substrate specificity enables the preparation of a range of α-deuterated L-amino acids, including leucine, in reasonable yields (43-95%).

[0589] In another method, racemic [2- 2 H] amino acids (Kelly et al., Tetrahedron Lett. 37:1517-1520 (1996)). Conversion of the acid to the methyl ester followed by alkaline protease-catalyzed resolution yields homochiral amino acids with >99% deuterium incorporation.

[0590] In another method, a chiral auxiliary and a template are used to synthesize α-deuterated α-amino acids (Rose et al., J. Chem. Soc., Perkin Trans. 1, 157-165 (1995)). Specifically, in refluxing MeO 2 H- 2 In H2O Base-catalyzed deuteration of bislactam ethers, (3R)- or (3S)-3-isopropyl-2,5-dimethoxy-3,6-dihydro-pyrazine, affords [6- 2 H2] isotope 9 without interfering with the stereocenter at C-3.

[0591] Chatterjee et al., Org. Lett. 18:5892–5895 (2016) have demonstrated ruthenium-catalyzed selective α-deuteration of amino acids. High deuterium incorporation, selectivity of α-CH2 protons over amine functional groups, and low catalyst loading make this protocol attractive and advantageous for laboratory and large-scale amino acid preparation. Complex 1 can be used to efficiently label amino acids, including leucine. Catalysis was performed on a range of amino acids using deuterium oxide, including leucine. See Table 3 of Chatterjee et al., Org. Lett. 18:5892–5895 (2016).

[0592] Example 6

[0593] Preparation of deuterated compounds at the β-carbon (C-3)

[0594] The aminotransferase-catalyzed exchange of α-protons for deuterium described in the above section can also be used to convert the α-protons to deuterium by reacting the α-protons with the aminotransferases described above before the enzymatic conversion. 2 Deuterium is incorporated into the β-position by pre-exchanging the α-keto acid in H2O-base, as described by Kelly et al., Tetrahedron Lett. 37:1517-1520 (1996). In another approach, some of the prochiral β-methylene groups can be exchanged using the enzyme cystathionine γ-synthase, which is suitable for preparing multigram quantities of homochiral deuterated L-leucine (Homer et al., Anal Biochem. 215:211-215 (1993)). The reaction is carried out in 33 mM Na2HPO4, 17 mM KH2PO4, 1 mM EDTA and 0.2 mM pyridoxal phosphate in 2 The assay was performed in a buffer solution (pH 7.2) in H2O. 2 After pre-exchange of solvent-exchangeable protons in H2O, L-leucine (20 mg / mL) was incubated with cystathionine γ-synthase at 37°C in the dark for three days. The product [2S,3R- 2 H2] leucine. To stereoselectively label the prochiral β-methylene group of L-leucine, a combined chemoenzymatic approach can be used as a guide for the synthesis of L-threo- and L-erythro-[1- 13 C,2,3- 2H2] amino acids (including leucine) are modified from methods reported previously (Oba et al., Tetrahedron Lett. 39: 1595-1598 (1998); Oba et al., J. Chem. Soc., Perkin Trans. 1, 1603-1609 (1995)). Stereoselective incorporation of deuterium into the α,β-position of protected amino acids is accomplished by catalytic deuteration of dehydrogenated amino acid derivatives followed by resolution with an acylase to afford L-threo-[2,3- 2 H2] amino acids. For the L-erythro isomer, the remaining D-threo isomer (from the initial resolution) needs to be racemized before further resolution. This approach can be extended to stereospecific labeling with deuterium combinations of β-methylene and prochiral δ-methyl groups.

[0595] Example 7

[0596] Preparation of deuterated compounds at the gamma carbon (C-4)

[0597] This chemoenzymatic method for labeling the delta carbon of L-leucine with deuterium, described in detail below (Fletcher et al., J. Chem. Soc., Perkin Trans. 1, 43-51 2000), can be used to synthesize leucine analogs with deuterium at the gamma carbon (C-4). This can be accomplished by using [ 2 H] sodium acetate as the isotope labeling source. For example, treatment of [2- 2 H] sodium acetate to obtain a mixed anhydride, which reacted with the lithium salt of 1 to give the acylated product 12 in 70% yield, which is [4- 2 H]-precursor of L-leucine.

[0598] Example 8

[0599] Preparation of deuterated compounds at the delta carbon (C-5)

[0600] A strategy for the stereoselective synthesis of leucine and valine bearing deuterium-labeled methyl groups has been reported.

[0601] In one method (Hill et al., Canadian Journal of Chemistry 72:10-113 (1994)), (R)-longifolia mint 1 is converted to (R)-citronellal 2 (R = H) according to published procedures. See Scheme 1. Reduction of the methyl ester 2 (R = CH3) with lithium aluminum deuteride gives citronellol-1,1-d2 3, which can be oxidized to citronellal-1-d 4 by pyridinium chlorochromate. The acidic hydrogen at C-2 is exchanged for deuterium by multiple exchanges with Na2CO3 in D2O-CH3OD to give citronellal-1,2,2-d35. Decarbonylation of the aldehyde is accomplished with Wilkinson's catalyst to give (6S)-[7,7,7- 2 H3]-2,6-dimethyl-2-heptene 6, into which a key asymmetric center containing a methyl group and a trideuterated methyl group was introduced, had a well-defined configuration and maintained the enantiomeric purity of pulegone. The double bond of 6 was oxidized to (4S)-[5,5,5-2~3]-4-methylpentanoic acid 7 by the Lemieux-Rudloff procedure (10). The amino group was introduced in a conventional manner by α-bromination followed by aminolysis, and the amino acid was resolved by hydrolysis of the N-acetyl derivative 9 catalyzed by porcine kidney acylase. The reaction produced the (2S,4S) diastereomer 10 of leucine-5-d3, and the acid hydrolysis of the recovered amide 11 gave the (2R,4S) diastereomer 12.

[0602] Solution 1

[0603]

[0604] Example 9

[0605] Synthesis of Acetyl-Leucine-2,3,3,4-d4 and Acetyl-L-Leucine-2,3,3,4-d4

[0606] Solution 2

[0607]

[0608] Step 1: 3-Methylbutanal-2,3-d2 (3).

[0609] 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) at room temperature. 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 (<2% remaining). Pd / C was removed by Celite filtration. The flask and filter were washed with D2O (3 x 4 mL). The filtrate and washings were combined, and the solution of 3-methylbutanal-2,3-d2 (3) in D2O was used as is in the next step. By 1 HNMR and GC-MS confirmed the structure of (3).

[0610] Step 2: 3-Methylbutanal-2,3,3-d3 (4).

[0611] 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 at 130° C. in a closed pressure tube overnight. 1 H-NMR analysis showed partial H / D exchange. The mixture was heated for an additional 5 days, after which complete deuterium incorporation was observed. The resulting solution of 3-methylbutyraldehyde-2,3,3-d3(4) in D2O / pyridine was used as is in the next step. 1 H NMR confirmed the structure of (4).

[0612] Step 3: 2-Hydroxy-4-methylpentanenitrile-3,3,4-d3 (5).

[0613] A crude solution of 3-methylbutanal-2,3,3-d3(4) (containing 0.1 eq pyridine in D2O) was cooled to 10 °C and sodium metabisulfite (11.73 g, 61.69 mmol) was added in small portions. After almost all the solids were 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 hours. The product was extracted with ethyl acetate (3x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give 2-hydroxy-4-methylvaleronitrile-3,3,4-d3(5) as an orange oil (4.8 g, 41 mmol). This material contained impurities but was used as is in the next step. 1 H NMR confirmed the structure of (5).

[0614] Step 4: 5-(2-Methylpropyl-1,1,2-d3)imidazolinidine-2,4-dione (6).

[0615] Finely powdered ammonium carbonate (9.3 g, 2.33 Eq, 96 mmol) was added to deuterium oxide (15 mL) and stirred until almost all of the solid was dissolved. Crude 2-hydroxy-4-methylvaleronitrile-3,3,4-d3 (5) (4.8 g, 1 Eq, 41 mmol) was transferred to the reaction mixture with the help of THF (15 mL). The mixture was heated at 100 °C in a sealed tube overnight. The volatiles (THF) were removed in vacuo, leaving a suspension in the deuterium oxide. The solid consisting primarily of the desired hydantoin 6 (2.6 g) was isolated 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 H-NMR spectrum showed that the incorporation rate of deuterium at the α position of the carbonyl group was 60%.

[0616] Step 5: Acetyl-Leucine-2,3,3,4-d4(1-rac)

[0617] 5-(2-Methylpropyl-1,1,2-d3)imidazoline-2,4-dione (6) (1.5 g, 1 Eq, 9.4 mmol) was suspended in a 40% solution of sodium deuteride 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% 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 at room temperature overnight. The solid was filtered off and 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 another 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 over a small silica gel plug using MeOH in DCM to remove inorganic impurities. This gave 430 mg (9.4 mmol, 29%) rac-acetyl-leucine-2,3,3,4-d4(1-rac) in >98% purity (ELSD). 1 H NMR and LCMS confirmed the structure of (1-rac).

[0618] Step 6: Acetyl-L-leucine-2,3,3,4-d4 (1)

[0619] Chiral resolution of acetyl-leucine-2,3,3,4-d4 (1-rac) was performed using chiral preparative HPLC. The concentrated fraction from the separation contained the ammonium salt of acetyl-L-leucine-2,3,3,4-d4. The 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.

[0620] Example 10

[0621] Synthesis of Acetyl-Leucine-2,3,3-D3 and Acetyl-L-Leucine-2,3,3-D3

[0622]

[0623] Acetyl-leucine-2,3,3-d3 and acetyl-L-leucine-2,3,3-d3 can be prepared using the method described in Example 9.

[0624] Embodiment 11

[0625] Measuring lysosomal volume using flow cytometry

[0626] The technology used in this study is described in te Vruchte et al., J. Clin. Invest. 3: 1320-1328 (2014). In short, human fibroblasts from patients with AB variants of familial Tay-Sachs disease were purchased from the NINDS human gene bank of the Coriell Institute, 403 Harden Avenue, Camden, New Jersey, USA (zip code 08103). Fibroblasts or Chinese hamster ovary cells were grown in T75 culture flasks, treated with compounds for 7 days, digested with trypsin, centrifuged (180g, 5 minutes), washed twice with 1x PBS, centrifuged again, and stained with 1ml 100nM LysoTracker-green DND-26 (Invitrogen) in PBS solution (10 minutes, in the dark). After incubation, cells were centrifuged (800 g, 5 minutes), resuspended in 0.5 ml FACS buffer (0.1% BSA, 0.02 M NaN3 in 1× PBS) and placed on ice for up to 1 hour before flow cytometric analysis (BD Biosciences FACSCanto II or Accuri C6 Plus). The hemocytometer was calibrated using Cytometer Setup and Tracking beads (BD) and compensated using Lysotracker or propidium iodide stained cells using BD FACSDiva software (BD) or BD Accuri C6 Plus software (BD).

[0627] 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, 1 mM acetyl-leucine-2,3,3,4-d4 showed a significant decrease in LysoTracker fluorescence levels compared to 1 mM acetyl-leucine. This effect was observed in both the NPC CHO cell line and the AB variant human fibroblast cell line. The results were Figure 1 and Figure 2 Shown in.

[0628] Example 12

[0629] Pharmacokinetic studies

[0630] 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 orally (po) to male BALB / c mice. Plasma and tissue samples were collected at pre-determined time points and analyzed using HR / MS. Plasma concentrations versus time were plotted in Figure 3-6Presented in.

[0631] Following oral administration of acetyl-leucine at a nominal dose of 100 mg / kg, the C of acetyl-D-leucine was reached 0.25 h after administration. max , is 86,100ng / ml, where AUC last The C of acetyl-L-leucine is 57,800 h*ng / ml; the C of acetyl-L-leucine is reached 0.25 hours after administration. max , is 3,410ng / ml, where AUC last is 2,600 h*ng / ml. Therefore, the ratio of L-type to D-type is max and AUC last Both are 0.04. Figure 3 .

[0632] Following 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 h post-dose. max , is 50,600ng / ml, where AUC last 99,600 h*ng / ml; the C of acetyl-L-leucine-2,3,3,4-d4(1) is reached 0.25 hours after administration max , is 3,880ng / ml, where AUC last is 3,430 h*ng / ml. Therefore, the ratio of L-form / D-form is max is 0.08, for AUC last is 0.03. Figure 4 .

[0633] Following oral administration of acetyl-L-leucine at a nominal dose of 100 mg / kg, the C of acetyl-D-leucine was reached 0.25 h after administration. max , is 436ng / ml, of which AUC last The C of acetyl-L-leucine was 573 h*ng / ml; the C of acetyl-L-leucine was reached 0.25 hours after administration. max , is 16,800ng / ml, of which AUC last is 11,400 h*ng / ml. Therefore, the ratio of L-form / D-form is max is 38.5, for AUC last is 19.8. Figure 5 .

[0634] Following oral administration of acetyl-L-leucine-2,3,3,4-d4 at a nominal dose of 100 mg / kg (1), the C of acetyl-D-leucine-2,3,3,4-d4 was reached 0.25 hours after administration. max , is 3,230ng / ml, of which AUC last The C of acetyl-L-leucine-2,3,3,4-d4(1) was 3,150 h*ng / ml; the C of acetyl-L-leucine-2,3,3,4-d4(1) was reached 0.25 h after administration. max , is 29,300ng / ml, where AUC last is 18,200 h*ng / ml. The ratio of L-form / D-form is max is 9.08, for AUC last is 5.78. Figure 6 .

[0635] These data indicate that the C of acetyl-D-leucine-2,3,3,4-d4 / acetyl-D-leucine increases when deuterated or non-deuterated acetyl-leucine is administered. max and AUC last The ratios of acetyl-L-leucine-2,3,3,4-d4(1) / acetyl-L-leucine are 0.59 and 1.72 respectively. max and AUC last The ratios are 1.14 and 1.32 respectively.

[0636] These data also show that the C of acetyl-D-leucine-2,3,3,4-d4 / acetyl-D-leucine increases when deuterated or non-deuterated acetyl-L-leucine is administered. max and AUC last The ratios of acetyl-L-leucine-2,3,3,4-d4(1) / acetyl-L-leucine are 7.40 and 5.50 respectively. max and AUC last The ratios are 1.75 and 1.61 respectively.

[0637] Now that the methods, compounds and compositions herein have been fully described, it will be understood by those skilled in the art that the same operations can be performed within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the methods, compounds and compositions provided herein or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or delaying the progression of a lysosomal storage disease, treating or delaying the progression of a neurodegenerative disease, treating or preventing migraine, treating or preventing restless legs syndrome, or treating or preventing vertigo.

5. The use according to claim 4, wherein the medicament is used to treat lysosomal storage disease or delay the progression of lysosomal storage disease.

6. The use according to claim 4, wherein the drug is used to treat a neurodegenerative disease or delay the progression of a neurodegenerative disease.

7. The use according to claim 4, wherein the medicament is used for treating or preventing migraine.

8. The use according to claim 4, wherein the medicament is used for treating or preventing restless legs syndrome.

9. The use according to claim 4, wherein the medicament is used for treating or preventing vertigo.

10. Use of the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for providing neuroprotection in a subject suffering from a lysosomal disorder.

11. A kit comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a subject to treat a lysosomal storage disease or delay the progression of a lysosomal storage disease, treat a neurodegenerative disease or delay the progression of a neurodegenerative disease, treat or prevent migraine, treat or prevent restless legs syndrome, or treat or prevent vertigo.

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