Deuterated analogs of acetyl-leucine

Abstract

To provide an improved method for treating lysosomal storage disorders.SOLUTION: Provided are compounds represented by Formula I, and pharmaceutically acceptable salts and solvates thereof: Wherein R1 is selected from the group consisting of hydrogen and C1 - (6-alkyl), R2 is C1 - (6-alkyl), R3 to R13 are each independently selected from the group consisting of hydrogen and deuterium, and the deuterium enrichment of any one or more of R3 to R13 is no less than about 15%. Also provided is a compound having Formula I for use in treating or delaying progression of a lysosomal storage disorder or a neurodegenerative disease, providing neuroprotection, treating or preventing migraine and symptoms associated therewith, or improving mobility and / or cognitive function in a subject.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides deuterated DL-, D-, and LN-acetylleucine analogs and their and deuterated DL-, D-, and LN-acetyl leucine alkyl ester analogs, and pharmaceutically acceptable salts and solvates thereof; The present disclosure also provides methods for treating or slowing the progression of lysosomal storage disorders. a method for providing neuroprotection in a subject having a lysosomal disorder; Methods for treating or slowing the progression of a neurodegenerative disease, comprising administering lysosomal Treating or slowing the progression of neurodegenerative diseases associated with defects in storage disorders Methods for treating or preventing migraine and related symptoms in a subject, rest Methods for treating or preventing less-legs syndrome and related symptoms, dizziness and and methods for treating or preventing symptoms associated with, or improving motor function and / or A method for improving cognitive function, comprising administering to a subject a deuterated N-acetyl leucine analog and a Pharmaceutically acceptable salts and solvates, or deuterated N-acetylleucine alkyl esters and administering to a subject phenylalanine analogs, and pharmaceutically acceptable salts and solvates thereof. Well, we provide a method. [Background technology]

[0002] Background technology Neurodegenerative diseases affect neurons, and the degenerative process is characterized by the progressive destruction of neuronal structures. Neurodegeneration may involve loss of function, progressive loss of neuronal function, or progressive neuronal cell death. Neurodegenerative diseases are often associated with defects in lysosomal storage diseases, including neurodegenerative lysosomal storage disorders. Alzheimer's disease and Parkinson's disease, which have been linked to lysosomal storage disorders and lysosomal defects, This includes many common neurodegenerative diseases, such as Parkinson's disease. Certain therapeutic agents may be used to treat diseases caused by underlying lysosomal storage disorders and other processes. This will have general application to neurodegenerative diseases, including those caused by neurotransmitters.

[0003] Lysosomal storage disorders (LSDs) are genetic disorders caused by defects in lysosomal homeostasis. LSD is a group of inherited metabolic disorders. LSD includes more than 70 disorders, with an overall clinical incidence of 1: These diseases are classified into two main groups: direct degradative pathways Primary storage disorders resulting from deficiency (typically lysosomal enzyme deficiency disorders) and downstream lysosomal These disorders can be classified as secondary storage disorders caused by dysfunction of rheumatoid arthritis proteins. Distinct LSDs resulting from the inactivation of different lysosomal proteins may produce similar conditions. Often shared. Most often involves multiple organs and tissues. Region-specific neurodegeneration. Symptoms are characteristic of most of these diseases.

[0004] Migraine is characterized by recurrent moderate to severe headaches. Typically, the headaches occur in the head. It affects half of the population, is pulsatile in nature, and lasts from 2 to 72 hours. Symptoms of migraine include vomiting, These include nausea, vomiting, and sensitivity to light, sound, or smell. It is emphasized by the activity. Approximately 15% of the world's population suffers from migraines.

[0005] Changes that occur with aging can cause problems with a person's ability to move around. Problems may include unsteadiness while walking, difficulty getting in and out of a chair, or falling. Muscle weakness, joint problems, pain, illness, and neurological disorders (brain damage) are common conditions in the elderly. and nervous system) can all cause motor impairment. , in combination, can have a serious impact on motor performance.

[0006] In addition to potential motor problems, all aging humans experience some degree of decline in cognitive abilities. Symptoms include forgetfulness, decreased ability to maintain concentration, decreased problem-solving skills, and Symptoms often include dementia and depression, or Alzheimer's disease. It can progress to more serious conditions such as Heimer's disease.

[0007] Oxidative stress and free radical damage, decreased hormone levels (estrogen, testosterone) steroids, DHEA, and pregnenolone), arterial lining (endothelial) dysfunction, insulin resistance to exercise, overweight, suboptimal nutrition, loneliness, lack of social networks, high stress Many factors are thought to contribute to age-related cognitive decline, including cognitive impairment.

[0008] Treating neurodegenerative diseases, LSD, and migraines, as well as improving motor and / or cognitive function Current therapeutic approaches to improve this condition are limited. For example, some LSDs affect the bone marrow. Responded to transplantation or enzyme replacement therapy. Clinical study of substrate synthesis inhibition therapy (SRT) using miglustat, an iminosugar drug Some benefits have also been reported in trials. Patterson, et al. ,Rev Neurol(separata)43:8(2006). Cerebellar ataxia (gait disorder) (showing improvement in ataxia) and Niemann-Pick Type C (NPC) (showing improvement in ataxia) Case studies of patients with acetyl-DL-leucine have also reported benefits. . Schniepp, R., et al., Cerebellum&Ataxias 3 :8(2016);Bremova,T.,et al.,Neurology 85: See 1368(2015).

[0009] Despite the beneficial effects of N-acetylleucine, there is a need for improved treatments for LSD It is also associated with defects in neurodegenerative diseases and lysosomal storage disorders. Developing improved treatments for neurodegenerative diseases, migraines, restless legs syndrome, and dizziness There is also a need for improved treatments to improve motor and / or cognitive function. needs to be developed. Summary of the Invention

[0010] In one aspect, the present disclosure provides compounds of the following formula, collectively referred to herein as "compounds of the present disclosure": A deuterated N-acetylleucine analogue represented by any one of I to V; and pharmaceutically acceptable salts and solvates thereof, and deuterated N-acetylleucine alkyl and alkyl ester analogs, as well as pharmaceutically acceptable salts and solvates thereof. The compounds of the present disclosure contain deuterium at an abundance at least 1000 times greater than the natural abundance of deuterium. It is enriched with at least one deuterium atom.

[0011] In another aspect, the present disclosure provides a method for treating or slowing the progression of LSD. and administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. provide.

[0012] In another aspect, the present disclosure provides a method of providing neuroprotection in a subject having an LSD. and administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. provide.

[0013] In another aspect, the present disclosure provides a method for treating neurodegenerative diseases or neurodegenerative disorders associated with lysosomal storage defects. A method for treating or slowing the progression of a sexually transmitted disease comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure. The method comprises administering the compound to a subject in need thereof.

[0014] In another aspect, a method for treating or preventing migraine and associated symptoms includes administering to a subject a therapeutically effective amount of and administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. do.

[0015] In another aspect, the present disclosure provides a method for improving motor and / or cognitive function, comprising treating and administering to a subject in need thereof an effective amount of a compound of the present disclosure. .

[0016] In another aspect, the present disclosure provides a method for treating or preventing restless legs syndrome and its associated symptoms. a method for preventing or preventing a rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof; The present invention provides a method for detecting a smeared image, the method comprising:

[0017] In another aspect, the present disclosure provides a method for treating or preventing dizziness and its associated symptoms. the method comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. Provide the law.

[0018] 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. and a carrier.

[0019] In another aspect, the present disclosure provides a method for treating or slowing the progression of LSD in a subject. and a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for the treatment of A composition is provided.

[0020] In another aspect, the present disclosure provides a method for the treatment of a pulmonary edema caused by a pulmonary edema (LSD) comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of steroid hormones, steroid hormones, and steroid hormones. and a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier. Provide something.

[0021] In another aspect, the present disclosure provides a method for treating a neurodegenerative disease associated with a lysosomal storage defect in a subject. or a compound of the present disclosure and an excipient for use in treating or slowing the progression of a neurodegenerative disease. and / or a pharmaceutically acceptable carrier.

[0022] In another aspect, the present disclosure provides a method for treating or preventing migraine and related symptoms. and a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for the The composition is provided in a subject.

[0023] In another aspect, the present disclosure provides a method for improving motor and / or cognitive function in a subject. and a pharmaceutical composition comprising a compound of the present disclosure and an excipient and / or a pharmaceutically acceptable carrier for the treatment of A composition is provided.

[0024] In another aspect, the present disclosure provides a method for treating restless legs syndrome and related conditions in a subject. A compound of the present disclosure and an excipient and / or pharmaceutical agent for use in the treatment or prevention of a condition. and a carrier acceptable thereto.

[0025] In another aspect, the present disclosure provides a method for treating or preventing dizziness and its associated symptoms in a subject. A compound of the present disclosure and an excipient and / or pharmaceutically acceptable carrier for use in the prevention of and (iii) a pharmaceutical composition comprising:

[0026] In another aspect, the present disclosure provides a method for treating or slowing the progression of LSD in a subject. The compounds of the present disclosure are provided for:

[0027] In another aspect, the present disclosure provides a method for the treatment of a pulmonary edema caused by a pulmonary edema (LSD) comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of steroid hormones, steroid hormones, and steroid hormones. The compounds of the present disclosure are provided as follows:

[0028] In another aspect, the present disclosure provides a method for treating a neurodegenerative disease or lysosomal storage defect in a subject. and (iii) providing a compound of the present disclosure for use in treating or slowing the progression of a neurodegenerative disease associated with rheumatoid arthritis. do.

[0029] In another aspect, the present disclosure provides a method for treating and preventing migraine and its associated symptoms in a subject. The present invention provides compounds of the present disclosure for use in

[0030] In another aspect, the present disclosure provides a method for improving motor and / or cognitive function in a subject. The compounds of the present disclosure are provided for:

[0031] In another aspect, the present disclosure provides a method for treating restless legs syndrome and related conditions in a subject. Provided are compounds of the disclosure for use in treating or preventing a Condition.

[0032] In another aspect, the present disclosure provides a method for treating or preventing dizziness and its associated symptoms in a subject. The present invention provides compounds of the present disclosure for use in preventing

[0033] In another aspect, the present disclosure provides a method for treating or slowing the progression of LSD in a subject. The present invention provides the use of a compound of the present disclosure for the manufacture of a medicament for treating atopic dermatitis.

[0034] In another aspect, the present disclosure provides a pharmaceutical composition for providing neuroprotection in a subject with an LSD. The present invention provides a use of a compound of the present disclosure for the manufacture of:

[0035] In another aspect, the present disclosure provides a method for treating a neurodegenerative disease or lysosomal storage defect in a subject. for the manufacture of a medicament for treating or slowing the progression of a neurodegenerative disease associated with , provides uses of the compounds of the present disclosure.

[0036] In another aspect, the present disclosure provides a method for treating or preventing migraine and its associated symptoms in a subject. The present invention provides the use of a compound of the present disclosure for the manufacture of a medicament for preventing

[0037] In another aspect, the present disclosure provides a method for improving motor and / or cognitive function in a subject. Provided is the use of a compound of the disclosure for the manufacture of a medicament.

[0038] In another aspect, the present disclosure provides a method for treating restless legs syndrome and related conditions in a subject. Use of a compound of the present disclosure for the manufacture of a medicament for treating or preventing a condition is provided. .

[0039] In another aspect, the present disclosure provides a method for treating or preventing dizziness and its associated symptoms in a subject. The present invention provides the use of a compound of the present disclosure for the manufacture of a medicament for preventing

[0040] In another aspect, the present disclosure provides a method for treating a neurodegenerative disease or lysosomal storage disorder that is an LSD in a subject. 2. A compound of the present disclosure for use in the treatment of a neurodegenerative disease associated with a deficiency of and a package insert containing instructions.

[0041] In another aspect, the present disclosure provides a method for treating or preventing migraine and its associated symptoms in a subject. a compound of the present disclosure for use in preventing and, optionally, a package insert containing instructions. Provide a kit.

[0042] In another aspect, the present disclosure provides a method for improving motor and / or cognitive function in a subject. and optionally, a package insert containing instructions for: do.

[0043] In another aspect, the present disclosure provides a method for treating restless legs syndrome and related conditions in a subject. a compound of the present disclosure for use in treating or preventing a condition, and optionally including instructions. and a package insert.

[0044] In another aspect, the present disclosure provides a method for treating or preventing dizziness and its associated symptoms in a subject. a compound of the present disclosure for use in preventing and, optionally, a package insert containing instructions. Provide a kit.

[0045] In another embodiment, the present disclosure provides a personalized therapeutic approach for a subject with an LSD or a neurodegenerative disease. provide a tailored medical procedure and have a high probability of success regarding the outcome of individual LSD or neurodegenerative subjects. This involves selecting the treatment option with the highest likelihood of success.

[0046] In another embodiment, the present disclosure provides an individualized method for treating migraine and related symptoms. providing a differentiated medical procedure for the treatment or management of migraine and related symptoms in a subject; This involves selecting the treatment options most likely to be successful in terms of prevention.

[0047] In another embodiment, the present disclosure provides a method for treating a person in need of improving motor and / or cognitive function. and providing a personalized medical procedure for a subject, the method comprising: It involves selecting the treatment option most likely to be successful in terms of improving function.

[0048] In another aspect, the disclosure provides methods of preparing the compounds of the disclosure.

[0049] Additional embodiments and advantages of the present disclosure are described in part in and may be derived from the following description. or may be learned by practice of the present disclosure. It will be realized and attained by means of the elements and combinations particularly pointed out in the claims.

[0050] Both the foregoing summary and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of the invention as claimed. It should be understood that this is not a limitation of the claimed invention. [Brief explanation of the drawings]

[0051] [Figure 1]Line graph showing the effect of acetyl-leucine (designated IB1000) and acetyl-leucine-2,3,3,4-d4 (designated DIB1000) in an NPC cell phenotypic assay. NPC CHO cells were treated with 1, 10, 100, 1000, and 5000 μM acetyl-leucine or acetyl-leucine-2,3,3,4-d4 for 7 days. 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 untreated samples (normalized as 1.0). Acetyl-leucine: 0.79 ± 0.05; acetyl-leucine-2,3,3,4-d4: 0.45 ± 0.03; unpaired t-test, two-tailed; **p<0.01, n=3.

[0052] [Figure 2] Bar graph showing the effect of acetyl-leucine (designated IB1000) and acetyl-leucine-2,3,3,4-d4 (designated DIB1000) in a Tay-Sachs AB human fibroblast assay. Fibroblasts from patients with a variant of Tay-Sachs AB disease were treated with 1 mM acetyl-leucine or acetyl-leucine-2,3,3,4-d4, and LysoTracker signals were compared. 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. Statistical analysis was performed using a one-way ANOVA. * / **p < 0.003 / 0.02.

[0053] [Figure 3] FIG. 1 is a line graph showing the plasma concentration versus time profiles of acetyl-D-leucine (referred to as N-acetyl-D-leucine) and acetyl-L-leucine (referred to as N-acetyl-L-leucine) after po administration of a 100 mg / kg dose of acetyl-leucine (referred to as N-acetyl-DL-leucine) in saline to male BALB / c mice.

[0054] [Figure 4]FIG. 1 is a line graph showing the plasma concentration versus time profiles of acetyl-D-leucine-2,3,3,4-d4 (also referred to as N-acetyl-D-leucine-d4) and acetyl-L-leucine-2,3,3,4-d4(1) (also referred to as N-acetyl-L-leucine-d4) after po administration of acetyl-leucine-2,3,3,4-d4(1-rac) (also referred to as N-acetyl-DL-leucine-d4) at a dose of 100 mg / kg in saline to male BALB / c mice.

[0055] [Figure 5] FIG. 1 is a line graph showing the plasma concentration versus time profiles of acetyl-D-leucine (referred to as N-acetyl-D-leucine) and acetyl-L-leucine (referred to as N-acetyl-L-leucine) after po administration of acetyl-L-leucine at a dose of 100 mg / kg in saline to male BALB / c mice.

[0056] [Figure 6] FIG. 1 is a line graph showing the plasma concentration versus time profiles 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 po administration of acetyl-L-leucine-2,3,3,4-d4(1) in saline at a dose of 100 mg / kg to male BALB / c mice. DETAILED DESCRIPTION OF THE INVENTION

[0057] The compounds of the present disclosure are useful for treating or slowing the progression of LSD in a subject. To provide neuroprotection in subjects with LSD, to treat neurodegenerative diseases or to slow the progression of the disease associated with a lysosomal storage defect in a subject. The present invention relates to administering to a subject a migraine or other neurodegenerative disorder to treat or slow the progression of the disorder. administering restless legs therapy to a subject to treat or prevent restless legs syndrome and related symptoms; and dizziness and vertigo in a subject to treat or prevent the syndrome and its associated symptoms. for treating or preventing symptoms associated therewith, or for improving motor function and / or It can be used to improve cognitive function.

[0058] In one embodiment, the compound of the present disclosure is a compound of formula I: [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0059] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0060] R 2 But C 1-6 is alkyl,

[0061] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0062] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 of The deuterium enrichment of any one or more of them is about 15% or more.

[0063] In another embodiment, the compounds of the present disclosure are compounds having Formula I, or a pharmaceutically acceptable salt thereof. a salt or solvate of

[0064] (a)R 13 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,

[0065] (b) The compound is not: [ka] TIFF2026016521000003.tif115170

[0066] In another embodiment, the compounds of the present disclosure are optically inactive compounds having Formula I, or The compound is a physiologically acceptable salt or solvate, i.e., the compound is racemic.

[0067] In another embodiment, the compounds of the present disclosure are optically active compounds having Formula I, or A pharmaceutically acceptable salt or solvate of

[0068] In another embodiment, the compounds of the present disclosure are compounds having formula II: [ka] 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 is related to formula I is as defined above.

[0069] In another embodiment, the compounds of the present disclosure are compounds having formula III: [ka] 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 is related to formula I is as defined above.

[0070] In another embodiment, the compounds of the present disclosure are compounds having formula IV: [ka] 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 is related to formula I is as defined above.

[0071] In another embodiment, the compounds of the present disclosure are compounds having formula V: [ka] 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 is related to formula I is as defined above.

[0072] In another embodiment, the compounds of the present disclosure have an enantiomeric excess (ee) of about 50% or greater. a compound having any one of formulas I to V, or a pharmaceutically acceptable salt thereof, In another embodiment, the ee is about 55% or more, about 60% or more, or about 65% or more, approximately 70% or more, approximately 75% or more, approximately 80% or more, approximately 85% or more, approximately 90% or more , about 95% or more, about 98% or more, or about 99% or more. , approximately 100%.

[0073] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen .

[0074] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is methyl do.

[0075] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V or a pharmaceutically acceptable salt or solvate thereof, wherein R 13 is hydrogen do.

[0076] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V 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 two or more of the following deuterium enriched is approximately 15% or more.

[0077] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V 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 Deuterium enrichment of any three or more of the following is approximately 15% or more.

[0078] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V or a pharmaceutically acceptable salt or solvate thereof, wherein R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Deuterium enrichment of any four or more of is approximately 15% or more.

[0079] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V 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 five or more of the following deuterium enriched is approximately 15% or more.

[0080] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V 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 Deuterium enrichment of any six or more of is approximately 15% or more.

[0081] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V 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 Any of seven or more deuterium enriched is approximately 15% or more.

[0082] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V 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 Deuterium enrichment of any eight or more of is approximately 15% or more.

[0083] In another embodiment, the compound of the present disclosure is a compound having any one of Formulas I-V or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0084] R 7 The deuterium enrichment is about 15% or more,

[0085] R 10 The deuterium enrichment is about 15% or more,

[0086] R 6 , R 8 , R 9 , R 11 , and R 12 is hydrogen.

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

[0088] R 7 and R 8 The deuterium enrichment is about 15% or more,

[0089] R 10 and R 11 The deuterium enrichment is about 15% or more,

[0090] R 9 and R 12 is hydrogen.

[0091] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of: A pharmaceutically acceptable salt or solvate thereof. [ka]

[0092] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of: A pharmaceutically acceptable salt or solvate thereof. [ka]

[0093] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of: A pharmaceutically acceptable salt or solvate thereof. [ka]

[0094] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of: A pharmaceutically acceptable salt or solvate thereof. [ka]

[0095] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of: A pharmaceutically acceptable salt or solvate thereof. [ka]

[0096] In another embodiment, the compound of the present disclosure is a compound selected from the group consisting of: A pharmaceutically acceptable salt or solvate thereof. [ka]

[0097] In another embodiment, the compound of the present disclosure is: [ka]

[0098] In another embodiment, the compound of the present disclosure is: [ka]

[0099] In another embodiment, the compound of the present disclosure is: [ka]

[0100] In another embodiment, the compound of the present disclosure is: [ka]

[0101] The term "N-acetyl-DL-leucine" or "acetyl-leucine" is used hereinafter It refers to a compound having the structure: [ka]

[0102] The term "N-acetyl-D-leucine" or "acetyl-D-leucine" means It refers to a compound having the structure below. [ka]

[0103] The term "N-acetyl-L-leucine" or "acetyl-L-leucine" means It refers to a compound having the structure below. [ka]

[0104] As used herein, "C 1-6 The term "alkyl" refers to a group of 1 to 6 carbon atoms. In another embodiment, the alkyl group is a straight-chain C 1-6 In another embodiment, the alkyl group is selected from a branched C 3-6 a In another embodiment, the alkyl group is selected from a linear C 1-4 Alkyl group In another embodiment, the alkyl group is selected from the group consisting of branched chain C 3-4 alkyl groups C 1-6 The term alkyl refers to an alkyl group containing at least about 1000 times more deuterium than the natural abundance of deuterium. and analogs having at least one deuterium in place of a hydrogen at greater than 2-fold abundance. Non-limiting exemplary C 1~6 Alkyl groups include methyl, -CH2D, -CHD2, and -CD 3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isopropyl These include 3-butyl, 3-pentyl, and hexyl.

[0105] Any one position in Formulas I-V is specifically designated as "H" or "hydrogen." When a position is designated as a hydrogen atom, that position is understood to have hydrogen at its natural abundance isotopic composition.

[0106] Any one position in Formulas I-V is specifically designated as "D" or "deuterium." When deuterium is present, the position is at least about 1% above the natural abundance of deuterium, which is about 0.015%. It is understood to have deuterium at 000 times greater abundance.

[0107] As used herein, the term "deuterium enriched" refers to a hydrogen atom in place of a hydrogen atom at that position. , refers to the percentage of deuterium incorporation at a given position in any one of Formulas I-V. In one embodiment, the deuterium enrichment is about 15% or more, i.e., less than the natural abundance of deuterium. In another embodiment, the deuterium enrichment is greater than about 20%, greater than about 25%, or greater than about 1000 times. or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 5 5% or more, approximately 60% or more, approximately 65% ​​or more, approximately 70% or more, approximately 75% or more, approximately 80% or more, Approximately 85% or more, approximately 90% or more, approximately 95% or more, approximately 98% or more, or approximately 99% or more In another embodiment, the deuterium enrichment is about 100%. Deuterium enrichment can be determined by mass spectrometry and It can be determined using conventional analytical methods known to those skilled in the art, including nuclear magnetic resonance spectroscopy. do.

[0108] As used herein, the term "stereoisomer" refers to any combination of the arrangement of their atoms in space. It is a general term for all isomers of individual molecules that differ only in orientation. This includes: Enantiomers and isomers of compounds with two or more chiral centers that are not mirror images of one another (diamers) stereomers).

[0109] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached. Refers to carbon atoms.

[0110] "Enantiomer" and "enantiomeric" c)" is not superimposable on its mirror image and is therefore optically active. An enantiomer is a molecule that rotates the plane of polarized light in one direction, and its mirror image compound is Rotates the plane of polarization in the opposite direction.

[0111] The term "racemic" refers to a mixture of equal parts of enantiomers, the mixture being optically It is essentially inactive.

[0112] The term "absolute configuration" refers to the spatial arrangement of atoms in a chiral molecular compound (or group) and its Stereochemical descriptions, e.g., R or S, are referred to.

[0113] Stereochemical terms and conventions used herein are those of Pure & A Chem 68:2193 (1996) means.

[0114] The term "enantiomeric excess" or "ee" refers to the amount of one enantiomer present relative to the other. For a mixture of R and S enantiomers, the enantiomeric excess is a measure of how much of a compound is present. The modulus is defined as |RS|*100, where R and S are balanced such that R+S=1. The optical resolution of a chiral substance is the mole or weight fraction of each enantiomer in a mixture. With knowledge of the enantiomeric excess, the enantiomeric excess is ([α] obs / [α] max )*100 is defined in the formula, obs is the optical rotation of a mixture of enantiomers, [α] max teeth , the optical rotation of pure enantiomers. NMR spectroscopy, chiral column chromatography or optical polarimetry, allowing determination of enantiomeric excess using a variety of analytical techniques is.

[0115] Salts and solvates, e.g., hydrates, of the compounds of the present disclosure may also be used in the methods disclosed herein. It can be used in

[0116] The present disclosure encompasses the preparation and use of salts of the disclosed compounds. "Pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of the present disclosure. Salts of the compounds of the present invention may be prepared during the final isolation and purification of the compounds or by converting the compounds to a suitable cation. The compounds of the present disclosure can be prepared separately by reacting them with an acid selected from the group consisting of benzophenone, benzophenone, benzotriazole ... Acceptable salts may be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form the salt include nitric acid, boric acid, hydrochloric acid, and hydrobromic acid. Inorganic acids such as benzoic acid, sulfuric acid, and phosphoric acid, as well as oxalic acid, maleic acid, succinic acid, and Non-limiting examples of salts of the compounds of the present disclosure include hydrochloride, bromine, and the like. Hydrogen chloride, hydrogen iodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphorus Acid salts, hydrogen phosphates, acetates, adipates, alginates, aspartates, benzoates Acid salt, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerol Phosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate , maleate, ascorbate, isethionate, salicylate, methanesulfonate Salt, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalene Sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate Phosphate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate Acetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecane Salt, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate Examples of suitable amines include, but are not limited to, sulfonates, and p-toluenesulfonates. Additionally, available amino groups present in the compounds of the present disclosure may be converted to methyl chloride, bromide, and iodide. , ethyl, propyl, and butyl; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and and diamyl sulfate; decyl chloride, bromide, and iodide, lauryl, myristyl, and stearyl and benzyl bromide and phenethyl bromide. Thus, any reference to a compound of the present disclosure appearing herein refers to the compound of the present disclosure, as well as to It is intended to include pharmaceutically acceptable salts, hydrates, or solvates of the compound.

[0117] The present disclosure encompasses the preparation and use of solvates of the compounds of the present disclosure. does not significantly alter the physiological activity or toxicity of the compound and is therefore a pharmacological equivalent. The term "solvate" as used herein refers to a compound of the present disclosure. a combination of, for example, a solvate, monosolvate, or hemisolvate, with a solvent molecule, physical association, and / or solvation, in which the ratio of solvent molecules to the compound of the present disclosure is The physical association is about 2:1, about 1:1, or about 1:2. In some cases, one or more solvent molecules The solvate will be capable of isolation, such as when incorporated in the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. The compounds of formula (I) are solvated with pharmaceutically acceptable solvents such as water, methanol, and ethanol. The present disclosure provides solvated and unsolvated forms of the compounds of the present disclosure. It is intended to include both aspects.

[0118] One type of solvate is a hydrate. "Hydrate" refers to a specific solvate in which the solvent molecule is water. Solvates typically function as pharmacological equivalents. The preparation of solvates is known in the art. For example, ethyl acetate and water can be used to prepare solvates. describes the preparation of solvates of fluconazole in M. Caira et al, J. See Pharmaceut. Sci., 93(3):601-611 (2004). Similar preparations of solvates, hemisolvates, hydrates, etc. are described by Tonder et al. AAPS Pharm.Sci.Tech.,5(1):Article 12(200 4),and ALBingham et al.,Chem.Commun.60 3-604 (2001). A typical, non-limiting preparation process for solvates is described below. The process involves incubating a compound of the present disclosure in a desired solvent (organic, aqueous, or a mixture thereof) at 20°C. Dissolve the compound at a temperature above about 25°C, then cool the solution at a rate sufficient to form crystals. , which may involve isolating the crystals by known methods, e.g., filtration. Analytical techniques such as can be used to confirm the presence of the solvent in the crystals of the solvate.

[0119] The terms "a," "an," "the," and "the" and the like in the context of describing this disclosure (especially The use of similar references (in the context of the claims) shall be construed as including the singular and the plural unless otherwise indicated. The recitation of ranges of values ​​herein should be construed to encompass both the plural and the plural. Unless otherwise indicated in the specification, a shorthand method of referring individually to each separate value falling within a range is used. are intended to function only as modulo factors, and each separate value shall be treated as if individually listed herein. Any and all examples or exemplary embodiments provided herein are incorporated herein by reference. The use of such language (e.g., "etc.") is intended to better illustrate the present disclosure, and in particular Unless claimed, no language in this specification is a limitation on the scope of the disclosure. , indicating no claimed element essential to the practice of the present disclosure. should not be interpreted as

[0120] Pharmaceutical Composition In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or excipient. provide.

[0121] The compounds of the present disclosure are typically selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions for use in accordance with the present disclosure are administered in admixture with pharmaceutical excipients. The compound of the present disclosure may be administered in the presence of one or more physiologically acceptable carriers, including excipients and / or adjuvants that facilitate processing of the compound of the present disclosure. These compounds may be formulated in a conventional manner using a physiologically acceptable carrier.

[0122] These pharmaceutical compositions can be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating or other suitable methods. The formulation may be prepared by encapsulation, entrapment, or freeze-drying processes. When a therapeutically effective amount of a compound of the present disclosure is administered orally, the composition The product is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition may further contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules, and powders may contain from about 0.01% to about 95%, e.g. For example, it contains about 1% to about 50% of a compound of the present disclosure. When administered in liquid form, it may contain water, petroleum, Alternatively, a liquid carrier such as an oil of animal or vegetable origin may be added. Forms include saline solution, dextrose or other sugar solution, or glycol. When administered in liquid form, the composition may contain from about 0.1% by weight to about 90% by weight of % by weight, for example, from about 1% to about 50% by weight of a compound of the present disclosure.

[0123] When a therapeutically effective amount of a compound of the present disclosure is administered by intravenous, cutaneous, or subcutaneous injection, The composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. pH, etc. The preparation of such parenterally acceptable solutions, taking into due consideration the tonicity, stability, etc., is well known to those skilled in the art. Compositions for intravenous, subcutaneous, or subcutaneous injection are typically isotonic Contains a sexual vehicle.

[0124] 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 listed in Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, PA, 19th ed. 1995. Suitable carriers include those that can be used to administer the active agent in the form of tablets, pills, dragees, capsules, or the like, for oral ingestion by the subject to be treated. It can be formulated as a pill, liquid, gel, syrup, slurry, suspension, etc. Pharmaceutical preparations for oral use may be prepared by adding suitable auxiliaries, if desired, to the present invention. A compound of the disclosure is added to a solid excipient, and optionally the resulting mixture is milled to form a granular mixture. The product can be processed to obtain tablets or dragee cores. Examples of suitable disintegrating agents include fillers and cellulose preparations. If desired, disintegrating agents may be added. It is possible.

[0125] The compounds of the present disclosure can be administered parenterally by injection, e.g., by bolus injection or continuous infusion. Injectable preparations can be formulated in unit dosage form, e.g., with added preservatives. The compositions may be presented in ampoules or multi-dose containers. The formulation may take the form of a suspension, solution, or emulsion containing suspending agents, stabilizing agents, and / or Alternatively, a compounding agent such as a dispersant may be included.

[0126] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Suspensions of the compounds may be prepared as appropriate oily injection suspensions. Solvents or vehicles include fatty oils or synthetic fatty acid esters. The liquid may include a substance that increases the viscosity of the suspension. Optionally, the suspension may also include: Contains suitable stabilizers or agents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions Alternatively, the compositions of the present invention can be dissolved in a suitable vehicle, such as a heat-generating It may be in powder form for composition with sterile water free of harmful substances.

[0127] The compounds of the present disclosure may also be administered rectally, for example, as suppositories or retention enemas, containing conventional suppository bases. In addition to the formulations described above, the compounds of the present disclosure can be formulated into depot preparations. Such long acting formulations can be formulated as implants (e.g., subcutaneously or intramuscularly). Intramuscular (intravenous) or intramuscular injection. Thus, for example, compounds of the present disclosure can be administered by: Suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or or ion exchange resins.

[0128] In particular, the compounds of the present disclosure, either alone or in admixture with excipients, are useful in the preparation of starch or In the form of tablets containing excipients such as lactose, or in capsules or ovules. (ovules) or elixirs or containing flavoring or coloring matter It can be administered orally, bucally, or sublingually in the form of a suspension. The product can be prepared using pharmaceutically acceptable additives such as suspending agents. The compounds can also be administered parenterally, for example, by intravenous, intramuscular, subcutaneous, or intracoronary injection. For parenteral administration, the compounds of the present disclosure are typically administered in solutions that are isotonic with blood. To achieve this, other substances, e.g., salts or simple sugars such as mannitol or glucose, may be included. It is used in the form of a sterile aqueous solution that can be swallowed.

[0129] In one embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. The solid pharmaceutically acceptable carrier may include flavoring agents, buffers, lubricants, stabilizers, Solubilizers, suspending agents, wetting agents, emulsifiers, dyes, fillers, flow agents, compression aids, inert binders one that may also function as a flavoring agent, sweetener, preservative, dye, coating agent, or tablet disintegrant The carrier may also be an encapsulating material. In powders, the carrier is The invention is a micronized solid mixed with a micronized active agent. In tablets, the active agent is The composition can be mixed in suitable proportions with a carrier having suitable compression properties and compressed into a desired shape and size. Powders and tablets may contain up to 99% of the active ingredient. Suitable solid carriers include, for example, lysates. Calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, Starch, gelatin, cellulose, polyvinylpyrrolidine, low melting wax, and ions In another embodiment, the pharmaceutically acceptable carrier may be a gel, and the composition The product may be in the form of a cream or the like.

[0130] A carrier may include one or more excipients or diluents. Examples of such excipients are gelatin, Ingredients: gum arabicum, lactose, microcrystalline cellulose, denatured milk Starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate These include silica, talc, and colloidal silicon dioxide.

[0131] In another embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is in the form of a solution. Liquid carriers are used in solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. The compounds of the present disclosure may be used in the preparation of aqueous, organic solvents, mixtures of both, or pharmaceutical compositions. Dissolved or suspended in a pharmaceutically acceptable liquid carrier such as 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, coloring agents, viscosity regulators, stabilizers, or osmotic agents Suitable examples of liquid carriers for oral and parenteral administration include water (including the above-mentioned additives). Additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose partially containing liquid), alcohols (monohydric and polyhydric alcohols, e.g., glycosaminoglycans, oils (including fractionated coconut oil) and their derivatives, For parenteral administration, Carriers have also been oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for the pressurized composition may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. It could be.

[0132] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered, for example, intramuscularly, intrathecally, epidurally, intraperitoneally, or intraperitoneally. It can be administered by intravenous, intravenous, and especially subcutaneous injection. Can be dissolved or suspended at the time of administration using saline or other appropriate sterile injectable medium It may be prepared as a sterile solid composition.

[0133] The compounds and compositions of the present disclosure may contain other solutes or suspending agents (e.g., to make the solution isotonic). (sufficient saline or glucose), bile salts, acacia, gelatin, sorbitan mononitrate Polysorbate 80 (oleic acid ester of sorbitol and ethylene glycol) It is administered orally in the form of a sterile solution or suspension, including but not limited to benzodiazepines, ... It is possible.

[0134] The compounds of the present disclosure and compositions thereof may also be administered orally in either liquid or solid composition form. Compositions suitable for oral administration include pills, capsules, granules, tablets, and solid forms, such as powders and tablets, as well as liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. do.

[0135] Alternatively, the compounds of the present disclosure and compositions thereof may be administered by inhalation (e.g., intranasally). The compositions may also be formulated for topical use, for example, as a cream or The ointment may be applied to the skin.

[0136] The compounds of the present disclosure and compositions thereof may be incorporated into slow or delayed release devices. Such devices may, for example, be inserted into the skin or under the skin and the medication may be administered for several weeks or Such devices may be used for long-term treatment with the compounds of the present disclosure. is required, usually requiring frequent administration (e.g., at least daily administration). This can be particularly advantageous.

[0137] In another embodiment, the pharmaceutical composition is in the form of a tablet suitable for oral administration. The disclosed compounds are mixed in suitable proportions with a vehicle having the necessary compression characteristics to form the desired shape and The tablets may contain up to 99% by weight of the compound of the present disclosure.

[0138] Pharmaceutical formulations in solid oral dosage form, such as tablets, may be prepared by any method known in the art of pharmacy. Pharmaceutical formulations typically contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the following manner: It is prepared by mixing with a conventional pharmaceutically acceptable carrier, diluent, or excipient. do.

[0139] How to use In another embodiment, the present disclosure provides a method for treating or slowing the progression of a lysosomal storage disorder. The method comprises administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. and

[0140] In another embodiment, the present disclosure provides neuroprotection in a subject with a lysosomal storage disorder. The method comprises administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. and

[0141] In another embodiment, the present disclosure provides a method for treating or slowing the progression of a neurodegenerative disease. The method includes administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. Well, we provide a method.

[0142] In another embodiment, the present disclosure provides a method for treating a neurodegenerative disease associated with a lysosomal storage defect. a method for preventing or delaying the progression of a steroid drug, comprising administering a therapeutically effective amount of a compound of the present disclosure to a patient in need thereof. and administering to a subject in need thereof.

[0143] In another embodiment, a method for treating or preventing migraine and its associated symptoms comprises The present invention provides a method for treating a rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. Provide.

[0144] In another aspect, the present disclosure provides a method for improving motor and / or cognitive function, comprising treating and administering to a subject in need thereof an effective amount of a compound of the present disclosure. .

[0145] In another aspect, the present disclosure is a method of treating or preventing restless legs syndrome. and administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. provide.

[0146] In another aspect, the present disclosure provides a method for treating or preventing dizziness, comprising administering a therapeutically effective amount of Methods are provided that include administering the disclosed compounds to a subject in need thereof.

[0147] The present disclosure also provides the following specific embodiments.

[0148] Embodiment I. A method of treating or slowing the progression of a lysosomal storage disorder. a therapeutically effective amount of a compound of the present disclosure having Formula I (see above) or a pharmaceutically acceptable salt thereof administering to a patient in need thereof an acceptable salt or solvate thereof, wherein:

[0149] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0150] R 2 is C 1-6 is alkyl,

[0151] R 3 , R 4 , R 5 , R 6 , R 7, R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0152] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 of The method, wherein the deuterium enrichment of any one or more of the components is about 15% or more.

[0153] Embodiment II. Method of Providing Neuroprotection in a Subject with a Lysosomal Storage Disorder Methods for treating or slowing the progression of degenerative diseases or lysosomal storage defects Methods for treating or slowing the progression of neurodegenerative disorders associated with neurodegenerative disorders, migraine and Methods for treating or preventing symptoms associated therewith, restless legs syndrome and Methods for treating or preventing dizziness and related symptoms, dizziness and related symptoms or to improve motor and / or cognitive function. a therapeutically effective amount of a compound of the present disclosure having Formula I (see above) or a pharmaceutically acceptable salt thereof administering to a subject in need thereof an acceptable salt or solvate thereof, wherein:

[0154] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0155] R 2 is C 1-6is alkyl,

[0156] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0157] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 of The method, wherein the deuterium enrichment of any one or more of the components is about 15% or more.

[0158] Embodiment III. The compound of embodiment I or Method II.

[0159] Embodiment IV. The optically active compound having formula I is a compound having formula II (see above). (see above).

[0160] Embodiment V. The compound having formula I is a compound having formula III (see above). ). The method of embodiment III, wherein

[0161] Embodiment VI. The compound having formula I is a compound having formula IV (see above). ). The method of embodiment III, wherein

[0162] Embodiment VII. The compound having formula I is a compound having formula V (see above). ). The method of embodiment III, wherein

[0163] Embodiment VIII.R 1 The method of any one of embodiments I-VII, wherein is hydrogen.

[0164] Embodiment IX. R 2 But, -CR 2a R 2b R 2c and

[0165] R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium;

[0166] R 2a , R 2b , and R 2c Deuterium enrichment of at least one of the following is approximately 15% or more: In another embodiment, R 2a , R 2 b , and R 2c are hydrogen, i.e., R 2 is methyl.

[0167] Embodiment XR 13 The method of any one of embodiments I-IX, wherein is hydrogen.

[0168] Embodiment XI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any two or more of Either one method.

[0169] Embodiment XII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment XI, wherein the deuterium enrichment of any three or more of method.

[0170] Embodiment XIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 and wherein the deuterium enrichment of any four or more of I's method.

[0171] Embodiment XIV.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any five or more of I's method.

[0172] Embodiment XV.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment XIV, wherein the deuterium enrichment of any six or more of method.

[0173] Embodiment XVI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment XV, wherein the deuterium enrichment of any seven or more of method.

[0174] Embodiment XVII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 and wherein the deuterium enrichment of any eight or more of I's method.

[0175] Embodiment XVIII.

[0176] R 7 The deuterium enrichment is about 15% or more,

[0177] R 10 The deuterium enrichment is about 15% or more,

[0178] R 6 , R 8 , R 9 , R 11 , and R 12 is hydrogen; or A pharmaceutically acceptable salt or solvate thereof.

[0179] Embodiment XIX.

[0180] R 7 and R 8 The deuterium enrichment is about 15% or more,

[0181] R 10 and R 11 The deuterium enrichment is about 15% or more,

[0182] R 9 and R 12 is hydrogen, or a pharmaceutically acceptable salt thereof. A salt or solvate thereof.

[0183] Embodiment XX. An embodiment wherein the compound having Formula I is selected from the group consisting of: Method I or II. [ka]

[0184] Embodiment XXI. The compound having Formula I is selected from the group consisting of: The method of Form III, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0185] Embodiment XXII. The compound having Formula I is selected from the group consisting of: Form III of the method, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0186] Embodiment XXIII. A compound of the present disclosure having formula I (see above), or A pharmaceutically acceptable salt or solvate thereof,

[0187] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0188] R 2 But C 1-6 is alkyl,

[0189] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

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

[0191] For use in methods of treating or slowing the progression of lysosomal storage disorders. a compound of the present disclosure having formula I above, or a pharmaceutically acceptable salt or solvate thereof, for Japanese food.

[0192] Embodiment XXIV. Providing neuroprotection in subjects with lysosomal disorders, neurodegenerative diseases and for the treatment or delay of progression of neurodegenerative diseases associated with lysosomal storage defects. Treatment or prevention of migraines and related symptoms, restless legs Treatment or prevention of vertigo syndrome and related symptoms, dizziness and related symptoms A compound of formula I for use in the treatment or prevention, or for improving motor and / or cognitive function. or a pharmaceutically acceptable salt thereof, A solvate comprising:

[0193] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0194] R 2 But C 1-6 is alkyl,

[0195] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0196] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 of The deuterium enrichment of any one or more of these is about 15% or more.

[0197] A compound of the present disclosure having the formula I above, or a pharmaceutically acceptable salt or solvate thereof .

[0198] Embodiment XXV. The compound having Formula I is optically active. Compounds I or XXIV for use.

[0199] Embodiment XXVI. The optically active compound having Formula I is a compound having Formula II The compound for use according to embodiment XXV, wherein: (see above).

[0200] Embodiment XXVII. The compound having Formula I is a compound having Formula III (see above). The compound for use according to embodiment XXV, wherein

[0201] Embodiment XXVIII. The compound having Formula I is a compound having Formula IV (see above). The compound for use according to embodiment XXV, wherein

[0202] Embodiment XXIX. The compound having formula I is a compound having formula V (see above). and).

[0203] Embodiment XXX.R 1 Any one of embodiments XXIII-XXIX, wherein is hydrogen. Compounds for use in

[0204] Embodiment XXXI.

[0205] R 2 But, -CR 2a R 2b R 2c and

[0206] R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium;

[0207] R 2a , R 2b , and R2c Deuterium enrichment of at least one of the following is approximately 15% or more: The compound for use according to any one of embodiments XXIII to XXX, wherein So, R 2a , R 2b , and R 2c are hydrogen, i.e., R 2 is methyl do.

[0208] Embodiment XXXII.R 13 is hydrogen. or compound for one use.

[0209] Embodiment XXXIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 wherein the deuterium enrichment of any two or more of A compound for use in any one of XXIII to XXXII.

[0210] Embodiment XXXIV.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any three or more of Compounds for use according to XXIII.

[0211] Embodiment XXXV.R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 Embodiment XX, wherein the deuterium enrichment of any four or more of Compound XIV for use.

[0212] Embodiment XXXVI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and embodiment X, wherein the deuterium enrichment of any five or more of Compounds for use in XXV.

[0213] Embodiment XXXVII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12

[0023] In an embodiment, the deuterium enrichment of any six or more of Compounds for use according to formula XXXVI.

[0214] Embodiment XXXVIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 1 1 , and R 12 The deuterium enrichment of any seven or more of the following embodiments is about 15% or greater: Compounds for use in form XXXVII.

[0215] Embodiment XXXIX.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and embodiment X, wherein the deuterium enrichment of any eight or more of Compounds for use according to XXVIII.

[0216] Embodiment XL.

[0217] R 7 The deuterium enrichment is about 15% or more,

[0218] R 10 The deuterium enrichment is about 15% or more,

[0219] R 6 , R 8 , R 9 , R 11 , and R 12 Use of embodiment XXXIII, wherein is hydrogen. or a pharmaceutically acceptable salt or solvate thereof.

[0220] Embodiment XLI.

[0221] R 7 and R 8 The deuterium enrichment is about 15% or more,

[0222] R 10 and R 11 The deuterium enrichment is about 15% or more,

[0223] R 9 and R 12 is hydrogen; or A pharmaceutically acceptable salt or solvate.

[0224] Embodiment XLII. The compound having Formula I is selected from the group consisting of: Compounds for use in Form XXIII or XXIV. [ka]

[0225] Embodiment XLIII. The compound having Formula I is selected from the group consisting of: The compound, or a pharmaceutically acceptable salt or solvate thereof, for use according to embodiment XXV. [ka]

[0226] Embodiment XLIV. The compound having Formula I is selected from the group consisting of: The compound for use in Form XXV, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0227] Embodiment XLV. For treating or delaying the progression of lysosomal storage disorders A compound of the present disclosure having formula I (see above), or a compound thereof, in the manufacture of a medicament. The use of a physiologically acceptable salt or solvate of

[0228] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0229] R 2 But C 1-6 is alkyl,

[0230] R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0231] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 of The deuterium enrichment of any one or more of these is about 15% or more.

[0232] The above use.

[0233] Embodiment XLVI. Providing neuroprotection in subjects with lysosomal disorders, neurodegenerative diseases and for the treatment or delay of progression of neurodegenerative diseases associated with lysosomal storage defects. Treatment or prevention of migraines and related symptoms, restless legs Treatment or prevention of vertigo syndrome and related symptoms, dizziness and related symptoms A compound of formula I for use in the treatment or prevention, or for improving motor and / or cognitive function. or a pharmaceutically acceptable salt thereof, A solvate comprising:

[0234] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0235] R 2 But C1-6 is alkyl,

[0236] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0237] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 of The deuterium enrichment of any one or more of these is about 15% or more.

[0238] A compound of the present disclosure having the formula I above, or a pharmaceutically acceptable salt or solvate thereof .

[0239] Embodiment XLVII. The compound having Formula I is optically active. Use of V or XLVI.

[0240] Embodiment XLVIII. The optically active compound having formula I is a compound having formula II. The use of embodiment XLVII, wherein the compound is a compound (see above).

[0241] Embodiment XLIX. The compound having Formula I is a compound having Formula III (see above). Use of embodiment XLVII, wherein

[0242] Embodiment L. The compound having formula I is a compound having formula IV (see above): Use of embodiment XLVII, wherein

[0243] Embodiment LI. The compound having formula I is a compound having formula V (see above): Use of embodiment XLVII, wherein

[0244] Embodiment LII.R 1 The use of any one of embodiments XLV-LI, wherein is hydrogen.

[0245] Embodiment LIII.

[0246] R 2 But, -CR 2a R 2b R 2c and

[0247] R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium;

[0248] R 2a , R 2b , and R 2c Deuterium enrichment of at least one of the following is approximately 15% or more: In another embodiment, R 2a , R 2b , and R 2c are hydrogen, i.e., R 2 is methyl.

[0249] Embodiment LIV.R 13 is hydrogen. use.

[0250] Embodiment LV.R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any two or more of Use of any one of LIV.

[0251] Embodiment LVI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment LV, wherein the deuterium enrichment of any three or more of use.

[0252] Embodiment LVII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 and wherein the deuterium enrichment of any four or more of Use of I.

[0253] Embodiment LVIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any five or more of Use of VII.

[0254] Embodiment LIX.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any six or more of Use of II.

[0255] Embodiment LX.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment LIX, wherein the deuterium enrichment of any seven or more of use.

[0256] Embodiment LXI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment LX, wherein the deuterium enrichment of any eight or more of use.

[0257] Embodiment LXII.

[0258] R 7 The deuterium enrichment is about 15% or more,

[0259] R 10 The deuterium enrichment is about 15% or more,

[0260] R 6, R 8 , R 9 , R 11 , and R 12 is hydrogen; or A pharmaceutically acceptable salt or solvate thereof.

[0261] Embodiment LXIII.

[0262] R 7 and R 8 The deuterium enrichment is about 15% or more,

[0263] R 10 and R 11 The deuterium enrichment is about 15% or more,

[0264] R 9 and R 12 is hydrogen, or a pharmaceutically acceptable salt thereof. A salt or solvate thereof.

[0265] Embodiment LXIV. The compound having Formula I is selected from the group consisting of: Use of form XLV or XLVI. [ka]

[0266] Embodiment LXV. The compound having Formula I is selected from the group consisting of: Use of Form XLVII, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0267] Embodiment LXVI. The compound having Formula I is selected from the group consisting of: Use of Form XLVII, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0268] Embodiment LXVII. Methods of Treating or Slowing the Progression of Lysosomal Storage Disorders a compound of the disclosure having formula I (see above), for use in the method, or A pharmaceutical composition comprising a pharmaceutically acceptable salt or solvate thereof,

[0269] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0270] R 2 But C 1-6 is alkyl,

[0271] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0272] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 of The deuterium enrichment of any one or more of these is about 15% or more.

[0273] The pharmaceutical composition.

[0274] Embodiment LXVIII. Providing neuroprotection in subjects with lysosomal disorders, neurodegeneration Treatment or delay of progression of neurodegenerative diseases, treatment of neurodegenerative diseases associated with lysosomal storage defects or delay of progression, treatment or prevention of migraine and related symptoms, restlessness Treatment or prevention of dizziness and related symptoms, 20. The method of claim 19, wherein the compound of formula (I) is a compound of formula (I) or (II) for use in the treatment or prevention of a condition or for improving motor and / or cognitive function. Compounds of the present disclosure having I (see above), or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a compound or a solvate thereof,

[0275] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0276] R 2 But C 1-6 is alkyl,

[0277] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0278] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 of The deuterium enrichment of any one or more of these is about 15% or more.

[0279] The pharmaceutical composition.

[0280] Embodiment LXIX. The compound having Formula I is optically active. Or a pharmaceutical composition of LXVIII.

[0281] Embodiment LXX. The optically active compound having formula I is a compound having formula II: The pharmaceutical composition of embodiment LXIX, wherein the hydroxybenzoate is hydroxybenzoate (see above).

[0282] Embodiment LXXI. The compound having formula I is a compound having formula III (see above). The pharmaceutical composition of embodiment LXIX, wherein

[0283] Embodiment LXXII. The compound having formula I is a compound having formula IV (see above). The pharmaceutical composition of embodiment LXIX, wherein

[0284] Embodiment LXXIII. The compound having formula I is a compound having formula V (see above). The pharmaceutical composition of embodiment LXIX, wherein

[0285] Embodiment LXXIV.R 1 is hydrogen. Any one of the pharmaceutical compositions.

[0286] Embodiment LXXV.

[0287] R 2 But, -CR 2a R 2b R 2c and

[0288] R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium;

[0289] R 2a , R2b , and R 2c Deuterium enrichment of at least one of the following is approximately 15% or more: Embodiments LXVII to LXVII In another embodiment, the pharmaceutical composition of any one of LXXIV. 2a , R 2b , and R 2 c are hydrogen, i.e., R 2 is methyl.

[0290] Embodiment LXXVI.R 13 is hydrogen. or one pharmaceutical composition.

[0291] Embodiment LXXVII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 wherein the deuterium enrichment of any two or more of Any one of the pharmaceutical compositions LXVII to LXXVI.

[0292] Embodiment LXXVIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 1 1 , and R 12 the deuterium enrichment of any three or more of the following is about 15% or greater: The pharmaceutical composition of form LXXVII.

[0293] Embodiment LXXIX.R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any four or more of Pharmaceutical composition of XXVIII.

[0294] Embodiment LXXX.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 and embodiment LX, wherein the deuterium enrichment of any five or more of Pharmaceutical composition of XIX.

[0295] Embodiment LXXXI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 and wherein the deuterium enrichment of any six or more of XXX pharmaceutical composition.

[0296] Embodiment LXXXII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12

[0023] In an embodiment, the deuterium enrichment of any seven or more of Pharmaceutical composition of LXXXI.

[0297] Embodiment LXXXIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 1 1 , and R 12 the deuterium enrichment of any eight or more of the Pharmaceutical composition of form LXXXII.

[0298] Embodiment LXXXIV.

[0299] R 7 The deuterium enrichment is about 15% or more,

[0300] R 10 The deuterium enrichment is about 15% or more,

[0301] R 6 , R 8 , R 9 , R 11 , and R 12 is hydrogen. The composition, or a pharmaceutically acceptable salt or solvate thereof.

[0302] Embodiment LXXXV.

[0303] R 7 and R 8 The deuterium enrichment is about 15% or more,

[0304] R 10 and R 11 The deuterium enrichment is about 15% or more,

[0305] R 9 and R 12 is hydrogen. A salt or solvate acceptable to

[0306] Embodiment LXXXVI. An embodiment wherein the compound having Formula I is selected from the group consisting of: The pharmaceutical composition of embodiment LXVII or LXVIII. [ka]

[0307] Embodiment LXXXVII. The compound having Formula I is selected from the group consisting of: , the pharmaceutical composition of embodiment LXIX, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0308] Embodiment LXXXVIII. The compound having Formula I is selected from the group consisting of: The pharmaceutical composition of embodiment LXIX, or a pharmaceutically acceptable salt or solvate thereof. . [ka]

[0309] Embodiment LXXXIX. Treating or delaying progression of a lysosomal storage disorder or provides neuroprotection in subjects with lysosomal storage disorders or neurodegeneration. Treating or slowing the progression of neurodegenerative diseases associated with lysosomal storage defects Treat or slow the progression of migraine and related symptoms Treating or preventing restless legs syndrome and its associated symptoms to treat or prevent dizziness and related symptoms, or to improve mobility and / or Compounds of the present disclosure having formula I (see above) or their analogs for improving cognitive function. A pharmaceutically acceptable salt or solvate of

[0310] R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl,

[0311] R 2 But C 1-6 is alkyl,

[0312] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 but , each independently selected from the group consisting of hydrogen and deuterium;

[0313] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 of The present disclosure having Formula I, wherein the deuterium enrichment of any one or more of or a pharmaceutically acceptable salt or solvate thereof, and administering the compound to a subject. and instructions for using the kit.

[0314] Embodiment XC. The compound having Formula I is optically active. Embodiment LXXXI X kit.

[0315] Embodiment XCI. The optically active compound having formula I is a compound having formula II: The kit of embodiment XC, wherein the medicament is a medicament for which ...

[0316] Embodiment XCII. The compound having Formula I is a compound having Formula III (see above). The kit of embodiment XC, wherein

[0317] Embodiment XCIII. The compound having Formula I is a compound having Formula IV (see above). The kit of embodiment XC, wherein

[0318] Embodiment XCIV. The compound having Formula I is a compound having Formula V (see above). and) the kit of embodiment XC.

[0319] Embodiment XCV.R 1 is hydrogen. One kit.

[0320] Embodiment XCVI.

[0321] R 2 But, -CR 2a R 2b R 2c and

[0322] R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium;

[0323] R 2a , R 2b , and R 2c Deuterium enrichment of at least one of the following is approximately 15% or more: In another embodiment, R 2a , R 2b , and R 2care hydrogen, i.e., R 2 is methyl.

[0324] Embodiment XCVII.R 13 is hydrogen. One kit.

[0325] Embodiment XCVIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 wherein the deuterium enrichment of any two or more of One of the kits LXXXIX~XCVII.

[0326] Embodiment XCIX.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 is about 15% or greater. VIII kit.

[0327] Embodiment CR 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 1 2 of embodiment XCIX, wherein the deuterium enrichment of any four or more of kit.

[0328] Embodiment CI.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 The kit of embodiment C, wherein the deuterium enrichment of any five or more of to.

[0329] Embodiment CII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 of embodiment CI, wherein the deuterium enrichment of any six or more of kit.

[0330] Embodiment CIII.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and BiR 12 and wherein the deuterium enrichment of any seven or more of I kit.

[0331] Embodiment CIV.R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12and wherein the deuterium enrichment of any eight or more of I kit.

[0332] Embodiment CV.

[0333] R 7 The deuterium enrichment is about 15% or more,

[0334] R 10 The deuterium enrichment is about 15% or more,

[0335] R 6 , R 8 , R 9 , R 11 , and R 12 is hydrogen. or a pharmaceutically acceptable salt or solvate thereof.

[0336] Embodiment CVI.

[0337] R 7 and R 8 The deuterium enrichment is about 15% or more,

[0338] R 10 and R 11 The deuterium enrichment is about 15% or more,

[0339] R 9 and R 12 is hydrogen, or a pharmaceutically acceptable salt thereof. Salts or solvates.

[0340] Embodiment CVII. The compound having Formula I is selected from the group consisting of: Kit of form LXXXIX. [ka]

[0341] Embodiment CVIII. The compound having Formula I is selected from the group consisting of: The kit of embodiment XC, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0342] Embodiment CIX. An embodiment wherein the compound having Formula I is selected from the group consisting of: XC, or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0343] In another embodiment, the compounds of the present disclosure are useful for treating LSD, neurodegenerative diseases, or migraines, respiratory syndromes, and the like. Useful in treating stressed legs syndrome or dizziness, or motor and / or cognitive The second therapeutic agent is administered in combination with a second therapeutic agent useful for improving function. The compounds of the present disclosure and the second therapeutic agent are different from the compounds of the present disclosure in order to achieve the desired effect. The compounds of the present disclosure and the second therapeutic agent can be administered simultaneously or sequentially. Administration can be from a single composition or from two separate compositions.

[0344] The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. Effective dose ranges for the second therapeutic agent are typically known in the art, and the second therapeutic agent may be administered at doses The drug is administered to a subject in need thereof within established ranges.

[0345] The compound of the present disclosure and the second therapeutic agent can be administered together in a single unit dose, They may be administered separately as multiple unit doses, with the compound of the present disclosure being administered before the second therapeutic agent. or vice versa. One or more doses of a compound of the present disclosure, and / or One or more doses of the second therapeutic agent can be administered.

[0346] As used herein, the term "subject" refers to a vertebrate, mammal, or domestic animal. Thus, the compositions according to the present disclosure can be used in any mammal, for example, domestic animals, e.g., pigs. animals, such as horses, cows, sheep, or pigs; pets, such as cats, dogs, rabbits, or guinea pigs; may be used to treat experimental animals, e.g., mice or rats, or It may also be used in other veterinary applications. In one embodiment, the subject is a human.

[0347] As used herein, the terms "treat," "treating," "treatment," and the like refer to Unless otherwise indicated, excludes a disease or condition and / or its associated symptoms; Treating a disease or condition includes, but is not limited to, Treatment does not require complete elimination of the disease, condition, or its associated symptoms. The term "to treat" and synonyms refer to the administration of a therapeutically effective amount of a compound of the present disclosure to a patient in need of such treatment. Treatment is intended to be administered to a subject suffering from a condition, e.g., symptomatic relief to suppress symptoms. It can be done over the short term and can be directed over the medium term. or it can be a long-term treatment, for example in the context of maintenance therapy.

[0348] As used herein, the terms "prevent," "preventing," and "prevention" The compounds are intended to prevent or treat the onset of a disease or condition and / or its associated symptoms. As used herein, "prevent" refers to a method of preventing a person from contracting a disease. "Preventing" and "prevention" also mean delaying the onset of a disease and / or its associated symptoms. "Preventing" and "prevention" include preventing a disease, as well as reducing the subject's risk of contracting the disease. The terms "preventing" and "preventing" refer to the treatment of a disease or condition or the prevention of a disease or condition. In subjects who do not have recurrences but are at risk or susceptible to them, reducing the likelihood of a disease or condition, or the recurrence of a previously controlled disease or condition; The term "prophylactic treatment" may also include "prophylactic treatment," which refers to the treatment of

[0349] As used herein, the term "therapeutically effective amount" or "effective dose" refers to a therapeutically effective amount of a compound administered in accordance with the methods of the present disclosure. When administered by a steroid, the compound for the treatment of a condition or disease of interest is administered to a subject in need thereof. The compounds disclosed herein are sufficient to be delivered to a desired subject and to produce a 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 be, for example, For example, delaying the onset of LSD symptoms or LSD-related characteristics, or may delay the time to onset of symptoms of neurodegenerative diseases.

[0350] As used herein, the term "lysosomal storage disorder" or "LSD" refers to a late stage LSD refers to any disorder involving dysfunction or disruption of the endosomal / lysosomal system. LSDs may also be associated with an increase in the volume and / or pH of the endosomal / lysosomal system. It may be accompanied by increased lipid or non-lipid accumulation.

[0351] LSD is a group of disorders characterized by primary lysosomal hydrolase deficiency, a defect in the post-translational processing of lysosomal enzymes, Defective transport of lysosomal enzymes, defective protection of lysosomal enzymes, soluble non-enzymatic lysosomal proteins The defect may be a protein defect, a transmembrane (non-enzyme) protein defect, or an unspecified defect.

[0352] Primary lysosomal hydrolase deficiencies include Gaucher disease (glucosylceramidase deficiency) GM1 gangliosidosis (GM1-β-galactosidase deficiency), Tei-Sa Schneider's disease (β-hexosaminidase A deficiency), Sandhoff disease (β-hexosaminidase A deficiency) A+B deficiency), Fabry disease (α-galactosidase A deficiency), Krabbe disease (β-galactosidase A deficiency), Lactosylceramidase deficiency), Niemann-Pick disease types A and B (sphingomyelinase) enzyme deficiency), metachromatic leukodystrophy (arylsulfatase A deficiency), MP S IH (Hurler syndrome; α-idronidase deficiency), MPS IS (Scheie syndrome) group; α-idronidase deficiency), MPS IH-S (Hurler-Scheie syndrome; α- Idronidase deficiency), MPS II (Hunter syndrome; idronate sulfatase deficiency) Heparan sulfamidase deficiency), MPS IIIA (Sanfilippo syndrome A; heparan sulfamidase deficiency) ), MPS IIIB (Sanfilippo B syndrome; acetyl-α-glucosaminidase deficiency) syndrome), MPS IIIC (Sanfilippo syndrome C; acetyl-CoA:α-glucosaminergic MPS IIID (Sanfilippo D syndrome) Group: N-acetylglucosamine-6-sulfatase deficiency), MPS IV A (mol Acetylgalactosamine-6-sulfatase deficiency), MPS IVB (Mollusca ulcerata) Lucio B disease; β-galactosidase deficiency, MPS V (redesignated ted) MPS IS), MPS VI (Maroto-Lamy syndrome; acetylgalactosamine MPS VII (sulfatase B deficiency), MPS IX (hyaluronidase deficiency), Wolman disease (WD; acid lipase deficiency), Farber disease (acid ceramidase deficiency), Lactic acid ester storage disease (acid lipase deficiency), Pompe disease (type II; α 1,4-glucuronidase) glycosidase deficiency), aspartylglucosaminuria (glycosylasparaginase deficiency) Fucosidosidosis (α-fucosidase deficiency), α-mannosidosis (α-mannosidase β-mannosidase deficiency), β-mannosidosis (β-mannosidase deficiency), Schindler disease (N-acetylcholinesterase deficiency), galactosaminidase deficiency), sialidosis (α-neuraminidase deficiency), Childhood neuronal ceroid lipofuscinosis (CLN1; palmitoyl protein thioesterase deficiency) deficiency), late infantile neuronal ceroid lipofuscinosis (CLN2; carboxypeptidase deficiency) disease), early infantile GM1 gangliosidosis, late infantile GM1 gangliosidosis, adult Human infantile GM1 gangliosidosis, Gaucher disease type 1 (non-neuropathic), Gaucher disease type 2 / Type 3 (neuropathic), ML1 (MLI; sialidosis, α-N-acetylneuraminic acidosis) sialidase deficiency, ML2 (MLII, I-cell disease; N-acetylglucosamine Aminophosphoryltransferase deficiency), ML3 (MLIII, pseudo-Hurler polymorphism N-acetylglucosamine phosphoryltransferase deficiency), ML 4 (MLIV, mucolipin 1 deficiency), neuronal ceroid lipofuscinosis type 4 (CLN4; Fus disease; adult NCL; palmotoyl protein thioesterase-1 deficiency (type A) Cathepsin F deficiency (type B), neuronal ceroid lipofuscinosis type 8 - northern epilepsy ( CLN8), Neuronal Ceroid Lipofuscinosis Type 8 - Turkish Late Infancy (CLN8), Neuroceroid Idlipofuscinosis type 9 - German / Serbian late infantile (CLN9), neuronal ceroid lipofuscinosis Congenital cathepsin D deficiency (CLN10), pyknodysostosis (cathepsin K deficiency), infantile-onset Pompe disease, late-onset Pompe disease, and cholesteryl ester storage disease However, it is not limited to these.

[0353] Post-translational processing defects in lysosomal enzymes include mucosulfatidosis These include multiple sulfatase deficiencies (MSDs), Not limited.

[0354] Lysosomal enzyme transport defects include mucolipidosis type II (I-cell disease; N-acetylglucosamine). glucosamine phosphoryltransferase deficiency), mucolipidosis type IDA (pseudoherbal Lar polydystrophy; N-acetylglucosamine phosphoryltransferase deficiency These include, but are not limited to, cerebrospinal fluid disorders (e.g., cerebrospinal fluid disorders), and mucolipidosis type IIIC.

[0355] Defects in lysosomal enzyme protection include galactosialidosis (protective protein cathepsin A (PPCA) deficiency), β-galactosidase deficiency, and neuraminidase deficiency. Deficiencies of soluble non-enzymatic lysosomal proteins include, but are not limited to, GM2 alleles. Activator protein deficiency (AB variant), sphingolipid activator protein (SAP) deficiency, and neuronal ceroid lipofuscinosis (NCL) (CLN5). However, the present invention is not limited to these.

[0356] Transmembrane (non-enzyme) protein deficiencies include Danon disease (lysosome-associated membrane protein 2 ( LAMP2) deficiency), NPC (NPC1 and / or NPC2 deficiency), cystinosis ( Cystinosin deficiency), infantile free sialic acid storage disease (ISSD; sialin deficiency), Salla disease ( Free sialic acid storage disease; sialin deficiency), juvenile neuronal ceroid lipofuscinosis (CLN3 , Batten disease), neuronal ceroid lipofuscinosis (NCL) (CLN6 and CLN8), and mucolipidosis type IV (mucolipin deficiency), but are not limited to these. stomach.

[0357] Unclassified deficiencies include neuronal ceroid lipofuscinosis (NCL) (CLN4 and CLN7) ), including but not limited to:

[0358] LSD treated, delayed, or ameliorated by the compounds, compositions, and methods of the present disclosure includes: NPC (NPC1 and / or NPC2 deficiency, primary or secondary), Smith-Lemli Opitz syndrome (SLOS), cholesterol synthesis inborn error of metabolism, Tatangier disease, Pelizaeus-Merzbacher disease, neuronal ceroid lipofuscinosis, primary glycosphingomyelinosis Lipitose (i.e., Gaucher disease, Fabry disease, GM1, GM2 gangliosides) Krabbe disease, and metachromatic leukodystrophy (MLD), Farber disease, and multiple myeloma sulfatase deficiency or

[0359] In some embodiments, NPC, Tay-Sachs disease, Sandhoff disease, GM1 ganglionic acid have significant central nervous system (CNS) involvement, such as dysbiosis or Fabry disease LSD can be treated or prevented by the compounds of the present disclosure and the compositions and methods described herein. or delayed.

[0360] Niemann-Pick disease is a heterogeneous group of autosomal recessive LSDs. Common cellular features include: showed abnormal sphingomyelin (SM) accumulation in mononuclear phagocytes and parenchymal tissues, and Among the three main subgroups (A-C), NPC (formerly NP) C and NPD, which are now understood to be a single disorder, are late-stage endocrine disorders. Abnormal intracellular cholesterol trafficking induces non-esterification in the endosomal / lysosomal compartment It is classified as a fatal neurovisceral LSD caused by the accumulation of oxidized cholesterol.

[0361] Outside the CNS, the cellular characteristics of NPCs include the accumulation of non-endosomal / lysosomal cells within late endosomal / lysosomal compartments. These include abnormal accumulation of esterified cholesterol and other lipids (e.g., GSLs). There is no net increase in cholesterol in the CNS (although its distribution is altered), but GSL The levels of GABAergic receptors in the cerebellum are highly elevated. It is characterized by the progressive degeneration of Purkin neurons, which is the cause of the cerebellar ataxia seen during the course of NPC. The onset and progression of the disease parallels other aspects of neurological dysfunction. NPC disease is caused by mutations in either the Npc1 or Npc2 gene The exact mechanistic link between these two genes remains unclear, and this The functional role of these proteins remains enigmatic. NPC1 is involved in the late endosome / lysosome assembly. NPC2 encodes a multi-spanning membrane protein of the lysosomal limiting membrane, and NPC3 encodes a soluble lysosomal protein. It is a cholesterol-binding protein. When NPC1 is inactivated, sphingosine is the first lipid to accumulate, which is why NPC1 normally regulates sphingolipid catabolism as part of the plays a role in the transport of sphingosine from lysosomes where it is produced as a This suggests that elevated sphingosine may lead to a defect in calcium entry into acidic depots. This then leads to a calcium-dependent Prevents late endosome-lysosome fusion, a critical process, and promotes late endocytosis Lipids (cholesterol, sphingomyelin, and glycosphingolipids), resulting in the secondary accumulation of phospholipids.

[0362] Other secondary consequences of inhibiting NPC1 function include defects in endocytosis and autophagy. These include poor clearance of the phagocytic vacuole. The NPC1 / NPC2 cellular pathway is involved in the pathogenesis of pathogenic bacteria. Targeted by Icobacteria and Promotes Their Survival in Late Endosomes In one embodiment, the Niemann-Pick disease is Niemann-Pick type A, Having type B, C1, or C2 disease.

[0363] Tay-Sachs disease is caused by a deficiency of the A (acid) isoenzyme of β-hexosaminidase It is a fatal inherited disorder of lipid metabolism characterized in CNS tissues due to β -Mutations in the HEXA gene, which encodes the alpha subunit of hexosaminidase, result in the A isoform Tay-Sachs disease is caused by a defect in GM2 ganglioside degradation. This is the prototype of GM2 gangliosidosis, characterized by Osidosis 2 (monosialylated ganglioside 2) accumulates in neurons, which In one embodiment, Tay-Sachs disease is caused by Tay-Sachs A. It is a type B variant.

[0364] Sandhoff disease is caused by the expression of both the A and B (basic) isoenzymes of β-hexosaminidase. It results from a deficiency of the HEXB gene, which encodes the beta subunit of beta-hexosaminidase. Mutations in cause B isoenzyme deficiency.

[0365] GM1 gangliosidosis is caused by a deficiency of β-galactosidase, which leads to lysosomal accumulation of GM1 ganglioside (monosialylated ganglioside) 1).

[0366] Fabry disease is caused by a deficiency of alpha-galactosidase, which causes ceramide This results in lysosomal accumulation of dotrihexoside.

[0367] As used herein, the term "neurodegenerative disease" refers to a condition that affects neurons and Progressive loss of neuronal structure, progressive loss of neuronal function, or progressive neuronal cell death Refers to any disorder involving cell death.

[0368] Neurodegenerative diseases include alcoholism, Alexander disease, Alper's disease, and Alzheimer's disease. Neuropathy, amyotrophic lateral sclerosis (ALS), ataxia, neuronal tubule ectasia, neuronal ceroid lymphoma Pofuscinosis, Batten disease, Bovine spongiform encephalopathy (BSE), Canavan disease, cerebral palsy, cockroach disease Syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Frontotemporal lobar degeneration, Gonadotropin-dependent neuropathy Chaffey's disease, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, dementia with Lewy bodies dementia, lysosomal storage disorders, neuroborreliosis, Machado-Joseph disease, multiple atrophy, multiple myelopathy Neuropathic sclerosis, multiple sulfatase deficiency, mucolipidosis, narcolepsy, nephropathy Niemann-Pick type C, Niemann-Pick disease, Parkinson's disease, lower body parkinsonism, Pelizaeus-Merzbacher disease, Pick's disease, Pompe disease, primary lateral sclerosis, prion diseases , progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder disease, secondary to pernicious anemia Subacute combined spinal degeneration, Spielmeyer-Voigt-Sjögren-Batten disease , cerebellar ataxia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson Olszewski's disease, tabes dorsalis, Sy-Sachs' disease, dentatorubral-pallidoluysian atrophy, period Sexual ataxia (EA)1, periodic ataxia (EA)2, periodic ataxia (EA)3, periodic ataxia (EA)4, periodic ataxia (EA)5, periodic ataxia (EA)6, periodic ataxia (EA) 7. Charlevoix-Saguenay autosomal recessive spastic ataxia (ARSACS), autosomal recessive Cerebellar ataxia type 1 (Bose's recessive ataxia (RAB)), autosomal recessive cerebellar ataxia type 2 (spinal Cerebellar ataxia autosomal recessive type 9 (SCAR9), ataxia with oculomotor apraxia type 1 (AOA1) , ataxia with oculomotor apraxia type 2 (AOA2), ataxia with vitamin E deficiency (AVED) ), Friedreich's ataxia syndrome (FRDA), and mitochondrial recessive ataxia syndrome (MIRAS) , Myoclonic Seizures Myopathy Sensory Ataxia (MEMSA), Sensory Ataxia Neuropathy dysarthria ophthalmoplegia (SANDO), ataxia with coenzyme Q10 deficiency, lactic acidosis Acidosis, Stroke Syndrome (MELAS), Myoclonic Seizures with Ragged Red Fibers Neuromuscular weakness, ataxia, and retinitis pigmentosa (NARP), Kens-Sayre syndrome (KSS), Fragile X Tremor / Ataxia Syndrome (FXTAS), Arts syndrome, Christianson type X-linked mental retardation syndrome, X-linked sideroblasts anemia, idiopathic late-onset cerebellar ataxia, sporadic adult-onset ataxia of unknown etiology (SAOA), Transmissible mink encephalopathy, chronic wasting disease, feline spongiform encephalopathy, exotic ungulate encephalopathy (exot ic ungulate encephalopathy), kuru, atypical Kreutzfeldt-Jakob disease Feldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial Insomnia, proximal dominant hereditary motor and sensory neuropathy, wobbly hedgehog syndrome (W HS), progressive muscular atrophy (Duchenne-Allan muscular atrophy), progressive bulbar palsy, pseudobulbar palsy These include HIV-associated neurocognitive disorder (HAND), parkinsonism, and scrapie. Examples include, but are not limited to:

[0369] In one embodiment, the spinocerebellar ataxia is infantile-onset spinocerebellar ataxia (SCA) A) 1, Spinocerebellar ataxia (SCA) 2, Spinocerebellar ataxia (SCA) 3 (Machado-Joseph) Spinocerebellar ataxia (SCA) 4, Spinocerebellar ataxia (SCA) 5 (Lincoln ataxia) ), Spinocerebellar ataxia (SCA) 6, Spinocerebellar ataxia (SCA) 7, Spinocerebellar ataxia (SC) A) 8, Spinocerebellar ataxia (SCA) 10, Spinocerebellar ataxia (SCA) 11, Spinocerebellar ataxia Spinocerebellar ataxia (SCA) 12, Spinocerebellar ataxia (SCA) 13, Spinocerebellar ataxia (SCA) 14, Spinocerebellar ataxia (SCA) Spinocerebellar ataxia (SCA) 15 / 16, Spinocerebellar ataxia (SCA) 17, Spinocerebellar ataxia ( SCA) 18 (sensory / motor neuropathy with ataxia), spinocerebellar ataxia (SCA) 19 / 22, Spinocerebellar ataxia (SCA) 20, Spinocerebellar ataxia (SCA) 21, Spinocerebellar ataxia (SCA) 23, Spinocerebellar ataxia (SCA) 24, Spinocerebellar ataxia (SCA) 25, Spinal Cerebellar ataxia (SCA) 26, Spinocerebellar ataxia (SCA) 27, Spinocerebellar ataxia (SCA) 28 (Spinocerebellar ataxia autosomal recessive type 4 (SCAR4); Saccade intrusion Spinocerebellar ataxia with saccadic intrusion (S CA) 29, Spinocerebellar Ataxia (SCA) 30, Spinocerebellar Ataxia (SCA) 31, Spinocerebellar Ataxia (SCA) 32, Spinocerebellar ataxia 35, Spinocerebellar ataxia (SCA) 36, X-linked spinal cord ataxia Spinocerebellar ataxia 1, X-linked spinocerebellar ataxia 2, X-linked spinocerebellar ataxia 3, X-linked spinocerebellar ataxia ataxia 4, or X-linked spinocerebellar ataxia 5.

[0370] 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 Parkinsonism. In one embodiment, the neurodegenerative disease is neuropathic Gaucher disease. In one embodiment, the neurodegenerative disease is Sandhoff disease. 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 frontotemporal dementia. In some cases, the neurodegenerative disease is hemiparkinsonism.

[0371] The main symptoms of Parkinson's disease (PD) are stiffness, tremors, and slow movements There are other diseases in which these symptoms are widespread. These diseases, and PD itself, PD is classified under the general term "parkinsonism." PD can be called primary parkinsonism. Other examples of Parkinsonism include multiple system atrophy, progressive supranuclear palsy, normal pressure hydrocephalus, and hemoglobinuria. Although it is not PD, which includes vascular or arteriosclerotic parkinsonism, it is considered parkinsonism. Those diseases that can be classified as "Parkinson-Plus" are Unlike PD patients, those with Parkinson-plus syndrome Individuals with Parkinsonism do not respond to L-dopa. As used herein, the term "parkinsonism" refers to , a motor syndrome whose main symptoms are tremor at rest, rigidity, slowed movement, and postural instability. Parkinsonism can be of any origin: primary or idiopathic, secondary or acquired , hereditary parkinsonism, and parkinsonism-plus syndrome or multiple system degeneration. It can be divided into subtypes.

[0372] In one embodiment, the parkinsonism is parkinsonism plus syndrome or multisystem degeneration. In one embodiment, the parkinsonism is vascular parkinsonism (arteriosclerotic Parkinsonism; lower body parkinsonism), multiple system atrophy with predominant parkinsonism (MSA-P), multiple system atrophy with cerebellar features (MSA-C; sporadic olivopontocerebellar degeneration) Optic pulmonary artery aneurysm (OPCA), Shy-Drager syndrome, Progressive supranuclear palsy (Steele-Richter syndrome) Dementia with Lewy bodies, Pick's disease, or frontotemporal dementia dementia and chromosome 17-linked parkinsonism.

[0373] As used herein, the phrase "delaying the progression of LSD" and the like refers to the delaying the onset of LSD symptoms or LSD-related characteristics in a subject (compared to those not affected) This means to prolong the time it takes for a disease or Substantially delay or prevent the onset of one or more symptoms and / or complications associated with a disease. It may involve preventing or even preventing altogether.

[0374] "Slowing the progression of neurodegenerative diseases" or "Diagnosing diseases associated with lysosomal storage defects" The phrase "delaying the progression of a neurodegenerative disease" refers to a condition that affects a person with a neurodegenerative disease or lysosomal storage disease. Symptoms of neurodegenerative diseases associated with a deficiency of ATP synthesis or symptoms of neurodegenerative diseases or lysosomal storage Delaying the onset of features associated with neurodegenerative disorders associated with the deficits, i.e., This refers to an increase in the amount of time spent in the stool (compared to what is typically observed). substantially delays the onset of one or more symptoms and / or complications associated with a disease, It may include preventing or even completely preventing the disease.

[0375] Therefore, slowing the progression of, for example, LSD, neurodegenerative diseases, or lysosomal Symptoms and conditions resulting from or associated with neurodegenerative diseases associated with defects in cellular accumulation and / or delaying or preventing complications. When provided prophylactically, acetylleucine is typically used to treat LSD, neurodegenerative diseases, or or before the onset of symptoms of a neurodegenerative disease associated with a defect in lysosomal storage. Such prophylactic administration is typically directed at LSDs, neurodegenerative diseases, or lysosomal storage defects. To delay or prevent the onset of symptoms of the associated neurodegenerative disease.

[0376] A "symptom" of LSD includes any clinical or laboratory manifestation associated with LSD, Symptoms described herein include, but are not limited to, those that can be felt or observed by a person. Examples of neurological symptoms include ataxia, dystonia, vertical and horizontal Psychiatric disorders such as depression or psychosis include supranuclear saccadic / gaze palsy and dementia. Most LSDs are based on the subject's medical history, clinical findings, biochemical markers, and genetic A diagnosis can be made based on subcutaneous examination.

[0377] The "symptoms" of neurodegenerative diseases, optionally associated with defects in lysosomal storage, are Any clinical or laboratory manifestation related to the disease that the subject feels or observes The conditions referred to herein include, but are not limited to, neurological conditions.

[0378] Progression may be due to the appearance of LSD symptoms or LSD-related features or symptoms of a neurodegenerative disorder. time to symptom resolution typically observed for subjects with LSD or neurodegenerative disease In some embodiments, a delay may be at least 5% longer than the 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%, An increase of at least 80%, at least 90%, or at least 100% of the time was observed. can be.

[0379] Disease treatment or progression can be assessed using one or more of the following: Symptom Assessment and Rating Scale (SARA), Spinocerebellar Ataxia Functional Index (SCAFI), Functional Disability Modified Harm Rating Scale (mDRS), EuroQol 5Q-5D-5L (EQ-5D-5L ), Visual Analogue Scale (VAS), Wechsler Adult Intelligence Scale-Revised (WAIS- R), Wechsler Intelligence Scale for Children (WISC-IV), or Montreal Cognitive Assessment For a specific LSD, such as NPC, a specific score, e.g., modified 6-d The main NP-C disability rating scale (mDRS score) has been developed over the past few decades, In this regard, specific scores on these tests may be indicative of symptomatic LSD. or characteristic of neurodegenerative subjects. "Slowing the progression of a neurodegenerative disease" means that the subject is a symptomatic LSD subject or a neurodegenerative disease subject. Sexual characteristics: SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WA IS-R, WISC-IV, and / or MoCA scores, or other relevant tests This may mean increasing the time it takes to reach the target (compared to what is typically observed). .

[0380] "Treatment of neurodegenerative diseases," "Treatment of neurodegenerative diseases associated with lysosomal storage defects," or "Treatment of LSD" is based on SARA, SCAFI, mDRS, EQ-5D-5L, VA Improvement in S, WAIS-R, WISC-IV, and / or MoCA scores, or neurological changes The results may be equivalent to the results of another test suitable for characterizing the sexual disorder or LSD subject. In some embodiments, treatment involves changing the score from a value characteristic of a symptomatic subject to a value characteristic of a non-symptomatic subject. Improve things like that.

[0381] Any changes in the progression of an LSD or neurodegenerative disease, e.g., over time or with treatment, may be observed. Throughout, one or more established tests may be used at two or more time points as further discussed herein. This can be monitored by using different methods and comparing the results.

[0382] Therefore, to assess the overall neurological status, the mDRS, a 4-domain scale (mobility, Brain function was assessed using an 8-item clinical assessment scale (gait, speech, and swallowing). SA: walking, stance, sitting, speech, fine motor skills, and taxis RA (ranging from 0 to 40, with 0 being the best neurological condition and 40 being the worst) and 8 m walking time (8 MW; excluding turns, from one line to another as quickly as possible, (performed by having the elephant walk twice), the 9-hole peg test (9HPT), and the 10 SCAFI, which includes the number of "PATA" repeats over a period of time, can be evaluated using Subjective disability and quality of life were assessed using the EQ-5D-5L questionnaire and VAS. To evaluate eye movement function, three-dimensional video eye movement recording (EyeSe eCam) to measure peak saccade velocity, smooth pursuit gain, and gaze-evoked nystagmus. Peak low-phase velocity (gaze maintenance function), peak low-phase velocity of optokinetic nystagmus, and horizontal vestibular Gain of the oculomotor reflex can be measured. Cognitive status, WAIS-R or WISC-I V, and MoCA to assess attention and concentration, executive function, memory, language, visual structure, and Visual construction skills, conceptual thinking, and computation The different cognitive domains, including directional measures, were assessed with a maximum of 30 points and a cutoff score of 2. 6. Those skilled in the art will know how to perform such tests. .

[0383] As used herein, the term "treatment of migraine" refers to the treatment of migraine or any of the headache, headaches, and headache-related headaches. It refers to reducing the frequency of, alleviating, or eliminating one or more symptoms.

[0384] As used herein, the term "migraine prophylaxis" refers to the prevention of migraine or related It refers to preventing one or more symptoms. The compounds of the present disclosure can be used prophylactically.

[0385] As used herein, the term "alleviating" refers to the relief of migraine headaches or headaches associated therewith. means making one or more symptoms less severe or milder than they would be in the absence of treatment .

[0386] As used herein, the term "reducing migraine frequency" refers to the reduction in the frequency of migraines in the absence of treatment. The incidence of migraine headaches or one or more of its associated symptoms within a specific time frame compared with the occurrence of This means reducing the occurrence.

[0387] In one embodiment, the compounds of the present disclosure are useful for treating headache, fatigue, aura, nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smell, sweating, difficulty concentrating, feeling hot or cold and reducing the frequency of or alleviating one or more migraine symptoms selected from abdominal pain and diarrhea. Reduce or eliminate

[0388] As used herein, a migraine-related symptom refers to any clinical or physical condition associated with migraine. or laboratory manifestations, and is limited to what the subject can sense or observe. do not have.

[0389] In another embodiment, the present disclosure treats or, more preferably, treats aura, e.g., visual aura. The present invention also provides compounds of the present disclosure for use in preventing or treating a variety of conditions.

[0390] In another embodiment, the present disclosure provides a method for treating migraine headaches associated with aura (e.g., "classic migraine"). Compounds of the present disclosure are provided for use in therapy or prophylaxis.

[0391] In another embodiment, the present disclosure provides a method for treating migraines that are not associated with aura (e.g., "common migraines") The present invention provides compounds of the present disclosure for use in the treatment or prevention of

[0392] In another embodiment, the present disclosure provides a method for the treatment or prevention of aura associated with migraine. The compounds of the present disclosure are provided as follows:

[0393] In another embodiment, the present disclosure provides a method for the treatment or prevention of aura that is not associated with migraine. The compounds of the present disclosure are provided for:

[0394] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating or preventing migraine. In this embodiment, the migraine headache is typically accompanied by motor weakness. headache and aura associated with rheumatoid arthritis.

[0395] In another embodiment, the present disclosure provides a method for the treatment or prevention of hemiplegic migraine. The compounds shown are provided.

[0396] In another embodiment, the present disclosure provides a method for treating or preventing vestibular migraine. Vestibular migraine is classified as a type of headache according to the International Classification Committee of the Barany Society. It can be defined according to established diagnostic criteria and is typically characterized by the following:

[0397] A. Moderate or severe vestibular symptoms (as defined by the Barany Society classification of vestibular symptoms) at least five episodes of dizziness lasting from 5 minutes to 72 hours;

[0398] B. Current or future migraine headaches with or without International Classification of Headache Disorders (ICHD) aura past medical history;

[0399] C. One or more migraine characteristics present in at least 50% of vestibular episodes:

[0400] 1. Headache with at least two of the following characteristics: unilateral location, pulsating quality, moderate intensity or severe pain intensity, worsening with everyday physical activity;

[0401] 2. Photophobia and phonophobia;

[0402] 3. Visual aura;

[0403] D. Anything not better explained by another vestibular or ICHD diagnosis.

[0404] In another embodiment, the present disclosure provides a method for the treatment or prevention of basilar migraine. In this embodiment, the migraine typically includes headache and aura, Symptoms include: difficulty speaking, spatial disorientation (world spinning), tinnitus, and others It is accompanied by one or more of the following brainstem-related symptoms:

[0405] In another embodiment, the present disclosure provides a method for the treatment or prevention of retinal migraine. In this embodiment, retinal migraine is typically characterized by visual disturbances or temporary headache accompanied by severe blindness.

[0406] In another embodiment, the present disclosure provides a method for the treatment or prevention of chronic migraine. As used herein, the term "chronic migraine" refers to a compound that is effective in treating migraine headaches in the absence of medication. Below, headaches on more than 15 days per month (of which more than 8 days were migraines) over a 3-month period Headache Disorders (HDDs) refers to subjects suffering from headache disorders (as defined by the International Headache Society).

[0407] In another embodiment, the present disclosure provides a method for the treatment or prevention of episodic migraine. As used herein, "paroxysmal migraine" refers to a compound of the formula (as defined by the International Headache Society) 15 days per month over a 3-month period in the absence of medication (as defined by This refers to subjects suffering from headaches less than 10 minutes after the start of treatment.

[0408] In another embodiment, the present disclosure provides a method for the treatment or prevention of acute migraine headaches. A compound is provided.

[0409] In another embodiment, the present disclosure provides a method for treating or preventing one or more prodromal symptoms associated with migraine. Preferably, the prodromal symptoms include mood changes, irritability, and / or nausea. Irritability, depression or elation, fatigue, cravings for certain foods, stiff muscles Choose from one or more of the following: meat (especially neck), constipation, diarrhea, and sensitivity to smells and noise. It is selected.

[0410] In another embodiment, the present disclosure provides a method for the treatment or prevention of pain associated with migraine. The compounds of the present disclosure are provided as follows:

[0411] In another embodiment, the present disclosure provides a method for treating or preventing one or more late symptoms associated with migraine. Preferably, the after-effect is in the area of ​​the migraine. pain in the abdomen, impaired thinking, fatigue, headache, cognitive impairment, gastrointestinal symptoms, mood changes, and weakness One or more of these may be selected.

[0412] In another embodiment, the present disclosure provides a compound of the present disclosure that reduces, alleviates, or eliminates migraine headaches. provide.

[0413] In another embodiment, the disclosure provides compounds of the disclosure that reduce or eliminate the aura.

[0414] In another embodiment, the present disclosure provides a method for treating visual impairment or loss, numbness or tingling, One or more of the following symptoms: dizziness, balance problems, movement disorders, difficulty speaking, and loss of consciousness The present invention provides compounds of the present disclosure that reduce the frequency of, or alleviate or eliminate the symptoms of,

[0415] In another embodiment, the present disclosure provides a method for preventing, for example, one or more of the above symptoms from occurring. The compounds of the present disclosure are provided to prevent the occurrence of aura by preventing the onset of aura.

[0416] In one embodiment, the present disclosure provides a method for evaluating cognitive function, motor function, or cognitive function and motor function in a subject. The present invention also provides compounds of the present disclosure for use in methods for improving performance.

[0417] In another embodiment, the present disclosure provides a method for improving cognitive function in a subject. Compounds of the present disclosure are provided.

[0418] In another embodiment, the present disclosure provides a method for improving exercise capacity in a subject. The disclosed compounds are provided.

[0419] In another embodiment, the subject is an elderly subject.

[0420] In another embodiment, the present disclosure provides a method for improving motor and / or cognitive function in elderly subjects. The present invention also provides compounds of the present disclosure for use in methods of:

[0421] In another embodiment, the present disclosure provides a method for improving motor and / or cognitive function in elderly subjects. The present invention provides a method for treating a cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure. Provide.

[0422] In another embodiment, cognitive functions include perception, memory, imagery, recognition, reasoning, thinking, and and judgment ability.

[0423] According to the present disclosure, compounds of the present disclosure are useful for preventing age-related declines in cognitive function and / or motor performance. It can be used to treat.

[0424] In another embodiment, the present disclosure provides a method for treating restless legs syndrome. The compounds shown are provided.

[0425] In another embodiment, the present disclosure provides a compound of the present disclosure for use in treating vertigo. do.

[0426] "Mobility" refers to the ability of a subject to move. In older adults, it can be assessed using one or more simple tests. Motility can be assessed. For example, the "stand and go" test measures mobility. This test is a simple test that allows you to stand up from a sitting position and walk to a target point. Analyze.

[0427] For example, the test may begin with the subject seated in a chair. The elephant must stand up and walk unassisted to the target location, which is between 2 and 10 meters away. When the target reaches the target point, the stop time is Any changes in exercise capacity, e.g., over time or through treatment, should be considered. Monitor by using the stand-and-go test at two or more time points and comparing the results. Other suitable tests for measuring motor skills include mobility, balance, A 20-point validated assessment tool for the assessment of frail elderly subjects, taking into account posture and important positional changes. These include those used in the Mobility Scale for the Elderly (EMS), a standard for assessing mobility.

[0428] The phrase "improved mobility" as referred to herein refers to a positive change in a subject's mobility. Positive changes can be measured using any of the above tests, e.g., from baseline The first opportunity to measure exercise capacity and the second opportunity to measure exercise capacity after a period of time (when treatment is administered) The subject may be evaluated on two or more occasions (e.g., two or more patients) to determine whether the patient is experiencing improvement in stability. The more confident you feel about your condition (e.g., treatment), the faster you will complete the test. If an increase in performance of at least approximately 5% is observed between the two time points, exercise capacity is considered to be improved. For example, in related tests, there is at least 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%, or at least At least about 70%, at least about 80%, at least about 90%, or at least about 100% Furthermore, in related tests, between two time points, e.g. 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% An increase in performance is observed. The two time points are 1 week apart, 2 weeks apart, 3 weeks apart, and 4 weeks apart. May be intervals, 2-month intervals, 3-month intervals, 4-month intervals, 5-month intervals, or 6-month intervals Treatment may be administered during an intervening period. Thus, by way of example, "improvement of exercise capacity" may refer to: When subjects were measured using the "stand and go" test as defined herein , can mean exhibiting an increase in velocity of at least about 5% from a baseline measurement. For example, subjects may have at least about 10%, at least about 15%, or 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 The subject may exhibit an increase in speed of about 90%, or at least about 100%. In this test, 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 may exhibit a speed increase of at least 100%.

[0429] In one embodiment, the subject has age-related mobility impairment.

[0430] As used herein, the term "age-related mobility impairment" refers to a condition that is a direct result of the aging process. It refers to impairments in motor function that are an indirect consequence of the aging process, not a direct result of the aging process. The clinical presentation is in contrast to age-related motor impairment. and subjects with motor impairments that are not a direct result of the aging process, e.g., ataxia. Ataxia can differ between subjects with and without ataxia. Ataxia is characterized by a subject's unsteadiness while walking. While this may be beneficial, age-related mobility impairments may contribute to an increased tendency for falls. Thus, for example, cerebellar ataxia is not an age-related movement disorder.

[0431] In addition to the motor function assessments disclosed above, the present invention also provides a method for assessing motor function in subjects with age-related motor impairments. The motor skills of the subject can be assessed, for example, using an assessment of balance and / or the number of falls experienced by the subject. may be monitored and / or tested using a "stand up and go" test.

[0432] In another embodiment, the present disclosure provides a method for the treatment of a rheumatoid arthritis, comprising administering to a subject a therapeutically effective amount of a rheumatoid arthritis drug for use in improving balance in a subject. Compounds of the present disclosure are provided, wherein the subject has an age-related balance disorder. , Age-related balance disorders are not dizziness.

[0433] According to the present disclosure, the subject may have, for example, benign paroxysmal positional vertigo (BPPV); vestibular neuritis; Meniere's disease, Wallenberg's syndrome, cerebral ischemia, perilymphatic fistula, or acoustic neuroma There may be no associated dizziness; or recurrent dizziness of traumatic or toxic origin.

[0434] In another embodiment, the present disclosure provides a method for treating age-related balance disorders. The compounds of the present disclosure are provided for:

[0435] In another embodiment, the present disclosure provides a method for controlling the stability of a subject, for example, while standing and / or walking. The present disclosure provides compounds of the present invention for use in increasing the quality of life of a subject, wherein the subject is There is a decrease in stability.

[0436] In another embodiment, the present disclosure provides a method for reducing instability in a subject during walking. The present disclosure provides compounds for treating a subject having age-related increased instability.

[0437] In another embodiment, the present disclosure provides a method for treating a subject having a gait disorder. The compounds of the present disclosure are provided, wherein the gait disorder is associated with aging. The subject has a geriatric gait disorder. obtain.

[0438] In another embodiment, the present disclosure provides a method for increasing walking speed and / or cadence in a subject. and a compound of the present disclosure for use in a subject, the compound comprising: a compound selected from the group consisting of a compound of the present disclosure for use in a subject; Has a hearing impairment.

[0439] In another embodiment, the present disclosure provides a method for treating a subject having a predisposition to falls. wherein the predisposition to falls is age-related.

[0440] "Cognitive functions" include, for example, perception, memory, image creation, recognition, reasoning, thinking, and judgment. It can refer to any mental process that involves symbolic operations such as cognitive abilities. Measures of intellectual functioning include assessment tools designed to measure, for example: ) general intelligence, (b) nonverbal intelligence, (c) achievement, (d) attention / executive function, and (e) memory and learning. (f) visual-motor and motor function; and (g) language. Such assessment tools are are well known in the field, e.g., the Wechsler Adult Intelligence Scale and the Woodcock-Johnson III Cognitive Abilities Test (both to assess general intelligence), Raven's Progressive Matrices (to assess non-verbal intelligence), Wide Range Achievement Test (WRA), Skill Development Test and Woodcock-Johnson III Academic Achievement Test (to assess academic performance), Conners Test of Sustained Attention II (to assess attention / executive function) (to assess memory and learning), comprehensive assessment of memory and learning, vendor-gaming Stalt test, Halsted-Leitan grip strength test, Halsted-Leitan finger test The Lafayette Grooved Pegboard Task (La fayette Grooved Pegboard Task) (all visual-motor and (to assess motor function), and the Peabody Picture Vocabulary Test (to assess language). Included.

[0441] Cognitive function can also be assessed by measuring reaction speed and activity, such as in psychomotor vigilance tests (e.g., as disclosed in the Examples). This may be assessed using fine motor skills, psychomotor and / or alertness tests. Components such as speed, attention deficits, arousal volatility, and fatigue-induced impulsivity were assessed. It is valued.

[0442] For example, the Psychomotor Vigilance Test (PVT) measures how quickly a subject responds to visual stimuli. This is a test of sustained attention and reaction timing. The subject watches the screen and waits for a visual stimulus to appear. The visual stimulus then disappears and the subject is given a prompt to press the screen as quickly as possible. ) reappear for example 10 times over the course of the test and the subject is asked to respond as soon as possible upon reappearance. Touch the screen. Test performance is quantified, for example, by averaging 10 reaction times. Any change in cognitive function, for example, over time or through treatment, may be observed at two or more time points. Monitoring can be done by using one or more established tests and comparing the results.

[0443] The phrase "improving cognitive function" referred to herein means improving a subject's ability to perform symbolic operations. Ability to perceive, remember, create mental images, have clarity of thought refers to a positive change in the ability to perceive, be aware, reason, think, or judge Positive changes can be seen in baseline cognitive function, e.g., using one of the tests listed above. A first opportunity to measure cognitive function and a second opportunity to measure cognitive function after a period of time (when treatment is administered) Cognitive function can be measured on two or more occasions (including multiple occasions). If an increase in performance of at least approximately 5% is observed between the two time points, the patient is considered to have improved. In the relevant tests, between two points in time, for example, at least At least about 10%, at least about 15%, at least about 20%, at least about 2% At least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least At least about 70%, at least about 80%, at least about 90%, or at least about 100% Furthermore, in related tests, between two time points, e.g. 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% An increase in performance is observed. The two time points are 1 week apart, 2 weeks apart, 3 weeks apart, and 4 weeks apart. May be intervals, 2-month intervals, 3-month intervals, 4-month intervals, 5-month intervals, or 6-month intervals Treatment may be administered during the intervention period. Thus, by way of example, "improvement of cognitive function" may be , subjects achieved baseline intelligence as measured using the established Wechsler Adult Intelligence Scale. It can mean that the subject exhibits at least about a 5% increase in performance from the baseline measurement. In this test, 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 or at least about a 100% increase in performance. In 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 At least 60%, at least 70%, at least 80%, at least 90%, or at least A 100% performance increase can be demonstrated.

[0444] In another embodiment, the present disclosure provides a method for measuring reaction speed, e.g., the speed at which a subject responds to a visual stimulus. The present invention provides compounds of the present disclosure for use in increasing

[0445] In one embodiment, the subject has age-related cognitive decline.

[0446] As used herein, the term "age-related cognitive decline" refers to cognitive decline that occurs during the aging process. refers to cognitive decline that is a direct result of the aging process, not cognitive decline that is not a direct result of the aging process. Clinical symptoms are seen in subjects with age-related cognitive decline. and subjects with cognitive decline that is not a direct result of the aging process. obtain.

[0447] The term "improve" when used in relation to motor and / or cognitive function Treating and / or ameliorating any motor dysfunction and / or cognitive decline in elephants Thus, age-related decline in motor and / or cognitive function may be prevented by the use of the compounds described herein. This can be partially or completely reversed using the compounds of the present disclosure.

[0448] As used herein, the term "restless legs syndrome" or "RLS" means: It includes any form of RLS, including primary RLS and secondary RLS. In another embodiment, RLS is primary RLS. In another embodiment, RLS is secondary RLS. In embodiments, the RLS is secondary to a disease or condition. Examples of 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 damage, rheumatoid arthritis, and sheath disease In another embodiment, the RLS is secondary to a drug or substance. Examples of such drugs or substances include alcohol, caffeine, anticonvulsants (e.g. phenytoin), antidepressants (e.g., amitriptyline, paroxetine), high blood pressure medications (e.g., beta-blockers), antipsychotics, and withdrawal(s) (e.g., vasodilator drugs Examples of neurodegenerative diseases include Parkinson's disease, Lemington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontal lobectomy Temporal dementia, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical dementia 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 Son's disease, Canavan disease, frontotemporal lobar degeneration, narcolepsy, Pelizaeus-Merzbach In one embodiment, the neurodegenerative disease is a primary or specific Primary, secondary or acquired, hereditary parkinsonism, and parkinsonism-plus syndrome or or Parkinsonism, including multiple system degeneration. , is associated with dopaminergic system dysfunction, including dopaminergic cell loss.

[0449] Symptoms associated with RLS include any clinical or laboratory symptoms associated with RLS. The symptoms of RLS are related to illnesses that can be felt or observed by the subject. Symptoms associated with RLS include, but are not necessarily limited to: Leg sensations, periodic leg movements during sleep (PLMS), unpleasant leg sensations, urge to move, restlessness, sleep disturbances These include, but are not limited to, excessive daytime sleepiness.

[0450] In another embodiment, the compounds of the present disclosure may be used to treat one or more symptoms associated with RLS, including those associated with a condition requiring RLS. used in a method for reducing, inhibiting, or eliminating a The method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0451] In another embodiment, the one or more symptoms are leg sensations, periodic leg movements during sleep, unpleasant leg sensations urge to move, restlessness, excessive daytime sleepiness, and / or sleep disturbances are selected from the

[0452] The severity of RLS or one or more symptoms of RLS may be measured using, for example, any known scale, index, rating, or score, e.g., a scale, index, rating, score, or other The preferred test is to assess the overall severity of RLS or the severity of one or more symptoms associated with RLS. In one embodiment, the treatments described herein may correspond to the level or severity of a symptomatic subject. Improve such assessment from a degree characteristic to a value or degree characteristic of a non-symptomatic subject.

[0453] In one embodiment, the treatments described herein improve such outcomes compared to baseline. The baseline may be, for example, a baseline measured before starting any treatment for RLS or after the start of the current study. The condition of the subject may be prior to initiating treatment of RLS with the indicated compound. The line may be, for example, the state of a subject after a period of treatment for RLS.

[0454] In one embodiment, treatment with a compound of the disclosure improves the subject's international rating compared to baseline. Decreases the Stress Legs Syndrome Rating Scale ("IRLS"). IRLS is at least 10%, at least 20%, less than baseline. In one embodiment, the I RLS is at least 60%, at least 70%, at least 80%, at least 90% , or 100% decrease.

[0455] As used herein, the term "dizziness" refers to, for example, benign paroxysmal positional vertigo (BP). PV): Vestibular neuritis; Meniere's disease, Wallenberg's syndrome, cerebral ischemia, perilymphatic fistula or dizziness associated with acoustic neuroma, or recurrent dizziness of traumatic or toxic origin. This includes any form of dizziness.

[0456] Symptoms of dizziness include any clinical or laboratory symptoms associated with dizziness. Symptoms of dizziness include nausea, vomiting, abnormal or spasmodic eye movements (eye strain), headache, sweating, and earache. These include, but are not limited to, ringing and / or hearing loss.

[0457] In the methods of the present disclosure, therapeutically active agents, typically formulated according to pharmaceutical practice, are used. An effective amount of a compound of the present disclosure is administered to a subject, e.g., a human, in need thereof. Whether or not further treatment is indicated will depend on the individual case and on the signs, symptoms, and / or considers the abnormality, specific signs, symptoms, and / or risk of developing the abnormality, and other factors. Subject to a medical evaluation (diagnosis) taking into consideration the patient's condition.

[0458] The compounds of the present disclosure can be administered by any suitable route, for example, oral, buccal, inhalation, sublingual, rectal, or vaginal. intracistern or intrathecal via lumbar puncture, transurethral, ​​transnasal, percutaneous ), i.e., transdermal, or parenteral (intravenous at specific sites) , intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, and intrapulmonary injection and / or by surgical implantation at a specific site). Parenteral administration can be accomplished using a needle and syringe or using high pressure techniques. Cut.

[0459] The pharmaceutical composition contains an effective amount of the compounds of the present disclosure to achieve its intended purpose. The exact formulation, route of administration, and dosage will depend on the diagnosed condition or disease. The dosage and interval should be determined by the individual physician in consideration of the dosage and interval required to maintain the therapeutic effect. can be individually adjusted to provide an appropriate level of the compounds of the present disclosure.

[0460] The toxicity and therapeutic efficacy of the compounds of the present disclosure may be determined, for example, by their lack of toxicity in animals. Cell culture to determine the maximum tolerated dose (MTD) of the compound, defined as the highest dose The maximum tolerated dose may be determined by standard pharmaceutical procedures in humans or experimental animals. The dose ratio between the therapeutic effect, e.g., slowing the progression of LSD or neurodegenerative disease, and The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. Determination of a therapeutically effective amount can be easily accomplished, especially in light of the detailed disclosure provided herein. It is well within the capabilities of one skilled in the art.

[0461] The therapeutically effective amount of a compound of the present disclosure required for use in therapy is determined by the amount of the compound required for the condition being treated. Varying depending on the nature, the length of time for which its activity is desired, and the age and condition of the subject; The dosage and interval should be determined as necessary to maintain the desired therapeutic effect. The desired dose can be individually adjusted to provide adequate plasma levels for the patient. In some cases, the drug may be administered as a single dose or at appropriate intervals, for example, once, twice, three, four or more times a day. can be administered as larger subdoses. Multiple doses are often desirable. For example, compounds of the present disclosure may be administered in four doses, once daily, four days apart. (q4d x 4), four doses delivered as a single daily dose spaced 3 days apart daily doses delivered every 5 days (qdx5); daily doses delivered every 3 weeks (qdx6); Over a period of time, patients received a once-weekly dose (qwk3), five daily doses, and two days off. Five doses daily (5 / 2 / 5), or any dosing regimen deemed appropriate for the situation In situations where chronic treatment is required, the patient may be given e.g. Approximately 3 months, approximately 6 months, approximately 1 year, approximately 2 years, approximately 3 years, approximately 5 years, approximately 10 years, or may be administered multiple times per day for longer periods.

[0462] The compounds of the present disclosure used in the methods of the present disclosure may be administered in doses ranging from about 1 to about 2,000 milligrams per dose. mg, about 100 to about 1,000 mg per dose, or about 250 to about 7 mg per dose For example, the compounds of the present disclosure can be administered in an amount of 1 to 1000 mg. All doses included, approximately 100, 150, 200, 250, 300, 350, 400, 4 50, 500, 550, 600, 650, 700, 750, 800, 850, 900, 9 It may be administered in amounts of 50, or 1,000 mg per dose.

[0463] The compound of the present disclosure used in the method of the present disclosure is administered in a dose of 250 to 15,000 mg per day, 500–10,000 mg per day, 1,000–5,000 mg per day, or It can be administered to a subject in an amount of 1,500 to 2,500 per day. The compound is administered in doses of about 250 mg, about 500 mg, about 750 mg, and about 1,000 mg per day. g, approx. 1,500mg, approx. 2,000mg, approx. 2,500mg, approx. 3,000mg, approx. 3 ,500mg, approx. 4,000mg, approx. 4,500mg, approx. 5,000mg, approx. 6,000 mg, about 7,000mg, about 8,000mg, about 9,000mg, about 10,000mg, Approximately 11,000mg, approximately 12,000mg, approximately 13,000mg, approximately 14,000mg, Alternatively, an amount of about 15,000 mg can be administered to a subject.

[0464] The total daily dose may be spread over multiple doses, i.e., the doses are administered as needed. It may be necessary to administer more than once a day to achieve the desired dose. The number of tablets required to provide the total daily dose may be divided into two doses (e.g., morning and evening) or may be divided into three doses (eg, morning, midday and evening).

[0465] The dosage of the compounds of the present disclosure or compositions containing them is 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 Doses of the composition may include, but are not limited to, about 1 μg / kg. The dosage of the composition can be about 1 μg / kg, about 10 μg / kg, about 25μg / kg, approximately 50μg / kg, approximately 75μg / kg, approximately 100μg / kg, approximately 125 μg / kg, approx. 150 μg / kg, approx. 175 μg / kg, approx. 200 μg / kg, approx. 225 μg / kg, approx. 250 μg / kg, approx. 275 μg / kg, approx. 300 μg / kg, approx. 325 μg / kg, approx. 350 μg / kg, approx. 375 μg / kg, approx. 400 μg / kg, approx. 425 μg / kg, approx. 450 μg / kg, approx. 475 μg / kg, approx. 500 μg / kg, approx. 525 μg / kg, approx. 550 μg / kg, approx. 575 μg / kg, approx. 600 μg / kg, approx. 625 μg / kg, approx. 650 μg / kg, approx. 675 μg / kg, approx. 700 μg / kg, approx. 725 μg / kg, approx. 750 μg / kg, approx. 775 μg / kg, approx. 800 μg / kg, approx. 825 μg / kg, approx. 850 μg / kg, approx. 875 μg / kg, approx. 900 μg / kg, approx. 925 μg / kg, approx. 950 μg / kg, approx. 975 μg / kg, approx. 1 mg / kg, approx. 5 mg / k g, about 10mg / kg, about 15mg / kg, about 20mg / kg, about 25mg / kg, about 3 0mg / kg, approx. 35mg / kg, approx. 40mg / kg, approx. 45mg / kg, approx. 50mg / kg, approx. 60mg / kg, approx. 70mg / kg, approx. 80mg / kg, approx. 90mg / kg, approx. 100mg / kg, approx. 125mg / kg, approx. 150mg / kg, approx. 175mg / kg, approx. The dose may be any dose including, but not limited to, 200 mg / kg or more. The dosages above are exemplary of the average case, but higher or lower dosages may be used. There may be individual cases where it would be beneficial, and such are within the scope of this disclosure. A physician will determine the most appropriate dosage for an individual subject, which may vary depending on the age, weight, and response of the particular subject. Determine the actual dosing regimen.

[0466] kit In another embodiment, the present disclosure provides a method for the preparation of a medicament for use in performing the methods of the present disclosure. The compound of the present disclosure (or a composition containing the compound of the present disclosure) packaged in such a manner as to In one embodiment, the kit comprises a label (and / or instructions) on the container. ) or is packaged in a container such as a sealed bottle or container The compounds or compositions may be included in kits that explain the use of the compounds or compositions to practice the methods of the disclosure. In one embodiment, the compound of the present disclosure (or a composition comprising a compound of the present disclosure) comprises: The compound or composition is packaged in a unit dosage form. The kit may also include a It may further comprise a device suitable for administering the composition by route.

[0467] Therefore, the term "container" refers to any container used to store, ship, distribute, and / or handle pharmaceutical products. "Containers and closures" refers to any suitable containers and closures.

[0468] The term "package insert" refers to the information provided by physicians, pharmacists, and patients to assist them in making informed decisions regarding the use of a product. product investments, along with the necessary safety and efficacy data to enable informed decisions to be made. Package inserts generally refer to the information that accompanies a drug product that provides instructions on how to administer the product. is considered a "label" for

[0469] Personalized Medicine In another embodiment, the present disclosure provides a method for treating LSD or neurodegenerative disorders, migraines, restlessness, Subjects with vertigo, dizziness, and related symptoms, or those with impaired mobility and providing personalized medical procedures for subjects in need of cognitive and / or cognitive function improvement; LSD or neurodegenerative disorders, migraines, restless legs syndrome, or dizziness Individual subjects with symptoms associated with these disorders, or those with improved motor and / or cognitive function This involves selecting the treatment option most likely to be successful for a subject in need of treatment. In some embodiments, the present disclosure provides a method for treating LSD or neurodegenerative diseases, migraines, and restless legs syndrome. or motor function in subjects with dizziness and related symptoms and / or therapeutic outcomes for a subject in need of improving cognitive function, e.g., Use of the assay(s) to predict the likelihood of a favorable response or successful treatment do.

[0470] In another embodiment, the present disclosure provides a method for treating an LSD or neurodegenerative disease with the disclosed compounds. selecting a subject, e.g., a human subject, for the analysis; and collecting a biological sample, e.g., blood cells, from the subject. Obtaining cerebrospinal fluid or cerebrospinal fluid and identifying LSD-related biomarkers or neurodegenerative disease-related biomarkers testing a biological sample from the subject for the presence of a biomarker; and If the patient has abnormal levels of biomarkers in their blood, e.g., accumulated or elevated levels in body fluids, levels of biomarkers, or depleted or reduced levels of biomarkers in body fluids and selecting the subject for treatment if the subject comprises: In one embodiment, the method comprises administering a therapeutically effective amount of a compound of the present disclosure to a biological sample if the biological sample contains a biomarker. In another embodiment, the method further comprises administering to the subject a method for treating migraine, restless legs syndrome, or other conditions. For the treatment of vertigo, dizziness, and related symptoms, or for the improvement of mobility and / or The same method can be applied to subjects for the treatment of rheumatoid arthritis or for the improvement of cognitive function.

[0471] In another embodiment, the present disclosure provides a method for treating a subject with an LSD or a neurodegenerative disease. A method for predicting outcome using LSD-related biomarkers or neurodegenerative disease-related biomarkers. testing a biological sample from a subject for the presence of a biomarker; Detection of the biomarker indicates that the subject will respond favorably to administration of a therapeutically effective amount of a compound of the present disclosure. Favorable responses include: These include, but are not limited to, delaying the onset of symptoms that would normally be expected. In embodiments, the same method for predicting a treatment outcome in a subject includes predicting a treatment outcome in a subject for migraine, restlessness, or other conditions. Subjects with leg syndrome or dizziness and associated symptoms or movements The present invention can be applied to subjects in need of improving cognitive function and / or function.

[0472] In another embodiment, the present disclosure provides a method of treating an LSD or neurodegenerative disease, comprising: The cells of the elephant contain LSD-related biomarkers or biomarkers related to neurodegenerative diseases. A subject, e.g., a human subject, having SD or a neurodegenerative disease is administered a therapeutically effective amount of a disclosed compound. In one embodiment, the subject's cells are , e.g., elevated levels of LSD-related biomarkers or neurodegenerative disease-related biomarkers. markers, or decreased levels of LSD-related biomarkers or neurodegenerative disease-related Once the biomarkers are determined to be present, the subject is selected for treatment with the compounds of the present disclosure. In another embodiment, the compound is selected from the group consisting of migraine headaches, restless legs syndrome, or dizziness, and for the treatment of steroids and their associated symptoms, or for the improvement of motor and / or cognitive function The same method can be applied to the subject.

[0473] In another embodiment, the method of treating a subject having an LSD or neurodegenerative disease comprises administering to the subject and obtaining biological samples from the subjects and determining whether the biological samples are LSD-related biomarkers or related to neurodegenerative diseases. Elevated levels of related biomarkers or LSD-related biomarkers or neurodegenerative diseases determining whether the biological sample contains a decreased level of a disease-associated biomarker and In cases where the level of a marker is elevated or the level of a marker is decreased, the subject is administered a therapeutically effective amount of the compounds of the present disclosure. In another embodiment, the method comprises administering a compound of formula (I) to a patient suffering from migraine, restless legs syndrome, or the like. For the treatment of subjects with or against vertigo, dizziness, or dizziness and related symptoms Applying the same methods to improve motor and / or cognitive performance in elephants can be done.

[0474] As used herein, the term "biomarker" refers to a biomarker that is detected in a subject, either in vivo or in vivo. or a protein that can be detected and / or quantified in a biological sample obtained from a subject. refers to any biological compound such as a protein, protein fragment, peptide, polypeptide, or nucleic acid. Furthermore, biomarkers can be whole, intact molecules or portions thereof. In one embodiment, the expression level of a biomarker is measured. The expression level of a biomarker can be determined, for example, by measuring the expression of a biomarker protein or RNA (e.g., Biomarkers can also be measured by detecting the level of It can also be measured by HPLC-MS / MS. Portions or fragments of biomarkers can be detected or expressed, for example, by antibodies or other specific binding agents. In some embodiments, measurable aspects of biomarkers can be measured. is associated with a given condition in a subject, e.g., a given stage of LSD. For biomarkers detected at the RNA level, such measurable aspects may include, for example, 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. Biomarkers detected at the nucleic acid level With respect to the mutation status, such measurable aspects may include, for example, mutation status, also referred to herein as mutation status. The type, rate, and / or extent of biomarker or biomarker mutations It may include isogenic types.

[0475] As used herein, the term "LSD-associated biomarker" refers to a pathological enzyme deficiency. in the subject as a result of the LSD or as a result of cellular pathological processes associated with LSD. Proteins, protein fragments, peptides, polypeptides, nucleic acids, etc. that accumulate or decrease due to Examples of LSD-related biomarkers include those related to Fabry disease. Globotriaosylceramide (Gb3), globotriaosylsphingosine (L LysoGb3), LysoGb3 analogs, or methylated / unmethylated Gb3 isoforms Glucosylceramide, chitotriosidase (ChT), pulmonary and pulmonary fibrosis associated with Gaucher disease and activation-regulated chemokine (CCL18 / PARC), macrophage inflammatory protein 1 -α and 1-β (MIP-1α and MIP-1β), cathepsin K, gangliosides, G M3 / monosialodihexosylganglioside, glucosylsphingosine, or os Theopontin; galactosylceramide, galactosylfingosine associated with Krabbe disease / Psychosine; Dermatan sulfate, heparan sulfate, keratan sulfate, and cocaine, which are associated with mucopolysaccharidosis Androitin-6-sulfate, chondroitin-4,6-sulfate, hyaluronic acid, glycosaminoglycans Aminoglycan fragment, β-galactosidase, collagen Iα, fatty acid binding protein 5, Nidogen-1, bone oligomeric matrix protein, insulin-like growth factor binding protein 7, or protein HEG1; sphingomyelin, free cofactor associated with Niemann-Pick disease Cholesterol (in fibroblasts), lysosphingomyelin (Lyso-SPM), cholesterol Tan-3β,5α,6β-triol (C-triol), 7-ketocholesterol (7- KC), 24(S)-hydroxycholesterol, NPCBA1 (3β-hydroxy, 7 β-N-acetylglucosaminyl-5-cholenoic acid), NPCBA2 (probably 3β,5α ,6β-trihydroxycholanoyl-glycine), calbindin D, lyso-sphingomyelin Erin-509; and / or glycogen, the tetrasaccharide glucose (Gl c4), myostatin, or insulin-like growth factor-I (IGF-I), For example, but not limited to, Labato et al., Diseases 4: 40(2016);Aerts et al.,J Inherit Metab Di s 34:605-619(2011);and Giese et al.,Orph anet Journal of Rare Diseases 10:78(2015 ) for LSD-related biomarkers.

[0476] As used herein, the term "neurodegenerative disease-associated biomarker" refers to a biomarker associated with a neurodegenerative disease. Proteins, protein fragments, proteins, It refers to any biological compound such as a peptide, polypeptide, or nucleic acid.

[0477] As used herein, the term "migraine-associated biomarker" refers to a biomarker that is a result of a migraine headache. Proteins, protein fragments, peptides, polypeptides, etc. that accumulate or decrease in a subject due to The term refers to any biological compound, such as a peptide, nucleic acid, or the like.

[0478] As used herein, the term "exercise-related biomarker" refers to a biomarker that is associated with a decrease in exercise capacity. Proteins, protein fragments, peptides, It refers to any biological compound such as a polypeptide or nucleic acid.

[0479] As used herein, the term "cognitive function-related biomarker" refers to a biomarker that is associated with a decline in cognitive function. or changes in the protein, protein fragments, or proteins that accumulate or decrease in a subject. The term "biological compound" refers to any biological compound, such as a fragment, peptide, polypeptide, or nucleic acid.

[0480] In certain aspects of the present disclosure, biomarkers are used to identify different phenotypic states (e.g., normal vs. disease). subjects with one phenotypic state (e.g., subjects with LSD) compared to subjects without the disease ) exist differentially.

[0481] In addition to individual biological compounds, the term "biomarker" as used herein is intended to include a group or set of multiple biological compounds. For example, lyso-SM The combination of α-509, lyso-Gb3 may comprise a biomarker. Io Marker" is available in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, It may contain 15, 20, 25, 30 or more biological compounds.

[0482] Determining the plasma level of a biomarker in a subject can be done, for example, by HPLC-MS / MS or or LysoTracker® technology, many of which are known in the art. The specific LSD in a subject or biological sample can be detected using any of the methods described above. Any method known in the art for quantifying relevant biomarkers may be used in accordance with the methods of this disclosure. It can be used in law.

[0483] As used herein, the term "biological sample" refers to a sample containing lyso-SM-509, such as plasma levels of lyso-SM-509. Refers to any tissue or fluid from a subject that is suitable for the detection of biomarkers. Examples of materials include biopsied tissues and / or cells, e.g., solid tumors, lymph nodes, and tissues associated with inflammation. Cavity tissue, tissue and / or cells involved in a condition or disease, blood, plasma, serous fluid, cerebrospinal fluid Other suitable biological fluids include, but are not limited to, saliva, urine, lymph, cerebrospinal fluid, etc. A biological sample will be known to those skilled in the relevant art. Any technique can be used to analyze biomarker expression and / or mutations. , can be obtained using techniques within the ordinary skill of a clinician. In some embodiments, the biological sample comprises blood cells.

[0484] The present disclosure relates to the following specific implementations of personalized medicine for subjects with LSD: Provides form.

[0485] Embodiment I: A method of treating a subject with LSD, comprising administering a therapeutically effective amount of a compound of the present disclosure. and administering to the subject an agent, wherein the cells of the subject are responsive to an elevated or decreased concentration of LS. The method further comprises a D-related biomarker.

[0486] Embodiment II: A method of treating a subject having an LSD, comprising:

[0487] (a) determining the concentration of an LSD-related biomarker in a biological sample from a subject; The concentration is higher or lower than that in a control sample, e.g., a sample from a normal, unaffected subject. or lower than the concentration of the control sample,

[0488] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0489] Embodiment III: Having elevated or decreased concentrations of LSD-related biomarkers A method for treating LSD in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. administering to an elephant.

[0490] The present disclosure relates to personalized medicine for subjects with neurodegenerative diseases, including the following specific The present invention provides an embodiment of the present invention.

[0491] Embodiment I: A method of treating a subject having a neurodegenerative disease, comprising administering a therapeutically effective amount of the present disclosure and administering to a subject a compound of formula (I) to induce cells of the subject to express an elevated or decreased concentration of the compound. The method further comprises a neurodegenerative disease-related biomarker of

[0492] Embodiment II: A method of treating a subject having an LSD, comprising:

[0493] (a) determining the concentration of a neurodegenerative disease-associated biomarker in a biological sample from a subject; and the concentration is higher than the concentration in a control sample, e.g., a sample from a normal, unaffected subject. or lower than the concentration of the control sample,

[0494] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0495] Embodiment III: Elevated or Decreased Concentrations of Neurodegenerative Disease-Associated Biomarkers 20. A method for treating a neurodegenerative disease in a subject having the disorder, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject. The method comprises administering to a subject a compound of formula (I).

[0496] The present disclosure relates to personalized medicine for subjects with migraine and related symptoms. Accordingly, the following specific embodiments are provided.

[0497] Embodiment I: A method of treating a subject having migraine and associated symptoms, comprising: The method comprises administering to a subject a therapeutically effective amount of a compound of the present disclosure, wherein cells of the subject are induced to have elevated levels or or a reduced concentration of a migraine-related biomarker.

[0498] Embodiment II: A method of treating a subject having migraine and associated symptoms, comprising:

[0499] (a) determining the concentration of a migraine-associated biomarker in a biological sample from a subject; The concentration is higher or lower than that in a control sample, e.g., a sample from a normal, unaffected subject. or lower than the concentration of the control sample,

[0500] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0501] Embodiment III: Having elevated or decreased concentrations of migraine-associated biomarkers 1. A method for treating migraine and associated symptoms in a subject, comprising administering to said subject a therapeutically effective amount of The method comprises administering to the subject an amount of a compound of the present disclosure.

[0502] The present disclosure relates to personalized medicine for subjects in need of improving exercise performance. , the following specific embodiments are provided.

[0503] Embodiment I: A method of treating a subject in need of improving exercise capacity, comprising: administering a therapeutically effective amount of a compound of the present disclosure to a subject, wherein cells of the subject are or a reduced concentration of a fitness-related biomarker.

[0504] Embodiment II: A method of treating a subject in need of improving exercise capacity, comprising:

[0505] (a) determining the concentration of a fitness-related biomarker in a biological sample from a subject; The concentration is higher or lower than that in a control sample, e.g., a sample from a normal, unaffected subject. or lower than the concentration of the control sample,

[0506] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0507] Embodiment III: Having elevated or decreased concentrations of fitness-related biomarkers 20. A method for improving exercise capacity in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. administering to an elephant.

[0508] The present disclosure relates to personalized medicine for subjects in need of improving cognitive function. In accordance with the present invention, the following specific embodiments are provided:

[0509] Embodiment I: A method of treating a subject in need of improving cognitive function, comprising: The method comprises administering to a subject an effective amount of a compound of the present disclosure, wherein cells of the subject exhibit elevated levels or comprises a decreased concentration of a cognitive function-related biomarker.

[0510] Embodiment II: A method of treating a subject in need of improved cognitive function, comprising:

[0511] (a) determining the concentration of a cognitive function-related biomarker in a biological sample from a subject; the concentration is higher than the concentration in a control sample, e.g., a sample from a normal, unaffected subject; or lower than the concentration of the control sample,

[0512] (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0513] Embodiment III: A method for treating cognitive function-related biomarkers with elevated or decreased concentrations 10. A method for improving cognitive function in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure. The method comprises administering to a subject. [Example]

[0514] Example 1 General preparation of deuterated N-acetyl-leucine (D-enantiomer, L-enantiomer and D,L-mixture) Selective replacement of one or more hydrogen atoms in leucine with deuterium ("D" or "2H") A wide variety of methods can be used to determine this. Such compounds can be prepared with morphological enrichment. One common method is to It involves deuterating leucine and then converting it to the N-acetyl form. In some cases, the N-acetyl form can be directly deuterated, e.g., This method is consistent for D, L, and D, L mixtures unless otherwise specified. For example, Yamauchi et al., Biosci. Biotech nol.Biochem.70:276-278(2006);Kelly et al .,Nat.Prod.Rep.14:205-219(1997);August e t al., Tetrahedron Lett.33:4617-4620(1992 );Oba et al., Tetrahedron Lett.39:1595-15 98(1998);Hill et al.,Can.J.Chem.72:110-1 13(1994);Kelly et al.,Tetrahedron Lett.3 6:8315-8318(1995);and Fletcher et al.,J. See Chem. Soc., Perkin Trans. I, 43-52 (2000) thing.

[0515] Example 2 Preparation of D-leucine-based compounds The synthesis of D-leucine and its labeled analogues was carried out by converting 2-oxo-4-methylvalerate to D-leucine. This is achieved by reductive amination with amino acid dehydrogenase (DAADH). This can be done.

[0516] While maintaining the pH at 10.5 by adding 1.0 M KOH solution, 10 mM glycine-KOH (pH 10.5), 5.0 mM NADPH, 70 mM NH Cl, 5.0 mM 2-oxoacid (sodium salt), and 2.9 mg DAADH The reaction mixture (1 mL) is incubated at 50°C for 1 hour. The pH value is measured using a pH meter. The reaction is terminated by adding trichloroacetic acid to a final concentration of 10%. After clarifying the mixture by centrifugation and filtration, the resulting D-leucine was separated. It can be purified on a reversed-phase column and detected using a fluorescence detector (at 350 nm). (Excitation at 450 nm and detection at 450 nm). Alternatively, the NADPH regenerating system can be glycine-KOH (pH 10.5), 1.0 mM NADPH or NADP+, 20 0.5 mM glucose, 70 mM NH4Cl, 5.0 mM 2-oxoacids, 2.9 mg D In a reaction mixture (1 mL) containing 0.32 mg of AADH, glucose dehydrogenase It can be used with GDH. By adding 1.0 M KOH solution, The GDH is incubated at 50°C for 1 hour while maintaining the pH at 10.5 by HCl. Leucine is isolated and purified as described above. To incorporate D onto the alpha carbon, The reaction can be carried out in deuterium dioxide. DAADH can be converted to the corresponding hydroxyl group in the presence of ammonia. It catalyzed the production of D-amino acids from 2-oxoacids in excellent yields (>99%) and It produces high enantioselectivity (>99%). (Akita et al., Biotech nol Lett 34:1693(2012)and Akita et al.,B iotechnol Lett 36:2245(2014)).

[0517] Example 3 Method for converting racemic leucine to the L-enantiomer Racemic amino acids can be converted into their L and D enantiomers by enzymatic or chemical procedures. The oxidase-aminotransferase coupled system can be used to A general method for converting amino acids into homochiral products has been reported (Sha h et al., Tetrahedron Lett.35:29-32(1994) This method uses D-amino acid oxidase (EC 1.4.3.3), catalase (E C1.11.1.6), leucine dehydrogenase (EC1.4.1.9), and formate dehydrogenase To produce L-leucine from the racemate by hydrogenase (EC 1.2.1.2), D-leucine can be used to + and ammonium formate In an enzyme system containing Leucine dehydrogenase converts NAD+ to the L-enantiomer completely. In the presence of methionine, various aliphatic L-amino acids, including methionine, are reversibly deacetylated to their α-oxo analogues. The reaction is catalyzed by the formate dehydrogenase reaction. Formate dehydrogenase converts NAD+ to NAD, which favors reductive amination. Catalyzes the irreversible oxidation of formate to CO2 with the concomitant reduction to H. The acid is spontaneously decarboxylated by oxidation with H2O2.

[0518] The reaction mixture was incubated at 37°C and pH 8.0-8.5 with DL-leucine in a final volume of 1 mL. ammonium chloride (25 μmol), Sodium formate (500 μmol), Tris-HCl buffer (pH 8.5; 100 μm ol), D-amino acid oxidase (5 units) from Sigma, Catalytic enzyme from Sigma Enzyme (2 units), Clostridium thermoaceticum AN 2 Leucine dehydrogenase (10 units) from 8-4 and from Boehringer Contains formate dehydrogenase (2 units). After 10 hours of incubation, HCl is added. Add to the mixture to a final concentration of 1.0 M. Add Dowex 50 (H + ) Column(1 × 10 cm) and eluted with 1 M NH4OH. The fractions are pooled, concentrated to a small volume, and then evaporated to dryness under reduced pressure. The residue is dissolved in a small amount of hot 80 % ethanol and crystallize L-leucine at 4°C. -Leucine (0.1M) was purified using a Daicel Crown packed column (0.4 id Based on the separation by enantioselective HPLC with a 1000×50 cm column, the L-enantiomer was converted to the L-enantiomer. (95% yield, i.e., 99% in 2 hours) (Nakajima et al. al.,J.Chem.Soc.,Chem.Commun.13:947-948(1 990)).

[0519] Example 4 Preparation of N-acetylated forms of deuterated leucine analogs Methods for the N-acetylation of amines and α-amino acids, including leucine, have been widely reported. The deuterated leucine analogs synthesized by the above reported methods were The deuterated leucine analogs obtained from the method described below were not N-acetylated. In one method described, acetylation is performed by one of the following methods: The tilizing agent is acetic acid which proceeds as follows: (CH3CO)2O + H2N-CH(R )-COOH → CH3CONH-CH(R)-COOH + CH3COOH. This reaction is It is carried out in an acetic acid environment or in a mixture of water and pyridine. The acetylation of D-leucine and D-leucine was achieved by heating the reaction mixture to 50-70°C. The reaction proceeds efficiently in solution. The optimum molar ratio of amino acid to acetic anhydride is 1.25 to 1. 5. The acetylated product crystallizes from aqueous solution upon cooling and is generally obtained in 75-80% yield. Distilled water (760 mL) was placed in a glass flask equipped with a stirrer and a thermometer. The mixture was placed in a gas reactor, and L-leucine (14.0 mol) was added. The mixture was stirred and heated to 50-55°C. Add acetic anhydride (198%) in small amounts while heating and stirring until completely dissolved. 0 mL, 21.0 mol) was added through a dropping funnel over 2.0 to 2.5 hours. This is added at a rate such that the temperature of the mixture does not exceed 70°C. Heat to 0°C for 0.5 hours and allow to cool to allow crystallization to occur. After mixing for a while, add hydrochloric acid (1060 ml, 37%) dropwise to a pH of 2.0-2.5. The resulting precipitate was collected by filtration and washed on the filter with ice water followed by alcohol. Wash and dry at 50-60°C, then dry in air at 25-30°C. The anhydrous product is obtained by vacuum drying to a constant weight. After evaporation on a rotary evaporator at a bath temperature of 70° C., a further 360 g of product is obtained.

[0520] Example 5 Preparation of compounds deuterated on the α-carbon (C-2) It is rapid, inexpensive, generally applicable, and has been shown to be effective for leucine. Preparations for labeling amino acid positions starting from commercially available amino acids have been reported ( Upson and Hruby, J.Org.Chem.42:2329-2330( In this method, leucine is refluxed in acetic acid and acetic anhydride to give the racemic N- -acetylleucine is obtained by the reaction of acetic anhydride with excess acetic acid in D2O. By treating the amino acid with this solution under reflux for a few minutes, At this position, acylation, racemization, and exchange occur. N-acetylleucine then becomes , pig kidney acylase, carboxypeptidase, or significant cleavage of enantiomeric compounds Other enzymes that can selectively cleave the acetyl group from one stereoisomer without To achieve high levels of exchange, high 2 The H / 1H ratio is required. This condition can be approached in several ways: (a) A high molar excess of acetic acid relative to the amino acid can be used; (b) the amino The acid-labile hydrogen can be subjected to prior exchange, and (c) the exchange reaction can be repeated. One treatment results in an 83% exchange, and a second treatment raises the exchange level to 91%. Fall.

[0521] All prothioleucine (0.01 mol) was added to 3.7 mL of DO by shaking. The mixture is frozen and lyophilized. Immediately, 21.7 mL of A C2O and 2.5 mL of D2O were added to the resulting powder, and the flask was placed in a 170 °C bath. The solution was refluxed for 2 minutes, then cooled (dry tube) and 2 mL of D2O was added. to destroy any remaining AcO and convert any azlactone back to N-acetylleucine. The hydrogen is detectable by proton nuclear magnetic resonance spectroscopy and is collected. The rate is (80%).

[0522] In another example, leucine dehydrogenase can be used to catalyze the exchange of α-protons. This allows the reaction to proceed smoothly. 2 When performed in H2O, L-[2- 2 Preparation of [H]leucine Before the enzyme transformation, 2 By pre-exchanging the α-keto acid in the H2O base, This method is applicable to gram-scale [2,3, 3- 2 This allows for the synthesis of a variety of isotopically labeled α-amino acids, including [H3]leucine. A dehydrogenase (FDH) catalytic system is used to recycle NADH and its α-keto acid and leucine dehydrogenase. The enzyme catalyzes the oxidation of formate to carbon dioxide and releases a hydride ion that reacts with NAD+. releases the hydroxyl group, thus driving the reversible reductive amination reaction in the required direction. , racemic, using an oxidase-aminotransferase coupling system. A general method for converting amino acids into homochiral products has been reported. (Kel ly et al.,Tetrahedron Lett.37:1517-1520( 1996) and Kelly et al., Nat. Prod. Rep. 14:205- 219(1997)).

[0523] Alternatively, enzyme-catalyzed transformations can be used to generate a series of alpha-deuterated L-alanines, including leucine. It has been shown to be useful for the preparation of amino acids (Kelly et al., Tet rahedron Lett.37:1517-1520(1996)). This approach The unlabeled L-amino acids in D20 were lyophilized to form tryptophan-containing enzymes. It involves incubation with dried E. coli B / It7-A cells. The excellent substrate specificity allows the synthesis of a series of α-deuterated α-olefins containing leucine in reasonable yields (43-95%). This makes it possible to prepare substituted L-amino acids.

[0524] Alternatively, the corresponding amino acid can be treated with 0.05 equivalents of benzaldehyde in deuterated acetic acid. By heating at 2000 K, racemic [2- 2 H] amino acids were prepared (Kelly et al. l., Tetrahedron Lett.37:1517-1520(1996)). Conversion of the acids to methyl esters followed by Alcalase-catalyzed decomposition yields over 99% of the A homochiral amino acid incorporating hydrogen was obtained.

[0525] Another method uses a template to synthesize α-deuterated α-amino acid chiral auxiliaries. (Rose et al., J.Chem.Soc., Perkin Trans.1 , 157-165 (1995)). Specifically, refluxing MeO 2 H- 2 Scho in H2O Illkopf's bis-lactim ether, (3R)- or (3S)-3-isopropyl Base-catalyzed deuteration of 2,5-dimethoxy-3,6-dihydropyrazine Without disturbing the stereocenter at C-3, 2 H2] isotope 9 is obtained.

[0526] Ruthenium-catalyzed selective α-deuteration of amino acids was reported by Chatterjee et al. al., Org. Lett. 18:5892-5895 (2016) High deuterium incorporation, selectivity of the α-CH2 proton for the amine functional group, and The low catalyst loading makes this protocol suitable for both laboratory and large-scale preparation of amino acids. It is attractive and advantageous to use complex 1 to efficiently label amino acids, including leucine. By using deuterium oxide, a series of amino acids including leucine can be synthesized. Catalysis was performed. Chatterjee et al., Org. Lett. 18:5 See Table 3 in 892-5895(2016).

[0527] Example 6 Preparation of compounds deuterated on the β-carbon (C-3) The aminotransferase-catalyzed exchange of α-protons with deuterium described in the previous section Using Kelly et al., Tetrahedron Lett. 37:15 17-1520 (1996) before enzymatic conversion. 2 In the H20 base, α-ketone Deuterium can also be incorporated into the β-position by pre-exchanging the hydroxyl group. Cystathionine, an enzyme suitable for the preparation of multigram quantities of homochiral deuterated L-leucine γ-synthase can be used to exchange certain prochiral β-methylene groups (Homer et al.,Anal Biochem.215:211-215(1 993)). 2 33 mM NaHPO, 17 mM KH in H0 (pH 7.2) The reaction was carried out in a buffer of PO4, 1 mM EDTA, and 0.2 mM pyridoxal phosphate. Respond. 2 After pre-exchange of solvent exchangeable protons in HO, L-leucine (20 1 mg / mL) was incubated with cystathionine γ-synthase in the dark at 37°C for 3 days. The product [2S,3R- 2 [H2] leucine was purified by standard procedures. To stereoselectively label the prochiral β-methylene group of L-leucine, A combination of chemoenzymatic approaches was used to synthesize L-threo- and L-erythro-[ 1- 13 C,2,3- 2 H2] used as a modification of those reported for the synthesis of amino acids (Oba et al., Tetrahedron Lett. 39:1 595-1598(1998);Oba et al., J.Chem.Soc.,Pe rkin Trans.1, 1603-1609 (1995)). Stereoselective incorporation of deuterium into the α,β positions of dehydroamino acid derivatives , followed by acylase-mediated decomposition to give L-threo-[2,3 - 2 H2] amino acids. In the L-erythro isomer, then (from the first resolution) The remaining D-threo isomer must be racemized and then subjected to further resolution. The approach provides stereospecificity through the combination of deuterium in the β-methylene group and the prochiral δ-methyl group. This can be extended to differentially label.

[0528] Example 7 Preparation of Compounds Deuterated on the Gamma Carbon (C-4) Deuterium labeling of the delta carbon of L-leucine is described in detail below. This chemoenzymatic method (Fletcher et al., J. Chem. Soc., Per Kin Trans.1,43-51 2000) is heavy at the gamma carbon (C-4). It can be used to synthesize hydrogen-containing leucine analogs, which serve as a source of isotopic labeling. Sodium acetate [ 2 This can be achieved by using phenyl chloride. Valoyl acetate sodium [2- 2 H] to give the mixed anhydride. This is reacted with the lithium salt of 1 to give [4- 2 H]-L-leucine, a precursor of acetylcholine The carboxylated product 12 was obtained in 70% yield.

[0529] Example 8 Preparation of compounds deuterated on the delta carbon (C-5) A strategy for the stereoselective synthesis of leucine and valine using deuterium-labeled methyl groups is reported. It has been done.

[0530] In one method (Hill et al., Canadian Journal of Chemistry 72:10-113(1994)), (R)-pulegone 1 was This is converted to (R)-citronellic acid 2 (R=H) by the procedure described in Scheme 1. See: Methyl ester 2 (R=CH3) using lithium aluminum deuteride Reduction of citronellol-1,1-d23 gave citronellol-1,1-d23, which was then reacted with pyridinium chlorochromate. It can be oxidized to citronellal-1-d4 by ammonium chloride. The acidic hydrogen at C-2 was exchanged with deuterium by several exchanges with NaCO in DO-CHOD, Decarbonylation of the aldehyde to give citronellal-1,2,2-d35 was carried out by Wilkinson. This was achieved by catalysis of (6S)-[7,7,7- 2 H3]-2,6-dimethyl-2-hept The compound 6 was obtained by methyl and trideuteriomethyl The asymmetric center of the rotation axis containing the hydroxyl group (hylomylene) is the cause of the unclear configuration and preservation of the enantiomerically pure form of pulegone. The double bond in 6 was introduced by the Lemieux-Rudloff procedure (10) It is oxidized by (4s)-[5,5,5-2~3]-4-methylpentanoic acid 7. The N-group is introduced in the usual way by α-bromination followed by ammonolysis, and the amino acid is converted to N- The α-acetyl derivative 9 is decomposed by porcine kidney acylase-catalyzed hydrolysis. This gave the (2S,4S) diastereomer 10 of leucine-5-d3, and the recovered amine Acid hydrolysis of 11 gave the (2R,4S) diastereomer 12. Scheme 1 [ka]

[0531] Example 9 Acetyl-leucine-2,3,3,4-d4 and acetyl-L-leucine-2,3,3, Synthesis of 4-d4 Scheme 2 [ka] Step 1: 3-Methylbutanal-2,3-d2(3). Palladium on carbon (1 g, 0.08 equiv., 9 mmol) in deuterium oxide (50 mL) To the mixture, 3-methylbut-2-enal 2 (10.0 g, 11.5 mL, 1 equiv., 1 19 mmol) was added at room temperature. The instrument was evacuated twice and a deuterium-filled balloon was used to The reaction mixture was stirred at room temperature while monitoring the conversion by GC-MS. After 7 days, GC-MS showed nearly complete consumption of the starting material (less than 2% remaining). The Pd / C was removed by filtration over Celite. The filtrate and washings were combined and washed with 3-methylbutadiene in D2O (3 x 4 mL). The solution of nal-2,3-d2 (3) was used directly in the next step. 1 Confirmed by 1 H NMR and GC-MS.

[0532] Step 2: 3-methylbutanal-2,3,3-d 3( 4). Crude 3-methylbutanal-2,3-d2(3)(11 in D2O (29861-24) 9 mmol) was poured into the pressure tube. Pyridine (941 mg, 0.96 mL, 0.1 eq. (11.9 mmol) was added and the mixture was heated in a sealed pressure tube at 130 °C overnight. Ta. 1 H-NMR analysis showed partial H / D exchange. The mixture was heated for an additional 5 days. After this, complete deuterium incorporation was observed. 3-Methylbutanal in DO / pyridine The resulting solution of -2,3,3-d3(4) was used directly in the next step. The structure of 1 Confirmed by 1 H NMR.

[0533] Step 3: 2-hydroxy-4-methylpentanenitrile-3,3,4-d3 (5). 3-Methylbutanal-2,3,3-d3(4) (D2 with 0.1 equivalent of pyridine) The crude solution (in O) was cooled to 10°C and sodium metabisulfite (11.73 g, 61.6 After almost all the solids had dissolved, the mixture was cooled to 4-5°C. Add potassium cyanide (7.305 g, 1 equiv., 112.2 mmol) in small portions. The mixture was stirred at room temperature for 2 hours. The product was extracted with ethyl acetate (3 times). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give 2-hydroxy-4- Methylpentanenitrile-3,3,4-d3 (5) was obtained as an orange oil (4.8 g, 4 1 mmol). The material contained impurities but was used directly in the next step. (5 ) structure 1 Confirmed by 1 H NMR.

[0534] Step 4: 5-(2-methylpropyl-1,1,2-d3)imidazolidine-2,4- Zeon (6) Finely powdered ammonium carbonate (9.3 g, 2.33 equivalents, 96 mmol) was dissolved in deuterium oxide ( 15 mL) and stirred until almost all of the solids were dissolved. Methylpentanenitrile-3,3,4-d3(5) (4.8 g, 1 equivalent, 41 mmol) The mixture was heated in a sealed tube at 100° C. Heated overnight. Volatiles (THF) were removed in vacuo, leaving a suspension in deuterium oxide. A solid was isolated by filtration consisting primarily of the desired hydantoin 6 (2.6 g). was triturated in DCM (10 mL) to give 1.5 g of impure 6 as a yellow solid. 1 Based on the H-NMR spectrum, the incorporation of deuterium into the carbonyl at the alpha position was 60%.

[0535] Step 5: Acetyl-leucine-2,3,3,4-d 4( 1-rac) 5-(2-methylpropyl-1,1,2-d3)imidazolidine-2,4-dione (6 ) (1.5 g, 1 equiv., 9.4 mmol) in DO (21 g, 15 mL, 1 equiv., 9.4 The mixture was suspended in a 40% solution of sodium deuteride in 100 mmol and heated to reflux for 72 hours. The mixture was neutralized with DCl (20% in DO). The neutralized mixture of acetic anhydride (3.8 g, 3 0.6 mL, 4 equiv., 38 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product was filtered off and extracted with THF to give 220 mg of impure product. The remaining aqueous phase was concentrated to dryness and the residue was extracted with THF to give 900 mg of product. Extraction gave an additional 120 mg of product. All product batches were combined and diluted with EtOAc. Precipitation from HCl gave 330 mg of product containing some inorganic impurities. Treatment with methyl ether afforded an additional 300 mg of product. Both precipitated product fractions were combined. 630 mg of material was obtained, which was purified by a small plate of silica gel using MeOH in DCM. The mixture was then flushed over a rag to remove inorganic impurities. l, 29%) of rac-acetyl-leucine-2,3,3,4-d4(1-rac) It was obtained with a purity of over 8% (ELSD). The structure of (1-rac) was 1 H NMR and LCM Confirmed by S.

[0536] Step 6: Acetyl-L-leucine-2,3,3,4-d4(1) Chiral resolution of acetyl-leucine-2,3,3,4-d4(1-rac) was performed using chiral Preparative HPLC was used. The enriched fraction from this separation was purified by acetyl-L-leucine-2 The ammonium salt of 3,3,4-d4 was removed by freeze-drying. 1.0g of 1-rac provides acetyl-L-leucine-2,3,3,4-d4 (320m g) and acetyl-D-leucine-2,3,3,4-d4 (340 mg) were isolated. Acetyl-L-leucine-2,3,3,4-d4 (1) was obtained with a purity of 99.6% (EL SD) and had an optical purity of 97% ee.

[0537] Example 10 Acetyl-leucine-2,3,3-d3 and acetyl-L-leucine-2,3,3-d3 Synthesis of [ka] Acetyl-leucine-2,3,3-d3 and acetyl-L-leucine-2,3,3-d 3 can be prepared using the method described in Example 9.

[0538] Example 11 Measurement of lysosomal volume by flow cytometry The techniques applied in this study are based on those described by Vruchte et al., J. Clin. Inve st.3:1320-1328(2014). Briefly, Tei Human fibroblasts derived from patients with Sachs disease, AB variant, were analyzed by the NINDS Human n Genetic Repository at the Coriell Inst itute,403 Haddon Avenue,Camden,New Jersey Fibroblasts or Chinese hamster ovary cells were purchased from Eppendorf, NY, 08103, USA. Cells were grown in T75 culture flasks, treated with compounds for 7 days, trypsinized, and centrifuged. The hearts were separated (180 g, 5 min), washed twice with 1x PBS, centrifuged again, and resuspended in 1x PBS. 00 nM LysoTracker-green DND-26 (Invitrogen) After incubation, the cells were centrifuged (80 0g, 5 min), 0.5 ml of FACS buffer (0.1% BSA, 0.02 M in 1x PBS) NaN3) and kept on ice for up to 1 hour before flow cytometry analysis ( BD Biosciences FACSCanto II or Accuri C6 Cytometer Setup and Tracking Beads Calibrate the cytometer using BD FACSDiva software ( BD) or BD Accuri C6 Plus software (BD) to Use cells stained with ysotracker or propidium iodide and provided compensation.

[0539] Acetyl-leucine-2,3,3,4-d4 (rac-N-acetyl-leucine-d4 ) is derived from acetyl-leucine (called N-acetyl-DL-leucine) For example, 1 mM acetyl-leucine-2,3,3,4- d4 significantly reduced LysoTracker fluorescence levels compared to 1 mM acetyl-leucine. The NPC CHO cell line and Tay-Sachs disease AB variant human fibroblasts showed a significant decrease. The effect was observed in both cell lines. The results are shown in Figures 1 and 2.

[0540] Example 12 Pharmacokinetic studies Acetyl-leucine, Acetyl-L-leucine, Acetyl-leucine-2,3,3,4 -d4(1-rac), and acetyl-L-leucine-2,3,3,4-d4(1), Male BALB / c mice were administered the drug orally (po). Plasma and tissue samples were collected at the designated Plasma concentrations versus time curves are shown in Figures 3 to 6. vinegar.

[0541] After administration of a nominal dose of 100 mg / kg acetyl-leucine po, 86,100 n g / ml of acetyl-D-leucine max was achieved 0.25 hours after administration, and AUC last was 57,800 h*ng / ml, and 3,410 ng / ml of acetyl-L -C of leucine max was achieved 0.25 hours after administration, and AUC last 2,600 hours Therefore, the ratio of L-isomer to D-isomer was C max and AUC last Both were 0.04. See Figure 3.

[0542] Acetyl-leucine-2,3,3,4-d4(1-ra) at a nominal dose of 100 mg / kg c) After po administration of 50,600ng / ml of acetyl-D-leucine-2,3,3 ,4-d4 C max was achieved 0.50 hours after administration, and AUC last is 99,600 time*ng / ml, and 3,880ng / ml of acetyl-L-leucine-2,3,3 ,4-d4(1)C max was achieved 0.25 hours after administration, and AUC last 3,4 30 hours*ng / ml. Therefore, the L / D ratio was C max So 0.08 and AUC last The result was 0.03. See Figure 4.

[0543] After administration of a nominal dose of 100 mg / kg acetyl-L-leucine po, 436 ng / ml of acetyl-D-leucine C max was achieved 0.25 hours after administration, and AUC la st was 573 h*ng / ml, and 16,800 ng / ml of acetyl-L-leucine C of N max was achieved 0.25 hours after administration, and AUC last 11,400 hours*n g / ml. Therefore, the ratio of L-isomer to D-isomer is C max is 38.5, and AU C last The figure was 19.8. See Figure 5.

[0544] Acetyl-L-leucine-2,3,3,4-d4(1) at a nominal dose of 100 mg / kg After po administration of acetyl-D-leucine-2,3,3,4- C of d4 max was achieved 0.25 hours after administration, and AUC last3,150 hours*n g / ml and 29,300 ng / ml of acetyl-L-leucine-2,3,3,4- d4(1) C max was achieved 0.25 hours after administration, and AUC last is 18,200 The L / D ratio was C max The AUC is 9.08. l ast The result was 5.78. See Figure 6.

[0545] These data were obtained after administration of either deuterated or non-deuterated acetyl-leucine. When acetyl-D-leucine-2,3,3,4-d4 / acetyl-D-leucine C m ax and AUC last The ratios of acetaldehyde and acetaminophen were 0.59 and 1.72, respectively. C of acetyl-L-leucine-2,3,3,4-d4(1) / acetyl-L-leucine max and AUC last The ratios were 1.14 and 1.32, respectively.

[0546] These data also show that the acetyl-L-leucine When administered, acetyl-D-leucine-2,3,3,4-d4 / acetyl-D-leucine Shin's C max and AUC last The ratios were also 7.40 and 5.50, respectively. This indicates that acetyl-L-leucine-2,3,3,4-d4(1) / acetyl-L-leucine Ishin's C max and AUC last The ratios were 1.75 and 1.61, respectively.

[0547] Although the methods, compounds, and compositions described herein have been fully described herein, The scope of the methods, compounds, and compositions provided herein or any embodiment thereof is not affected by the claims. and to do so within a wide range of equivalent conditions, formulations, and other parameters without It will be understood by those skilled in the art that all of the patents cited herein are incorporated by reference. All patent applications and publications are incorporated herein by reference in their entirety. The present application provides the following aspects of the invention. (Aspect 1) A compound having formula I, (chemical 1) TIFF2026016521000039.tif38170, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; 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 the following is about 15% or more; however, (a)R 13 is hydrogen, R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 1 0 , R 11 , and R 12 at least one of is hydrogen, (b) The compound, or a pharmaceutically acceptable salt thereof, is not: A salt or solvate thereof. (chemical 2) TIFF2026016521000040.tif99170TIFF2026016521000041.tif146170(Aspect 2) The compound of embodiment 1, wherein the compound having formula I is optically active, or A pharmaceutically acceptable salt or solvate. (Aspect 3) The compound according to aspect 2, having formula II: (C3) TIFF2026016521000042.tif38170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 4) The compound of embodiment 2 having formula III: (C4) TIFF2026016521000043.tif37170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 5) A compound according to aspect 2 having formula IV: (C5) TIFF2026016521000044.tif37170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 6) The compound of embodiment 2 having formula V: (6) TIFF2026016521000045.tif37170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 7) R1 is hydrogen; or a pharmaceutically acceptable salt thereof. Acceptable salts or solvates. (Aspect 8) R 2 But, -CR 2a R 2b R 2c and R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium , R 2a , R 2b , and R 2c Deuterium enrichment of at least one of these is approximately 15% or more. A compound according to any one of aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Or a solvate. (Aspect 9) R 2a , R 2b , and R 2c is hydrogen, or a pharmaceutical composition thereof. A physiologically acceptable salt or solvate thereof. (Aspect 10) R 13 is hydrogen; or a pharmaceutical composition thereof. A salt or solvate acceptable to (Aspect 11) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 11. The method of any one of aspects 1 to 10, wherein the deuterium enrichment of any two or more of the or a pharmaceutically acceptable salt or solvate thereof. (Aspect 12) R 3, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 12. The compound of embodiment 11, wherein the deuterium enrichment of any three or more is about 15% or greater; or A pharmaceutically acceptable salt or solvate thereof. (Aspect 13) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 13. The compound of embodiment 12, wherein the deuterium enrichment of any four or more is about 15% or greater; or A pharmaceutically acceptable salt or solvate thereof. (Aspect 14) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 14. The compound of embodiment 13, wherein any five or more deuterium enrichments are greater than or equal to about 15%; or A pharmaceutically acceptable salt or solvate thereof. (Aspect 15) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 15. The compound of embodiment 14, wherein the deuterium enrichment of any six or more is about 15% or greater; or A pharmaceutically acceptable salt or solvate thereof. (Aspect 16) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 15. The compound of embodiment 14, wherein any seven or more deuterium enrichments are about 15% or greater; or A pharmaceutically acceptable salt or solvate thereof. (Aspect 17) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 17. The compound of embodiment 16, wherein the deuterium enrichment of any eight or more is about 15% or greater; or A pharmaceutically acceptable salt or solvate thereof. (Aspect 18) R 7 The deuterium enrichment is about 15% or more, R 10 The deuterium enrichment is about 15% or more, R 6 , R 8 , R 9 , R 11 , and R 12 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. (Aspect 19) R 7 and R 8 The deuterium enrichment is about 15% or more, R 10 and R 11The deuterium enrichment is about 15% or more, R 9 and R 12 is hydrogen; or a pharmaceutically acceptable salt thereof. A salt or solvate thereof. (Aspect 20) A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: salts or solvates thereof. (C7) TIFF2026016521000046.tif132170 (Aspect 21) 3. A compound according to aspect 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: salts or solvates thereof. (8) TIFF2026016521000047.tif132170 (Aspect 22) 3. A compound according to aspect 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: salts or solvates thereof. (9) TIFF2026016521000048.tif133170 (Aspect 23) A compound according to any one of aspects 1 to 22, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising the solvate and a pharmaceutically acceptable excipient. (Aspect 24) A method for treating or slowing the progression of a lysosomal storage disorder, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound having formula I, (C10) TIFF2026016521000049.tif37170, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, R3 , 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 The method, wherein the deuterium enrichment of any one or more of the above is about 15% or more. (Aspect 25) A method of providing neuroprotection to a subject having a lysosomal storage disorder, comprising: administering to a subject a therapeutically effective amount of a compound having formula I, (Case 11) TIFF2026016521000050.tif36170, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 The method, wherein the deuterium enrichment of any one or more of the above is about 15% or more. (Aspect 26) A method for treating or slowing the progression of a neurodegenerative disease, comprising administering to a person in need thereof administering to a subject a therapeutically effective amount of a compound having formula I, (C12) TIFF2026016521000051.tif36170, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 brain The method, wherein the deuterium enrichment of any one or more of the components is about 15% or more. (Aspect 27) Treating or slowing the progression of neurodegenerative diseases associated with lysosomal storage defects to improve mobility and / or or improve cognitive function, treat or prevent restless legs syndrome, or A method for treating or preventing dizziness or vertigo, comprising administering to a subject in need thereof an effective amount of a compound having formula I; (C13) TIFF2026016521000052.tif37170, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11、 R 12 , and R 13 of The method, wherein the deuterium enrichment of any one or more of the components is about 15% or more. (Aspect 28) 28. The compound of any one of embodiments 24 to 27, wherein the compound having formula I is optically active. How to post. (Aspect 29) The optically active compound having formula I is a compound having formula II: (C14) TIFF2026016521000053.tif38170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 30) The compound having formula I is a compound having formula III, (C15) TIFF2026016521000054.tif37170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 31) The compound having formula I is a compound having formula IV, (C16) TIFF2026016521000055.tif37170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 32) The compound having formula I is a compound having formula V: (C17) TIFF2026016521000056.tif36170 or a pharmaceutically acceptable salt or solvate thereof. (Aspect 33) R 1 is hydrogen. A salt or solvate acceptable to (Aspect 34) R 2 But, -CR 2a R 2b R 2c and R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen and deuterium , R 2a , R 2b , and R 2c Deuterium enrichment of at least one of the following is approximately 15% or more: 34. The method of any one of Aspects 24 to 33, wherein: Or a solvate. (Aspect 35) R 2a , R 2b , and R 2c is hydrogen. A physiologically acceptable salt or solvate thereof. (Aspect 36) R 13 is hydrogen. A physiologically acceptable salt or solvate thereof. (Aspect 37) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 37. The method of any one of embodiments 24 to 36, wherein the deuterium enrichment of any two or more of the or a pharmaceutically acceptable salt or solvate thereof. (Aspect 38) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 38. The method of embodiment 37, wherein any three or more deuterium enrichments are greater than or equal to about 15%. A pharmaceutically acceptable salt or solvate of (Aspect 39) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 , R 10 , R 11 , and R 12 Our house 39. The method of embodiment 38, wherein any four or more deuterium enrichments are greater than or equal to about 15%; or A pharmaceutically acceptable salt or solvate of (Aspect 40) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 40. The method of embodiment 39, wherein any five or more deuterium enrichments are greater than or equal to about 15%; or A pharmaceutically acceptable salt or solvate of (Aspect 41) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 41. The method of embodiment 40, wherein any six or more deuterium enrichments are greater than or equal to about 15%. A pharmaceutically acceptable salt or solvate of (Aspect 42) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 42. The method of embodiment 41, wherein any seven or more deuterium enrichments are greater than or equal to about 15%. A pharmaceutically acceptable salt or solvate of (Aspect 43) R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Our house 43. The method of embodiment 42, wherein any eight or more of the deuterium enrichments are greater than or equal to about 15%. A pharmaceutically acceptable salt or solvate of (Aspect 44) R 7 The deuterium enrichment is about 15% or more, R 10 The deuterium enrichment is about 15% or more, R 6 , R 8 , R 9 , R 11 , and R 12 is hydrogen. or a pharmaceutically acceptable salt or solvate thereof. (Aspect 45) R 7 and R 8 The deuterium enrichment is about 15% or more, R 10 and R 11 The deuterium enrichment is about 15% or more, R 9 and R 12 is hydrogen, or a pharmaceutically acceptable salt thereof. A salt or solvate thereof. (Aspect 46) Any of aspects 24-27, wherein the compound having formula I is selected from the group consisting of: 10. The method according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof. (C18) TIFF2026016521000057.tif132170 (Aspect 47) The method of embodiment 46, wherein the compound having formula I is selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof. (C19) TIFF2026016521000058.tif132170 (Aspect 48) The method of embodiment 46, wherein the compound having formula I is selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof. (20) TIFF2026016521000059.tif133170 (Aspect 49) Methods for treating or slowing the progression of lysosomal storage disorders, neurodegenerative diseases Methods for treating or delaying the progression of neurodegenerative disorders associated with lysosomal storage defects - Patent Application 20070122999 Methods for treating or slowing the progression of sexual disorders, migraines and related symptoms Methods for treating or preventing restless legs syndrome and related symptoms Methods for treating or preventing dizziness, and methods for treating or preventing dizziness and related symptoms for use in a method of preventing or improving motor and / or cognitive function, A compound having formula I, (21) TIFF2026016521000060.tif37170 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; 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 the following is about 15% or more: A compound having the formula I above, or a pharmaceutically acceptable salt or solvate thereof. (Aspect 50) 1. A compound of formula I for use in providing neuroprotection in a subject with a lysosomal disorder. a compound having (22) TIFF2026016521000061.tif37170 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; 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 the following is about 15% or more: A compound having the formula I above, or a pharmaceutically acceptable salt or solvate thereof. (Aspect 51) Treating or slowing the progression of lysosomal storage disorders, treating neurodegenerative diseases and the treatment of neurodegenerative diseases associated with defects in lysosomal storage, which may improve or delay the progression of such diseases. Treat or slow the progression of migraines and related symptoms May prevent or treat restless legs syndrome and related conditions to treat or prevent dizziness and related symptoms, or to improve mobility A compound having formula I in the manufacture of a medicament for improving motor activity and / or cognitive function. (23) TIFF2026016521000062.tif38170 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , R 12 , and R 13 The deuterium enrichment of any one or more of the following is about 15% or more: The above use. (Aspect 52) In the manufacture of a medicament for providing neuroprotection in a subject with a lysosomal disorder, A compound having formula I, (24) TIFF2026016521000063.tif38170 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; 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 the following is about 15% or more: The above use. (Aspect 53) Methods for treating or slowing the progression of lysosomal storage disorders, neurodegenerative diseases Methods for treating or delaying the progression of neurodegenerative disorders associated with lysosomal storage defects - Patent Application 20070122999 Methods for treating or slowing the progression of sexual disorders, migraines and related symptoms Methods for treating or preventing restless legs syndrome and related symptoms Methods for treating or preventing dizziness, and methods for treating or preventing dizziness and related symptoms for use in a method of preventing or improving motor and / or cognitive function, A compound having formula I, (25) TIFF2026016521000064.tif38170 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 The compound having formula I, wherein the deuterium enrichment of any one or more of or a pharmaceutically acceptable salt or solvate thereof; a pharmaceutically acceptable carrier; and A pharmaceutical composition comprising: (Aspect 54) 1. A compound having formula I for use in providing neuroprotection in a subject with a lysosomal disorder. Compounds (26) TIFF2026016521000065.tif38170 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 The compound having formula I, wherein the deuterium enrichment of any one or more of or a pharmaceutically acceptable salt or solvate thereof; a pharmaceutically acceptable carrier; and A pharmaceutical composition comprising: (Aspect 55) A compound having formula I, (27) TIFF2026016521000066.tif39170 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 The compound having formula I, wherein the deuterium enrichment of any one or more of or a pharmaceutically acceptable salt or solvate thereof with a compound for treating a lysosomal storage disorder. or slowing the progression of a neurodegenerative disease, and treating or slowing the progression of neurodegenerative diseases associated with lysosomal storage defects. Delay, treat or prevent migraines and related symptoms, restlessness Treating or preventing leg syndrome and related symptoms, to treat or prevent symptoms associated with, or improve motor and / or cognitive function and instructions for administering the compound to a subject to improve the efficacy of the compound. (Aspect 56) A compound having formula I, (28) TIFF2026016521000067.tif38170 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 But hydrogen and C 1-6 is selected from the group consisting of alkyl, R 2 But C 1-6 is alkyl, 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; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 The compound having formula I, wherein the deuterium enrichment of any one or more of or a pharmaceutically acceptable salt or solvate thereof, and a subject having a lysosomal disorder and instructions for administering the compound to a subject to provide neuroprotection in the Hmm, Kit.

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, which is 【Chemistry 1】 。

2. A compound, or a pharmaceutically acceptable salt or solvate thereof, which is 【Chemistry 2】 。

3. Methods for treating or slowing the progression of lysosomal storage disorders, neurodegenerative diseases Methods for treating or delaying the progression of neurodegenerative disorders associated with lysosomal storage defects - Patent Application 20070122999 Methods for treating or slowing the progression of sexual disorders, migraines and related symptoms Methods for treating or preventing restless legs syndrome and related symptoms Methods for treating or preventing dizziness, and methods for treating or preventing dizziness and related symptoms and a pharmaceutical composition for use in a method for preventing or improving motor and cognitive function.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solution thereof. The pharmaceutical composition comprises a vehicle and a pharmaceutically acceptable carrier.

4. For use in methods of treating or slowing the progression of lysosomal storage disorders The pharmaceutical composition according to claim 3.

5. The lysosomal storage disorder is Niemann-Pick type C (NPC), Tay-Sachs disease, 4. The method of claim 3, wherein the disease is Ndhoff's disease, GM1 gangliosidosis, or Fabry's disease. A pharmaceutical composition comprising:

6. For use in a method for treating or preventing migraine headaches and associated symptoms, The pharmaceutical composition according to claim 3.

7. Methods for treating or preventing restless legs syndrome and related symptoms 4. The pharmaceutical composition according to claim 3 for use in

8. For use in a method for treating or preventing dizziness and related symptoms, The pharmaceutical composition according to claim 3.

9. 4. The pharmaceutical composition of claim 3 for use in a method for improving motor and cognitive function.

10. Pharmaceutical compositions for use in providing neuroprotection in subjects with lysosomal disorders 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprises the solvate and a pharmaceutically acceptable carrier.

11. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof. , treating or slowing the progression of lysosomal storage disorders, treating neurodegenerative diseases - Patents.com and the treatment of neurodegenerative diseases associated with defects in lysosomal storage, which may improve or delay the progression of such diseases. Treat or slow the progression of migraines and related symptoms May prevent or treat restless legs syndrome and related conditions to treat or prevent dizziness and related symptoms, or to improve mobility and instructions for administering the compound to a subject to improve motor and cognitive function. Hmm, Kit.

12. The instructions include administering a lysosomal storage disorder to a subject in need thereof for the treatment or slowing the progression of the disorder. The kit of claim 11 for administering the compound to a subject.

13. The lysosomal storage disorder is Niemann-Pick type C (NPC), Tay-Sachs disease, 13. The method according to claim 12, wherein the disease is Ndhoff's disease, GM1 gangliosidosis, or Fabry's disease. Kit included.

14. The instructions are for administering a prescription to treat or prevent migraines and related symptoms.

12. The kit of claim 11, for administering the compound to a subject.

15. The instructions are for treating or preventing restless legs syndrome and its associated symptoms. The compound of claim 11 is for administering to a subject for prophylaxis. tt.

16. The instructions are for use in treating or preventing dizziness and related symptoms.

12. The kit of claim 11, for administering the compound to a subject.

17. The instructions are for administering the compound to a subject to improve motor and cognitive performance. The kit of claim 11 ,

18. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof. administering the compound to provide neuroprotection in a subject with a lysosomal disorder and instructions for using the kit.

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