Vesdofloradimos and related structures as nurr1 agonists

Abstract

The present invention relates to a method of treating or ameliorating a neurodegenerative disease (e.g. Parkinson's disease or multiple sclerosis) using a compound according to formulae (I) to (V) or using a compound according to formula (VI) or a pharmaceutically acceptable salt or solvate thereof (e.g., vidofludimom for use as a Nurr1 agonist).

Description

TECHNICAL FIELD

[0001] Described herein are methods of treating or ameliorating a neurological disease (e.g., a neurodegenerative disease such as Parkinson’s disease (PD) or multiple sclerosis (MS)) using a compound according to Formula (I) to (V) or using a compound according to Formula (VI) or a pharmaceutically acceptable salt or solvate thereof (in particular, vidofludimus), which, in addition to the known mode of action as a dihydroorotate dehydrogenase (DHODH) inhibitor, unexpectedly also acts as a nuclear receptor-related factor 1 (Nurr1) agonist. This dual mode of action provides significant benefits: a) inhibition of DHODH is beneficial to counter inflammation, and b) activation of Nurr1 is known to protect neurons from injury and death. Compounds previously described as DHODH inhibitors, as well as novel compounds, were shown to directly bind to Nurr1, activate the expression of Nurr1, and mediate activity through Nurr1 in cells. Thus, the compounds can be used to inhibit DHODH and / or activate Nurr1, providing benefits for treating neurological diseases, e.g., inflammatory neurological diseases such as PD, MS, and the like. BACKGROUND

[0002] Neurodegenerative diseases are characterized by progressive loss of neuronal structure and function. In subjects with these diseases, neurodegeneration typically worsens over time, leading to impaired or lost nervous system function. To date, there are no known cures for neurodegenerative diseases.

[0003] The rising prevalence of neurodegenerative diseases has prompted research into improved methods of diagnosing affected subjects, as well as therapeutic methods that can slow or reduce disease progression and / or ameliorate disease symptoms. For certain diseases, biomarkers associated with neurodegeneration provide valuable information about the molecular mechanisms by which their absence or dysfunction can cause disease. Exemplary biomarkers include, but are not limited to, Nurr1, NFL, GFAP, GDNF, BDNF, VMAT2, TH, L-DOPA, CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B, and combinations thereof.

[0004] Nurr1 is the second member of the nerve growth factor-induced orphan nuclear receptor b subfamily (NR4A2). Nurr1 is a neuroprotective transcription factor that is mainly present in the central nervous system and is highly expressed in neurons. Nurr1 has neuroprotective and anti-neuroinflammatory activities and emerges as an attractive target for the treatment of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). The expression level of miR-132 is negatively correlated with its downstream molecule Nurr1, which is one of the key factors to maintain dopaminergic function and is downregulated in PD.

[0005] Neurofilament light chain (NFL) can be measured in cerebrospinal fluid (CSF) and can be used to diagnose and predict the progression of several neurodegenerative diseases (Delaby et al. (Sci. Rep. 2020; 10: 9161) and Gaetani et al. (J. Neurol. Neurosurg. Psychiatry 2019; 90: 870).

[0006] GFAP can be very suitable to detect relapse-independent neurodegeneration compared to the worsening of disability associated with relapses in MS (Meier et al., JAMA Neurol. 2023; 80: 287).

[0007] Other representative examples of biomarkers whose induction or activity of the gene / protein has been associated with neurodegenerative diseases are GDNF, BDNF, VMAT2, TH, L-DOPA, or GFAP in serum, plasma, or CSF. In a study of age-related MS severity, other biomarkers such as CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B, NFL, and combinations thereof have been used to predict the severity of disability worsening in MS (Nat. Commun. 2023; 14: 6903).

[0008] These studies suggest that the exemplary biomarkers play a role in the development and / or progression of multiple sclerosis. MS is a neurodegenerative disease characterized by autoimmune attacks on myelin in neurons in the brain and spinal cord. Symptoms of MS include physical impairments such as fatigue, loss or changes in sensation and coordination, vision impairment, muscle weakness and / or spasticity, and mental impairments such as cognitive impairment, emotional instability, depression, and anxiety. There is currently no known cure for MS, and treatment of disease symptoms is particularly challenging due to the combined effects of inflammation and neurodegeneration in multiple disease pathways. In addition, MS manifests in different forms, such as relapsing (relapsing MS or RMS), in which disease symptoms occur in isolated episodes, and progressive (progressive MS or PMS), in which disease symptoms gradually worsen over time. Patients show wide heterogeneity in the appearance, duration, progression, and response to treatment of symptoms. Thus, while current disease-modifying therapies (DMTs) for MS can delay disability onset in some patients, most DMTs only address relapse-related disability worsening issues and show the greatest benefit in patients with relapse-associated worsening of disability (RAW) at the earliest stages of MS. To date, most DMTs have been approved for treating relapses associated with RMS or PMS, while other forms of MS are not adequately treated. There is an unmet need for therapeutic approaches suitable for different forms of MS, as well as for therapeutic approaches for both early and late stages of MS.

[0009] Recent preclinical and clinical studies using vedolizumab have shown that this potent DHODH inhibitor is effective in treating immune-related disorders, including MS. In an animal model of relapsing-remitting MS (RRMS), treatment with vedolizumab calcium resulted in greater reduction of brain lesions compared to control treatment (Muehler et al., Mult. Scler. Relat. Disord. 2020; 43: 102129). Similar results were demonstrated in the EMPhaSIS clinical trial (NCT03846219), in which RRMS patients treated with vedolizumab calcium for 12 or 24 weeks had significantly fewer unique active brain lesions and lower confirmed disability worsening rates over time compared to patients treated with placebo (U.S. Patent No. 11877994B2). The positive impact on relapsing-remitting multiple sclerosis patients can be attributed to the anti-inflammatory properties of vedolizumab, such as those mediated by DHODH inhibition.

[0010] In other studies, veddiflunamide has proven to be effective and well tolerated in human patients. In the COMPONENT trial (NCT01010581), safety data for veddiflunamide were established in patients with rheumatoid arthritis (Muehler et al., Drugs R D 2019; 19:351). Safety, tolerability, and pharmacokinetics were also determined in healthy subjects (Muehler et al., Eur. J. Drug Metab. Pharmacokinet. 2020; 45:557). Furthermore, the antiviral effect of veddiflunamide was confirmed in studies on mammalian viruses (Kim et al., Viruses 2020; 12:821) and SARS-CoV-2 (Hahn et al., Viruses 2020; 12: 1394; Stegmann et al., iScience 2022; 25: 104293; and Vehreschild et al., Infect. Dis. Ther. 2022; 11: 2159). Finally, veddiflunamide has been investigated as a farnesoid X receptor (FXR) modulator (Zhu et al., Front. Pharmacol. 2020; 11:590 and Heering et al., ACS Chem. Biol. 2022; 17:3159), a New Delhi metallo-beta-lactamase 1 (NDM-1) inhibitor, an antibiotic protector (Chinese patent application No. CN113842380), and a potential treatment for inflammatory diseases including Alzheimer’s disease (patent application No. WO 2018 / 177151).

[0011] Overall, these studies suggest that veddiflunamide is a promising candidate for the treatment of many disorders, including MS. However, there is still a need in the art for new methods of applying the knowledge of immune diseases, neurodegenerative diseases, and biomarkers to the diagnosis and / or treatment of neurodegenerative diseases. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 Depicted is the binding of Example 1 (veddiflunamide) and Example 3 to the transcription factor Nurr1 (NR4A2) in an isothermal titration calorimetry (ITC) assay according to Example 1. Data show K d 0.7 µM and 0.3 µM, respectively.

[0013] Figure 2 Depicted are representative plots of the activation of the transcription factor Nurr1 (NR4A2) using compound Example 1 in a Gal4 assay according to Example 101-A (left) and a full-length assay according to Example 101-B (right). Data show EC 50(Gal4-Nurr1) was 0.40 ± 0.20 µM.

[0014] Figure 3 Gene expression of tyrosine hydroxylase (TH) is shown using compound Example 1 (as its calcium salt IMU-838) and Example 3. Dose-dependent activation of target gene vesicular amino acid transporter 2 (VMAT2) is depicted using compound Example 3.

[0015] Figure 4 Gene expression of Nurr1 target gene brain-derived neurotrophic factor (BDNF) in PBMCs is shown when treated with IMU-838 (3 µM), while the comparative DHODH inhibitor teriflunomide has no effect at the same concentration.

[0016] Figure 5 Reduction of apoptosis in a neuronal-like cell line is shown when treated with Example 3.

[0017] Figure 6 Plots of change in serum neurofilaments from baseline versus number of relapses during the main treatment period. Cohort 1 and cohort 2 full analysis set for patients with no relapse up to week 24.

[0018] Figure 7 A powder X-ray diffraction pattern of polymorph A of IMU-838 is depicted.

[0019] Figure 8 Plots of disability progression versus time for RRMS, active SPMS, non-active SPMS, and PPMS are shown.

[0020] Figure 9 Serum neurofilament data from biomarker interim analysis CALLIPER (phase 2 PMS) of IMU-838: change from placebo to week 24 (in % of baseline).

[0021] Figure 10 CALLIPER interim neurofilament data compared to historical studies in PPMS and SPMS. Reduction in NFL is an advantage compared to other PMS available therapies. SUMMARY

[0022] One aspect of the present disclosure relates to a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection in a subject having a neurodegenerative disease, wherein the compound is a compound of Formula (V):

[0023] (V),

[0024] wherein:

[0025] - Ring A is , , , , , , or ;

[0026] - E is , , , , or ; and

[0027] - Y is , , , , , , or .

[0028] In some embodiments, the subject exhibits an abnormal level of a biomarker associated with a neurodegenerative disorder prior to the administration.

[0029] In some embodiments, the compound is:

[0030] , , , , , , , or .

[0031] In some embodiments, the compound is

[0032] .

[0033] In some embodiments, the compound is

[0034] .

[0035] In some embodiments, the biomarker is Nurr1.

[0036] In some embodiments, the abnormal level of a biomarker associated with a neurodegenerative disorder is downregulated Nurr1.

[0037] In some embodiments, the neurodegenerative disorder is multiple sclerosis.

[0038] In some embodiments, the neurodegenerative disorder is multiple sclerosis, wherein the disability is obtained by progression independent of relapsing activity (PIRA).

[0039] In some embodiments, the neurodegenerative disorder is brain atrophy induced by multiple sclerosis.

[0040] In some embodiments, the neurodegenerative disorder is non-inflammatory multiple sclerosis exacerbation.

[0041] In some embodiments, the neuroprotection is slowing down or preventing loss of neurons induced by multiple sclerosis.

[0042] In some embodiments, the neuroprotection is slowing down or preventing loss of dopaminergic neurons induced by multiple sclerosis.

[0043] In some embodiments, the neurodegenerative disorder is Parkinson's disease.

[0044] In some embodiments, the method comprises:

[0045] - determining the level or activity of Nurr1 in an ex vivo biological sample of the subject using an assay selected from the group consisting of: (a) real-time PCR assay of the expression of the Nurr1 gene relative to the expression of a related housekeeping gene / internal control (e.g. GAPDH), (b) immunoassay (e.g. ELISA) using a suitable antibody for Nurr1 protein, or (c) Western blot of Nurr1 protein from a biological sample selected from the group consisting of peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF or peripheral blood mononuclear cells; and

[0046] - administering to the patient an effective amount of a compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof, if the test sample from the patient comprises a level of Nurr1 that is not greater than about 90% of the level in a healthy subject of the same age, gender and / or BMI.

[0047] In some embodiments, the method comprises:

[0048] - a) obtaining the level of a protein in a subject, wherein the protein is downstream of Nurr1 in a biological pathway of the subject; and

[0049] - b) deciding whether to administer a Nurr1 agonist to the subject based on the level of the protein in the subject.

[0050] In some embodiments, the protein is selected from the group consisting of BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNFα, iNOS, and IL-1β.

[0051] One aspect of the present disclosure relates to a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection in a subject having a neurodegenerative disease, wherein the compound is

[0052] , and wherein the disorder is PIRA.

[0053] In some embodiments, the compound is

[0054] , and wherein the disorder is PIRA.

[0055] In some embodiments, the neurodegenerative disorder is multiple sclerosis, wherein disability is obtained by progression independent of relapsing activity (PIRA).

[0056] In some embodiments, the therapeutically effective amount is about 5 mg to about 100 mg.

[0057] In some embodiments, the administering is oral via a solid dosage form.

[0058] In some embodiments, the administering is over a first period and a second period, wherein: a) the first period is once daily dosing of a first period amount of the compound for five to ten consecutive days, wherein the first period amount of the compound is about 15 mg to about 25 mg; b) the second period is subsequent to the first period; and c) the second period comprises once daily dosing of a second period amount of the compound, wherein the second period amount is about 30 mg to about 50 mg.

[0059] In some embodiments, the method is intended to stop or slow disease progression and secondary damage by stopping or at least slowing (reducing) neuronal loss.

[0060] Another aspect of the present disclosure relates to a method of treating multiple sclerosis (MS) in a patient diagnosed with progression independent of relapse (PIRA), the method comprising administering to the subject a compound of Formula (V), wherein the compound is:

[0061] .

[0062] Another aspect of the present disclosure relates to a method of treating multiple sclerosis (MS) in a subject, comprising administering to the subject a compound of Formula (V), wherein the compound is

[0063] ; and

[0064] The MS is characterized by progression independent of relapses (PIRA).

[0065] Another aspect of the present disclosure relates to a method of treating progression independent of relapses (PIRA) in a subject having multiple sclerosis (MS), comprising administering to the subject a compound of Formula (V), wherein the compound is

[0066] .

[0067] Another aspect of the present disclosure relates to a method of treating multiple sclerosis (MS) in a subject, comprising administering to the subject a compound of Formula (V), wherein:

[0068] The compound is

[0069] ; and

[0070] The subject has MS characterized by progression independent of relapses (PIRA).

[0071] In some embodiments, the patient has no evidence of relapse within 24 months.

[0072] In some embodiments, the MS is progressive MS (PMS).

[0073] In some embodiments, the PMS is characterized by few or no active lesions.

[0074] In some embodiments, the MS is primary progressive MS (PPMS).

[0075] In some embodiments, the MS is non-active secondary progressive MS (n-aSPMS).

[0076] In some embodiments, the n-aSPMS is characterized by no lesions within 12 months.

[0077] In some embodiments, the MS is active secondary progressive MS (a-SPMS).

[0078] In some embodiments, the method reduces serum NFL levels in the subject compared to a control.

[0079] In some embodiments, the method reduces serum GFAP levels in the subjects compared to controls.

[0080] In some implementations, the method reduces the percentage change in brain volume (PBVC) in the subjects compared to controls.

[0081] In some implementations, the method reduces the rate of change in brain parenchymal fraction (BPF) in the subjects compared to controls.

[0082] In some implementations, the method increases the time before disability deterioration is confirmed in the subjects compared to controls, for example, based on the Extended Disability Status Scale (EDSS).

[0083] In some implementations, the method prevents and / or slows disease progression and secondary damage by stopping or at least slowing (mitigating) neuronal loss.

[0084] In some embodiments, the compound is administered at a therapeutically effective dose of about 5 mg to about 100 mg.

[0085] In some embodiments, the compound is administered orally in a solid dosage form.

[0086] In some embodiments, the compound is administered during a first period and a second period, wherein: a) the first period is a first period dose of the compound administered once daily for five to ten consecutive days, wherein the first period dose of the compound is about 15 mg to about 25 mg; b) the second period is after the first period; and c) the second period includes a second period dose of the compound administered once daily, wherein the second period dose is about 30 mg to about 50 mg. Detailed Implementation

[0087] Overview

[0088] This document describes in particular methods for treating or improving a disease in subjects who have a disease, are suspected of having a disease, or are at risk of developing a disease, the methods comprising administering to the subject a therapeutically effective amount of a compound of formula (I) to (V) or a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof, particularly vedofluradimo. Compounds (I), (II), (III), (IV), (V), and (VI), as well as their salts and solvates, are described in detail herein.

[0089] In some implementations, the disease is a neurological disease, such as a neurodegenerative disease.

[0090] In some embodiments, the present disclosure provides a method of treating a disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof

[0091] (I),

[0092] wherein: A is an unsubstituted or substituted ring; Z 1 and Z 2 each independently is O, S, or NR 9 ; E is a linker or is absent; G is a linker or is absent; Y is a ring; R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 or NR 11 R 12 ; R 3 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted; each R 8 , R 9 , R 11 , R 12 , R 13 and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted; n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and r is 0 or 1, wherein the disorder is a neurodegenerative disorder.

[0093] In one embodiment, the present disclosure provides a method of neuroprotection in a subject having a neurodegenerative disease, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as outlined above. In one embodiment, the subject exhibits an abnormal level of a biomarker associated with a neurodegenerative disorder prior to the administration.

[0094] In one embodiment, the method of neuroprotection in a subject having a neurodegenerative disease comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) as outlined above. In one embodiment, the subject exhibits an abnormal level of a biomarker associated with a neurodegenerative disorder prior to the administration, in particular an abnormal level of Nurr1 in the subject.

[0095] In one embodiment, veddiflaperamide or a compound according to the structure of Formula (I) to (V) or according to Formula (VI) modulates Nurr1 and thus can be used to treat Parkinson's Disease (PD), amyotrophic lateral sclerosis (ALS), schizophrenia, PIRA in MS patients and drug addiction using a compound according to the structure of Formula (I) to (V) or using a compound according to Formula (VI).

[0096] Veddiflaperamide or a compound according to the structure of Formula (I) to (V) or according to Formula (VI) within the scope of the present application are characterized in that they bind directly to Nurr1 and that they have a different structure-activity relationship compared to DHODH, acting as Nurr1 agonists in cells (see Example 102).

[0097] The neurodegenerative disease or neurodegenerative disorder that can be treated according to the present application can be selected from multiple sclerosis (MS), Parkinson's disease.

[0098] In some embodiments, the disorder is Parkinson's disease (PD).

[0099] In some embodiments, the present disclosure provides a method of treating Parkinson's disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

[0100] (I),

[0101] wherein: A is an unsubstituted or substituted ring; Z 1 and Z 2 are each independently O, S, or NR 9 ; E is a linker or is absent; G is a linker or is absent; Y is a ring; R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 or NR 11 R 12 ; R 3 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; each R 8 , R 9 , R 11 , R 12 , R 13 and R 14independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and r is 0 or 1.

[0102] In one embodiment, the subject exhibits an abnormal level of a biomarker associated with Parkinson's disease prior to the administration.

[0103] In some embodiments, the disorder is drug addiction.

[0104] In some embodiments, the present disclosure provides a method of treating drug addiction in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0105] (I),

[0106] wherein: A is an unsubstituted or substituted ring; Z 1 and Z 2 are each independently O, S, or NR 9 ; E is a linker or is absent; G is a linker or is absent; Y is a ring; R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 or NR 11 R 12 ; R 3 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; each R 8 , R 9 , R 11 , R 12 , R 13 and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and r is 0 or 1. In one embodiment, the subject exhibits a level of a biomarker associated with drug addiction prior to the administration.

[0107] In some embodiments, the disease is multiple sclerosis (MS).

[0108] In some embodiments, the present disclosure provides a method of treating multiple sclerosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0109] (I),

[0110] wherein: A is an unsubstituted or substituted ring; Z 1 and Z 2 are each independently O, S, or NR 9 ; E is a linker or is absent; G is a linker or is absent; Y is a ring; R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 or NR 11 R 12 ; R 3 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; each R 8 , R 9 , R 11 , R 12 , R 13 and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and r is 0 or 1.

[0111] In one embodiment, the subject exhibits an abnormal level of a biomarker associated with multiple sclerosis prior to the administration.

[0112] In some embodiments, the present disclosure provides a method comprising: a) obtaining a level of Nurr1 in a subject; and b) deciding whether to administer a Nurr1 agonist to the subject based on the level of Nurr1 in the subject.

[0113] In some embodiments, the present disclosure provides a method comprising: a) obtaining a level of Nurr1 in a subject experiencing a therapy for a neurodegenerative disorder; and b) determining whether to continue the therapy for the neurodegenerative disorder based on the level of Nurr1 in the subject, wherein the therapy is Nurr1 agonism.

[0114] In some embodiments, the present disclosure provides a method comprising: a) obtaining a level of a protein in a subject, wherein the protein is downstream of Nurr1 in a biological pathway of the subject; and b) determining whether to administer a Nurr1 agonist to the subject based on the level of the protein in the subject.

[0115] In some embodiments, the present disclosure provides a method comprising: a) obtaining a level of a protein in a subject experiencing a therapy for a neurodegenerative disorder, wherein the protein is downstream of Nurr1 in a biological pathway of the subject, wherein the therapy is Nurr1 agonism; and b) determining whether to continue the therapy for the neurodegenerative disorder based on the level of the protein in the subject.

[0116] In some embodiments, the present disclosure provides a method comprising: a) obtaining a level of activity of a gene in a subject, wherein the gene is downstream of Nurr1 in a biological pathway of the subject; and b) determining whether to administer a Nurr1 agonist for a neurodegenerative disorder to the subject based on the level of activity of the gene in the subject.

[0117] In some embodiments, the present disclosure provides a method comprising: a) obtaining a level of activity of a gene in a subject experiencing a therapy for a neurodegenerative disorder, wherein the gene is downstream of Nurr1 in a biological pathway of the subject, wherein the therapy is Nurr1 agonism; and b) determining whether to continue the therapy for the neurodegenerative disorder based on the level of activity of the gene in the subject.

[0118] In some embodiments, the present disclosure provides a method comprising: a) determining that a subject exhibits downregulated Nurr1; b) determining that the subject exhibits upregulated miR-132; and c) identifying the subject as being at risk for a disorder based on determining that the subject exhibits downregulated Nurr1 and determining that the subject exhibits upregulated miR-132.

[0119] In some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder and / or a method of neuroprotection, wherein the method comprises: a) determining the level or activity of Nurr1 in an ex vivo biological sample from a subject using an assay selected from: (a) a real-time PCR assay of Nurr1 gene expression relative to a related housekeeping gene / internal control (e.g., GAPDH), (b) an immunoassay (e.g., ELISA) using a suitable antibody for Nurr1 protein, or (c) a Western blot of Nurr1 protein from a biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, and peripheral blood mononuclear cells; and b) administering to the patient an effective amount of a compound herein if the level or activity of Nurr1 is not greater than about 90% of the level in a healthy subject of the same age, gender, and / or BMI.

[0120] I. Neurodegenerative Diseases and Biomarkers

[0121] One aspect of the present disclosure relates to a method of treating or ameliorating a disease, such as a nervous system disease (e.g., a neurodegenerative disease), in a subject, the method comprising administering to the subject a compound according to Formulae (I) to (V) or a compound according to Formula (VI). In some embodiments, the compound is Verdelfuradim. In some embodiments, Verdelfuradim can act as a Nurr1 agonist.

[0122] In some embodiments, the nervous system disease is Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia (FTD), Kennedy's disease, Krabbe disease, kuru, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum's disease, Sandhoff disease, Shy-Drager syndrome, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0123] In some embodiments, the disease is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is Alzheimer's disease.

[0124] In some embodiments, the disease is multiple sclerosis (MS). In some embodiments, the MS is relapsing multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS). In some embodiments, the MS is progressive multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0125] A neurodegenerative disease can be characterized by a change in a measure of a biomarker in a subject having, suspected of having, or at risk of developing a neurodegenerative disease compared to a reference measure. In some embodiments, the reference measure is a measure of a biomarker obtained from a healthy control subject. In some embodiments, the measure of the biomarker is an increase or decrease in expression and / or activity of the biomarker and / or rate of change of expression and / or activity of the biomarker. For example, a low level of Nurr1 in the central nervous system of a subject compared to a reference can be indicative of a neurodegenerative disease in the subject.

[0126] In some embodiments, biomarkers associated with a neurodegenerative disease include, but are not limited to, Nurr1, GFAP, miR132, neurofilament light chain (NFL), BDNF, GDNF, C-RET, YKL-40 (CHI3L1), DAT, Pituitary homeobox 3 (Pitx3), tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), superoxide dismutase (SOD), and aromatic amino acid decarboxylase (AADC). In some embodiments, a change in a measure of one or more of these biomarkers is indicative of a neurodegenerative disease.

[0127] Nurr1 or NR4A2 is a protein encoded by the NR4A2 gene in humans. Nurr1 is a nuclear receptor and plays a key role in maintaining the brain dopaminergic system. The term "Nurr1" can refer to the nucleotide sequence or protein sequence of human NR4A2 (e.g., Entrez 4929, Uniprot P43354, RefSeq NM_006186.3, or RefSeq NP_006177.1).

[0128] For example, Nurr1 patients typically show lower Nurr1 expression or have lower Nurr1 protein levels compared to healthy controls. Expression can be determined by measuring Nurr1 RNA levels or Nurr1 protein levels in blood-derived cells. Activity of Nurr1 can also be determined by measuring the amount of target genes modulated in brain cells, blood-derived cells, CSF-derived cells, plasma, serum or CSF or the levels of the associated proteins (see e.g. Front. Immunol. 2021; 12: 676644 or Sci. Rep. 2020; 10: 10755). Activity of Nurr1 can also be determined by measuring the corresponding cellular phenotypes. For example, one can measure the modulation of apoptosis / survival in neurons (e.g. this can be determined by measuring NFL in serum, plasma or CSF of the patient). Nurr1 activation induces survival factors for dopaminergic neurons. Loss of this survival signal leads to an increase in the number of dying neurons. From the literature it is known that NFL is a marker for dying neuronal axonal damage. Thus, activation of Nurr1 by a compound according to formulae (I) to (V) or a compound according to formula (VI) can reduce the NFL levels in serum, plasma or CSF.

[0129] Glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein and a marker for brain injury. GFAP is expressed in cells of the central nervous system, including astrocytes. GFAP levels in serum of patients are associated with the situation of neurodegeneration mediated by astrocytes. Activated astrocytes increase their production of GFAP. GFAP can be degraded into GFAP-BDP. Both products can be detected in CSF, serum or plasma due to astrocyte damage (see e.g. Trends Neurosci. 2015; 38: 364). In some embodiments, Nurr1 activity, when activated by a compound according to formulae (I) to (V) or a compound according to formula (VI), reduces astrocyte proliferation, thereby reducing astrocyte damage, leading to reduced GFAP / BDP levels.

[0130] The relative expression of Nurr1 protein or target genes in healthy controls and patients has been reviewed in Int. J. Mol. Sci. 2019; 20: 4858. The relative expression of Nurr1 in patients or healthy controls can be obtained from peripheral blood by peripheral blood lymphocyte isolation, total RNA extraction followed by real-time PCR determination of Nurr1 gene expression against the internal control GAPDH (see e.g. J. Neurol. Sci. 2008; 273: 29).

[0131] The term "NR4A3" refers to nuclear receptor 4A3 (nuclear receptor subfamily 4, group A, member 3; NR4A3), also known as neuron-derived orphan receptor 1 (NOR1), is a protein that in humans is encoded by the NR4A3 gene. NR4A3 is a member of the nuclear receptor family of intracellular transcription factors.

[0132] miR-132 is a short non-coding RNA molecule. This microRNA modulates the expression level of other genes through various mechanisms, often decreasing protein levels by cleaving the mRNA or repressing its translation. Expression of miR-132 in serum, plasma or CSF can be used to determine Nurr1 brain expression levels and, in some embodiments, is a marker that can be used to distinguish patients who can benefit more from treatment with a compound according to formula (I) to (V) or with a compound according to formula (VI).

[0133] Neurofilament light chain (NFL) is a marker of overall axonal injury and neuronal destruction, particularly in MS. Low levels of NFL are associated with neuronal protection / survival. In PD, where Nurr1 shows lower expression levels compared to healthy volunteers and low levels of Nurr1 are significantly associated with loss of dopaminergic neurons, NFL is a potential biomarker of decreased motor ability. The main motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra compacta. Nurr1 activation leads to survival signals within neurons, so lower levels of NFL can be a result of Nurr1 activation (e.g. caused by a compound according to formula (I) to (V) or a compound according to formula (VI)) and beneficial for patients with neurodegenerative diseases.

[0134] Quantification of NFL in blood and CSF can be assessed by high-sensitivity electrochemiluminescence (ECL)-based immunoassay (e.g. PLOS One 2013;8:e75091). For blood samples with lower NFL levels compared to CSF, the single-molecule or "Simoa" assay (Quanterix Corp.) is currently the most commonly used method, as it is very sensitive with a lower limit of quantification of 0.1 pg / mL (eBioMedicine 2024;101:104970). Quanterix received FDA Breakthrough Device Designation for the method for testing NFL in MS patients in 2022.

[0135] In some embodiments, NFL levels in blood and CSF are measured by electrochemiluminescence (ECL)-based immunoassay. In some embodiments, NFL levels in blood are measured by the single-molecule or "Simoa" assay (Quanterix Corp.).

[0136] The same applies to the Roche Elecsys platform, which can also be one of the standards to be used.

[0137] In some embodiments, patients with neurological diseases have higher NFL levels in serum (sNFL) compared to patients with neurological diseases without evidence of structural central nervous system (CNS) damage and healthy controls, e.g. AD (30.8 pg / mL), GBS (79.4 pg / mL) or ALS (95.4 pg / mL). Similar differences are also observed in corresponding CSF samples (PLOS One 2013;8:e75091). NFL levels increase during normal aging, e.g. from an average sNFL of 20.4 pg / mL at age < 50 to an average sNFL of 45.9 pg / mL at age > 70 (Nat. Commun. 2020;11:812), indicating accelerated neuronal damage at higher ages, which can be driven by subclinical comorbidity pathologies. This has to be taken into account when defining NFL levels for healthy controls or when using the treatment with a compound according to formulae (I) to (V) or with a compound according to formula (VI) is successful. An overview of neurofilaments as biomarkers in neurological disorders is given in Nat. Rev. Neurol. 2018;14:577. In addition to NFL, Yuang and Nixon also describe other neurofilament proteins that can be quantified and monitored during the treatment of neurological diseases (Front. Neurosci. 2021;15:689938).

[0138] Brain-derived neurotrophic factor (BDNF) is a protein whose expression level is controlled by Nurr1. Activation of Nurr1 leads to enhanced expression of BDNF. Measurements of the mature form of the BDNF protein in plasma, serum or CSF can be used as a marker for Nurr1 activity and for the assessment of the effect of the treatment with a compound according to formulae (I) to (V) or with a compound according to formula (VI). An increase in mature BDNF levels is associated with higher neuronal survival. Protein levels of various BDNF subtypes in CSF, blood and plasma samples can be determined with commercially available immunoassay kits (see e.g. Int. J. Neuropsychopharmacol. 2011;14:347 or Nat. Rev. Neurosci. 2005;6:603).

[0139] Glial cell line-derived neurotrophic factor (GDNF) is also a target gene of Nurr1. Activation of Nurr1 leads to enhanced expression of GDNF. Measures of GDNF expression in plasma, serum, or CSF can be used as a marker of Nurr1 activity and for assessing the efficacy of treatment using a compound according to Formula (I)-(V) or using a compound according to Formula (VI). An increase in GDNF levels is associated with higher neuronal survival.

[0140] C-RET is a RET proto-oncogene that encodes a receptor tyrosine kinase for members of the GDNF family of extracellular signaling molecules and promotes survival of dopaminergic neurons. Nurr1 activity induces expression of C-RET in dopamine neurons. C-RET expression can be measured at the RNA or protein level from brain biopsy tissue of patients with neurodegenerative diseases. In some embodiments, lower expression of C-RET in the brain of patients with neurodegenerative diseases compared to controls is associated with greater benefit of treatment of patients with a compound according to Formula (I)-(V) or with a compound according to Formula (VI).

[0141] Glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein that is a marker of brain injury. GFAP is expressed in cells of the central nervous system, including astrocytes. GFAP levels in serum of patients are associated with the extent of neurodegeneration mediated by astrocytes. Activated astrocytes increase their production of GFAP. GFAP can be degraded into GFAP-BDP. Both products can be detected in CSF, serum, or plasma due to astrocyte damage (see, e.g., Trends Neurosci. 2015; 38:364). In some embodiments, Nurr1 activity, when activated by a compound according to Formula (I)-(V) or a compound according to Formula (VI), reduces astrocyte proliferation, thereby reducing astrocyte damage, leading to reduced levels of GFAP / BDP.

[0142] YKL-40 (CHI3L1) is a glycoprotein that is mainly produced by reactive astrocytes and microglia in chronic active MS lesions (J. Neuroimmunol. 2016; 292:52). YKL-40 levels are elevated in serum of patients with RRMS compared to controls and are therefore considered a useful marker of the inflammatory process in MS (Arq. Neuropsiquiatr. 2021; 79:795). Within the CNS, CHI3L1 is associated with neuroinflammatory processes and reactive gliosis (Neurol. Neuroimmunol. Neuroinflamm. 2022; 9:e1164), which can be reduced by Nurr1 activity (see above).

[0143] Dopamine active transporter (DAT; also known as SLC6A3) is a transmembrane protein responsible for re-uptake of dopamine from the synapse back into the cytosol of dopaminergic neurons. DAT is a target gene of Nurr1 (Development 2009; 136:2363). In PD patients, DAT can be reduced by 50-70%. DAT imaging using single photon emission computed tomography (SPECT) can be used to confirm or rule out the diagnosis of dopamine-deficient Parkinson’s disease. Patients with low levels of Nurr1 expression and activity have lower levels of expression and activity of dopamine transporters, and thus benefit from activation of Nurr1 by a compound according to Formula (I) to (V) or a compound according to Formula (VI).

[0144] Pituitary homeobox 3 (Pitx3) is a gene encoding a member of the RIEG / PITX homeobox family, which belongs to the bicoid class of homeodomain proteins and acts as a transcription factor. Pitx3 is involved in the maintenance of dopaminergic neurons. The term “Pitx3” can refer to the nucleotide sequence or protein sequence of human Pitx3.

[0145] Tyrosine hydroxylase (TH) is an enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). In humans, tyrosine hydroxylase is encoded by the TH gene. In some embodiments, activation of Nurr1 in dopaminergic neurons leads to upregulation of tyrosine hydroxylase expression. Tyrosine hydroxylase activity converts tyrosine to L-DOPA. L-DOPA is converted to dopamine, a neurotransmitter that signals for performance, motor control, motivation, arousal, reinforcement, and reward. Low-level functions are suckling, sexual gratification, and nausea.

[0146] Vesicular monoamine transporter 2 (VMAT2; also known as solute carrier family 18 member 2 or SLC18A2) is an integral membrane protein that transports neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from the cytosol of a cell into synaptic vesicles. VMAT2 is a direct target gene of Nurr1 and is upregulated by Nurr1 activation. Expression of VMAT2 can be determined at the RNA and protein levels in neurons from brain biopsy tissue. In addition, VMAT2 activity can be determined by DTBZ-PET. 11C] Dihydrotetrabenazine (DTBZ) can be used as a radioligand for VMAT2 and can be visualized by PET imaging. VMAT2 is involved in the packaging of dopamine. The function of SLC18A2 is also required for vesicular release of the neurotransmitter GABA in dopaminergic neurons of the nigrostriatal pathway and the mesolimbic pathway. In some embodiments, activation of Nurr1 by a compound according to Formula (I)-(V) or a compound according to Formula (VI) induces higher VMAT2 expression, and thus is beneficial for patients who lack proper VMAT2 activity due to mutations, have low Nurr1 activation status, or have a history of cocaine abuse. Increased expression of VMAT2 through two single nucleotide polymorphisms (SNPs) in the promoter region reduces the risk of PD. In some embodiments, it is beneficial to induce higher expression and activity levels of VMAT2 in neurodegenerative diseases.

[0147] Superoxide dismutase (SOD) is an enzyme that catalytically dismutates (or allocates) superoxide (O2 − ) free radicals into ordinary molecular oxygen and hydrogen peroxide. SOD is upregulated by activation of Nurr1. SOD is an enzyme that reduces oxidative stress in neurons, and thus reduces apoptotic signals in neurons. SOD expression can be measured at the RNA or protein level from brain biopsy tissue, CSF, or blood samples. Patients who exhibit lower SOD levels compared to controls can benefit from treatment with a compound according to Formula (I)-(V) or a compound according to Formula (VI) due to enhanced Nurr1 activation.

[0148] Aromatic amino acid decarboxylase (AADC; also known as DOPA decarboxylase, DDC) is a lyase enzyme. AADC is a direct target gene of Nurr1 and is upregulated by activation of Nurr1. AADC mediates the last step in the synthesis of the neurotransmitters dopamine and serotonin. Lower levels of AADC or AADC dysfunction in neurons leads to accumulation of intracellular L-DOPA, which is then chemically converted to 5-hydroxytryptophan and 3-O-methyldopa. 5-hydroxytryptophan (5-HTP) and 3-O-methyldopa (3-OMD) in the blood can be determined by using UPLC-MS / MS (described in, e.g., J. Chromatogr. B Biomed. Appl. 2021; 1185: 122999). In some embodiments, patients with lower levels or lower function of AADC compared to controls, as determined by UPLC-MS / MS, can benefit from treatment with a compound according to Formula (I)-(V) or a compound according to Formula (VI) by activating Nurr1 and subsequently upregulating AADC.

[0149] II. Multiple Sclerosis

[0150] Another aspect of the present disclosure relates to a method of treating or ameliorating multiple sclerosis (MS) in a subject having MS, the method comprising administering to the subject a compound according to Formulae (I) to (V) or a compound according to Formula (VI), e.g. vafidemstat.

[0151] Multiple sclerosis (MS) can be divided into relapsing MS (RMS) and progressive MS (PMS). Relapsing-remitting MS (RRMS) and active secondary progressive MS (active SPMS) are mainly driven by focal inflammatory disease, characterized by the presence of magnetic resonance imaging (MRI) lesions and relapses. However, from a recent meta-analysis of a large patient database it is known that disability worsening in these two subtypes is driven by relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). RRMS is characterized by relapses and MRI lesions dominating the clinical course. Active SPMS (aSPMS) is characterized by relapses and less lesions and continuous disability progression (see Figure 8 ).

[0152] Primary progressive MS (PPMS) and non-active secondary progressive MS (non-active SPMS or n-aSPMS) are two forms of MS that are mainly progressive, characterized by continuous disability worsening, with no or almost no MRI lesions or relapses present. From a recent meta-analysis of a large patient database it is known that disability worsening in these two subtypes is almost completely driven by PIRA. Non-active SPMS is characterized by continuous disability progression, while relapses have ceased. PPMS is characterized by disability worsening from the start (see Figure 8 ).

[0153] The definition and subclassification of PPMS and SPMS can vary. In one exemplary definition, all SPMS can be considered to belong to the PMS category, thus all SPMS patients are considered PMS patients, with no distinction between aSPMS and n-aSPMS. In another exemplary definition, active SPMS can be considered to belong to the RMS category, while non-active SPMS can be considered to belong to the PMS category. Thus, the terms “n-aSPMS” and “SPMS” are used synonymously in the present invention.

[0154] PIRA separation can be made as follows (JAMA Neurol. 2023;80:151) compared to RAW: A PIRA event can be defined as experiencing a confirmed disability worsening (CDW) in the Expanded Disability Status Scale (EDSS) scale at 6 months in the Post-First Relapse (PFR) period. The PFR is the time between two consecutive relapses, starting 3 months after a relapse (or 6 months after the first demyelination event). The first EDSS score obtained at least 6 months after the first onset or 3 months after any other onset is referred to as the baseline EDSS score and the re-baseline EDSS score, respectively. The re-baseline EDSS score is set not to be lower than the first recorded (baseline) EDSS score. A confirmed disability accumulation (CDA) is defined as an increase in the EDSS score of 1.5, 1.0, or 0.5 if the baseline / re-baseline EDSS score is 0, 1.0 to 5.0, or greater than 5.0, respectively. The date of PIRA is the date of the confirmation of the CDA. Any other CDA episode that does not meet the PIRA criteria (i.e., occurring outside the PFR) is considered a RAW event. Those patients with at least 1 CDA but without any PIRA event are considered RAW patients.

[0155] In the clinical study by Kopp et al. (Mult. Scler. Relat. Disord. 2021;56:103319), the following inclusion criteria applied to the MS population with a clinical SPMS diagnosis assigned by a MS neurologist and to RRMS patients meeting the MSBase definition for diagnosis of transition to SPMS. This m-EXPAND criteria identified patients with recent EDSS score worsening that can not be explained with a recent relapse:

[0156] (a) EDSS of 3.0 to 6.5, inclusive (at the landmark date + / - 6 months); and

[0157] (b) EDSS progression in the last 2 years prior to data extraction, defined as EDSS progression of 1 point or more in patients with EDSS score below 6.0, or EDSS progression of > 0.5 points in patients with EDSS score > 6.0, without relapse in the 6 months prior to progression, and EDSS > 3.0 at the time of progression; and

[0158] (c) disability progression.

[0159] Currently, there are no FDA-approved treatment options for SPMS other than mitoxantrone. However, for treatment with mitoxantrone, no distinction is made between relapsing activity (active SPMS vs. non-active SPMS). Notably, mitoxantrone treatment is associated with significant toxicities, including cardiotoxicity and secondary malignancies, which limit the treatment length to ~3 years (lifetime dose of 140 mg / m 2). Furthermore, the patient population in this trial was primarily suffering from relapsing SPMS, and the benefit in non-active SPMS is not known. Siponimod, natalizumab, and interferon beta-1b are approved for active SPMS, but have not shown benefit in non-active SPMS. For PPMS patients, ocrelizumab has been approved, but contains a black box warning for progressive multifocal leukoencephalopathy and immune-mediated colitis due to the strong dampening of the immune response. Other treatment options currently being tested in clinical trials, such as fingolimod with the risk of liver injury, also do not offer the good safety profile of vidofludimus. Thus, given the lack of effective therapies for the entire PIRA, there is an urgent unmet need.

[0160] MS usually starts with a clinically isolated syndrome (CIS). This is the first onset of symptoms caused by inflammation and damage to the myelin sheath covering the nerves in the brain or spinal cord. In CIS, the individual has an attack suggestive of demyelination, but does not meet the criteria for MS. Between 30% and 70% of individuals who experience CIS will later develop MS.

[0161] There is also another subgroup of MS patients, namely MS patients who shift between relapsing MS and PIRA. For this disease, the term “shifting MS” is used in this text. Shifting MS patients can be identified by one or more of the following test methods:

[0162] (a) Symbol Digital Modalities Test (SDMT),

[0163] (b) Multiple Sclerosis Functional Composite Score (MSFC),

[0164] (c) EDSS,

[0165] (d) Timed 25-Foot Walk (T25FW),

[0166] (e) 9-Hole Peg Test (9HPT),

[0167] (f) MS ProDiscuss TM clinical tool,

[0168] (g) a composite score integrating several tests such as EDSS, Timed 25-Foot Walk (T25FW), SDMT, and 9-Hole Peg Test (9HPT), MS ProDiscuss TM clinical tool.

[0169] III. Progression Independent of Relapses (PIRA)

[0170] Another aspect of the application relates to a method of treating progression of MS, e.g. progression independent of relapses (PIRA), in a subject, the method comprising administering to the subject a compound according to formulae (I) to (V) or a compound according to formula (VI). In some embodiments, the compound is vafidemstat.

[0171] PIRA is a contributing factor in all forms of multiple sclerosis (MS). PIRA plays an important role in disease worsening in RRMS and is the main way in which patients acquire disability in progressive multiple sclerosis (PMS), e.g. forms of PMS in which there are few or no relapses. PIRA can even occur in the early stages of the disease, as shown in a study of patients who, using an effective DMT, had successfully suppressed inflammation, providing evidence that there is persistent treatment-resistant pathology from the outset.

[0172] This raises the importance of any new drug that reduces or slows PIRA, measured as confirmed disability worsening, but also by assessing brain atrophy. It can also be important to provide a new drug that: (a) reduces relapse activity, and (b) reduces or slows PIRA, measured as confirmed disability worsening, but also by assessing brain atrophy.

[0173] Thus, in one embodiment, the application aims to treat the accumulation of disability worsening independent of relapses.

[0174] Thus, the application aims to treat progression independent of relapse activity (PIRA)

[0175] The accumulation of disability worsening independent of relapses or progression independent of relapse activity has been defined by Fred Lublin at https: / / doi.org / 10.1093 / brain / awac016 (Brain 2022; 145:3147), wherein the detection of disability worsening independent of relapse activity or progression is as described by Fred Lublin at https: / / doi.org / 10.1093 / brain / awac016 (Brain 2022; 145:3147) and is incorporated herein by reference as one embodiment.

[0176] There are two major mechanisms by which patients with multiple sclerosis acquire disability: (i) the gradual accumulation of lesions due to incomplete recovery from relapses [i.e. relapse-associated worsening (RAW)] and (ii) progression independent of relapsing activity (PIRA). While the former is considered the main source of permanent disability in relapsing multiple sclerosis, the latter is considered to drive the insidious progression typical of primary and secondary progressive multiple sclerosis (PPMS and SPMS). One example of PIRA detection and measurement is according to Kurtzke, JF “Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)”, Neurology. 1983; 33: 1444-1452.

[0177] There is currently no satisfactory drug available for the treatment of the relapse-independent, smoldering component of disability worsening. Surprisingly, the present invention shows that compounds according to formulae (I) to (V) or compounds according to formula (VI), in particular veldolamide, as dual DHODH inhibitors and Nurr1 agonists, can act as neuroprotective drugs in addition to their established activity as anti-inflammatory drugs.

[0178] In particular, patients with low levels of Nurr1 will benefit from treatment with compounds according to formulae (I) to (V) or with compounds according to formula (VI). Thus, for the first time there is evidence that patients with reduced Nurr1 activity benefit more from treatment with veldolamide calcium (IMU-838) than patients with Nurr1 activity in the range: DHODH inhibition is good for inflammation, Nurr1 activation is new and aims to protect neurons from death. Diseases and conditions that exhibit reduced survival or function of dopaminergic neurons share a reduction in neurodegeneration.

[0179] Patients with diseases that include brain and spinal cord disorders or neurodegeneration can be treated beneficially with compounds according to formulae (I) to (V) or with compounds according to formula (VI). These conditions include diseases with symptoms such as motor deficits, cognitive deficits, fatigue, depression, or drug addiction.

[0180] When focusing on the disease MS, the positive effect on RRMS patients can be attributed to the anti-inflammatory properties of compounds of formulae (I) to (V) or compounds according to formula (VI), preferably veldolamide, or an isotopic variant, a pharmaceutically acceptable salt or a solvate thereof.

[0181] In some embodiments, MS patients can be divided into two groups: (a) patients with relapses, i.e. relapse associated worsening (RAW) patients, and (b) other patients with progressive (smoldering) disease worsening, i.e. patients with progression independent of relapse activity (PIRA), which require fundamentally different treatment. In some embodiments, group (a) requires anti-inflammatory treatment, while group (b) requires neuroprotective treatment to reduce disease worsening. For group (b), there are almost no treatment options, especially since pure DHODH inhibitors are not expected to result in a beneficial treatment. In one embodiment, the compound according to the present application can act as nuclear receptor related factor 1 (Nurr1).

[0182] Thus, so far, Vdohydrochloride has not been tested in a group of MS patients without any relapses or relapse-free period of at least 12 or 24 months. Surprisingly, we found that the compound according to formula (I) to (V) or the compound according to formula (VI) (preferably Vdohydrochloride) or an isotopic variant, a pharmaceutically acceptable salt or a solvate thereof not only has a beneficial effect on group (a) but also on group (b), which seems to even outperform the other treatment options currently tested for this group. This can be attributed to the neuroprotective Nurr1 agonism induced by the compound according to formula (I) to (V) or the compound according to formula (VI) (preferably Vdohydrochloride). This new finding opens up the use of the compound according to formula (I) to (V) or the compound according to formula (VI) (preferably Vdohydrochloride) for all diseases with abnormal Nurr1 levels.

[0183] In one embodiment, the patient treated according to the present application is a MS patient without any relapses or relapse-free period of at least 12 months. In another embodiment, the patient treated according to the present application is a MS patient without any relapses or relapse-free period of at least 24 months.

[0184] In one embodiment, the patient treated according to the present application is a PIRA patient without any relapses or relapse-free period of at least 12 or 24 months.

[0185] In one embodiment of the present application, PIRA is defined as a confirmed disability worsening (CDW) event of 3 or 6 months or preferably 12 or 24 months, preceded by no relapse or onset more than 90 days after the date of the start of the last investigator-reported relapse (irrespective of EDSS confirmation).

[0186] In addition, to qualify as a PIRA event, no relapse must have occurred within 30 days prior to and 30 days after the EDSS confirmation. If a relapse occurs and is not complete, the baseline (i.e., reference EDSS value) can be reset >90 days after the relapse onset to identify the next PIRA event. The baseline can be reset multiple times (i.e., after each relapse) in an individual patient until a PIRA event is found or until the individual EDSS profile ends.

[0187] A persistent PIRA can be a 3 or 6 month PIRA event in which the EDSS worsening is sustained in all subsequent assessments, i.e., the patient never recovers in the available longitudinal data.

[0188] Clinical evidence of disability can come from surrogate endpoints, e.g.,

[0189] - annualized rate of percent brain volume change up to 120 weeks

[0190] - annualized change rate of global atrophy.

[0191] Clinical evidence can also come from the response of the following biomarkers:

[0192] - at least 5% slowing or reduction of the increase in serum NfL levels (or defining the hazard ratio as 0.9)

[0193] - at least 3% reduction in GFAP levels in CSF, serum or plasma within 48 weeks.

[0194] Disability progression can be assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combination thereof.

[0195] The method of assessing disability progression can comprise assessing the onset of composite 12-week confirmed disability progression (cCDP12), wherein the onset of cCDP12 comprises at least one progression event selected from:

[0196] a. at least 1.0 point increase in EDSS score from baseline in subjects with a baseline EDSS score of less than or equal to 5.5; or at least 0.5 point increase in EDSS score from baseline in subjects with a baseline EDSS score of greater than 5.5;

[0197] b. at least 20% increase in time to complete the 9-HPT from baseline; and

[0198] c. at least 20% increase in T25FWT from baseline,

[0199] and wherein the progression event is confirmed at least 12 weeks after the initial progression.

[0200] Observational and controlled clinical trials provide evidence that PIRA can be the most common manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including CIS and early RRMS, providing another perspective on the conceptual distinction between relapsing and progressive disease courses or stages. In some embodiments, the following determinants can be used to diagnose PIRA in both RRMS and progressive MS as an additional set of determinants:

[0201] A. Baseline / reference score: A running baseline can be applied, with a new reference score set each time an individual measure of EDSS or composite score is lower than the previous measure and confirmed at the next follow-up. The reference score can also be reset if a relapse results in residual disability.

[0202] B. Event score: An increase in EDSS or composite measure can be considered for classification into PIRA if not determined within 30 days before and 90 days after the onset of a researcher-reported relapse. In addition to EDSS (1.5 points increase if baseline is 0, 1.0 points increase if between 1 and 5.5, 0.5 points increase if > 5.5), a composite measure can be recommended, which should include upper limb function (9HPT, threshold: > 20% decrease), gait speed (T25FWT, threshold; > 20% decrease), and cognitive testing (SDMT, threshold: 4-point decrease or > 10% decrease).

[0203] C. Confirmation score: Confirmation visits can be performed no earlier than 3 months, preferably 6 or 12 months, after the initial increase in disability and should not be performed within 30 days before and 90 days after the onset of a researcher-reported relapse.

[0204] D. Persistence score: The EDSS score defining PIRA can not improve reasonably within 12 months or even 24 months after the onset of PIRA before the end of follow-up.

[0205] In one embodiment, the patient treated according to the present application is a PIRA patient without any relapse or with a relapse-free period of at least 12 or 24 months, and the drug is vafidemstat at a daily dose of 30 mg to 45 mg per daily dose of vafidemstat calcium.

[0206] In one embodiment, the patient treated according to the present application is a PIRA patient without any relapse or with a relapse-free period of at least 12 or 24 months, and the drug is vafidemstat at a daily dose of 30 mg per daily dose of vafidemstat calcium.

[0207] In one embodiment, the patient treated according to the application is a PIRA patient without any relapse or with a relapse-free period of at least 12 or 24 months and the drug is vafidemstat at a daily dose of 45 mg per day of vafidemstat calcium.

[0208] It has been found that MS patients acquire disability not only from relapse-associated worsening (RAW) but also, to a large extent, from progression independent of relapse activity (PIRA).

[0209] PIRA can be quantified with the help of confirmed disability worsening (CDW) events. PIRA can start early in the disease course, can occur in all phenotypes, and can be the main driver of disability accumulation in the stage of disease progression.

[0210] PIRA is the main driver of disability accumulation in the stage of disease progression. PIRA can be accompanied by worsening unknown “hidden symptoms”, such as fatigue, sphincter and cognitive symptoms. Patients can have MS that shifts between relapsing and progressive disease. There is a potential progression process in all MS patients, independent of disease classification. In one embodiment, PIRA patients can be SPMS patients who have not had a relapse recently, have no MRI activity suggesting active inflammation, and have evidence of recent progression independent of relapse.

[0211] PIRA and RAW can be subdivided into smaller groups, such as “early PIRA”, “late PIRA”, “active PIRA” or “non-active PIRA” (JAMA Neurol. 2023; 80: 151).

[0212] Early PIRA patients have a significantly steeper rate of increase in the Expanded Disability Status Scale (EDSS) compared to late PIRA patients.

[0213] In addition, early PIRA patients have a greater risk of reaching EDSS 6.0 at a faster rate compared to late PIRA patients.

[0214] PIRA can be an irreversible phenomenon associated with adverse long-term disability outcomes, especially if such PIRA events occur early in the disease course.

[0215] Identifying all people who develop PIRA, especially early PIRA, as soon as possible after the first demyelination event can lead to better treatment choices and thus better long-term outcomes.

[0216] Provided herein is a method of treating PIRA in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of vedocizumab, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, preferably vedocizumab as "Form A." Also provided is a method of treating PIRA in a subject in need thereof, comprising administering to the subject about 30 to 45 mg of vedocizumab, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, preferably vedocizumab as "Form A," once daily in a maintenance period. Also provided is a compound for use in a method of treating PIRA in a subject in need thereof, wherein the compound is about 30 to 45 mg of vedocizumab, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, preferably vedocizumab as "Form A," once daily in a maintenance period. In other embodiments, provided herein is a compound for the manufacture of a medicament for use in treating PIRA in a subject in need thereof, wherein the compound is about 30 to 45 mg of vedocizumab, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, preferably vedocizumab as "Form A," once daily in a maintenance period. In some embodiments, the treatment of PIRA is assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combination thereof. In some embodiments, the treatment of PIRA is assessed based on time to confirmed disability progression (e.g., 12-week or 24-week CDP) onset or based on time to composite confirmed disability progression (e.g., 12-week or 24-week cCDP) onset. For example, in some embodiments, a subject having PIRA is treated by administering to the subject about 30 to 45 mg of vedocizumab, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, preferably vedocizumab as "Form A," once daily in a maintenance period, resulting in a delay in EDSS worsening (e.g., an increase of 0.5, 1.0, 1.5, or more points compared to baseline), a delay in 9-HPT time worsening (e.g., more than 20% compared to baseline), a delay in T25FWT time worsening (e.g., more than 20% compared to baseline), a delay in CDP12 onset, a delay in CDP24 onset, a delay in cCDP12 onset, a delay in cCDP24 onset, a delay in onset of at least one progression event, a reduction in risk of at least one progression event, or a reduction in disability in a subject having PIRA.In other embodiments, treatment of the PIRA is assessed based on MSIS-29, Neuro-QoL Upper Limb, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25EWT, EDSS, SDMT, MRI, NFL levels, GFAP levels, BDNF levels, or Nurr1 expression levels. In other embodiments, treatment of the PIRA is assessed based on BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNFα, iNOS, YKL-40, or IL-1β. For example, in some embodiments, treating a subject having a PIRA comprises delaying progression of the PIRA, wherein the progression is assessed based on MSIS-29, Neuro-QoL Upper Limb, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25EWT, EDSS, SDMT, MRI, NFL levels, GFAP levels, BDNF levels, or Nurr1 expression levels; or assessed based on the onset of at least one progression event, which can be described by CDP12, cCDP12, CDP24, or cCDP24. In some embodiments, treating a PIRA comprises delaying progression of the PIRA. In certain embodiments, treating a PIRA comprises delaying the onset of at least one progression event in the subject. In some embodiments, treating a PIRA comprises reducing the risk of the subject experiencing at least one progression event. In certain embodiments, treating a PIRA comprises delaying progression or delaying the onset of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% (e.g., assessed using T25FWT time or 9-HPT time or EDSS score or CDP12 or cCDP12 or CDP24 or cCDP24, etc.). In certain embodiments, treating a PIRA comprises delaying progression or delaying the onset of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% as compared to another subject having a PIRA (e.g., a comparative subject), wherein the other subject is not administered verdafyno or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof. In some embodiments, the delay is at least 5%. In some embodiments, the delay is at least 10%. In some embodiments, the delay is at least 15%. In some embodiments, the delay is at least 20%. In some embodiments, the delay is at least 25%.In some embodiments, the delay is at least 30%. In some embodiments, the delay is at least 35%. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody). In other embodiments, treating PIRA comprises reducing the risk of having at least one progression event in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In certain embodiments, the risk is reduced over a period of time, e.g., over 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks. In some embodiments, the risk is reduced as compared to another subject with PIRA (e.g., a comparative subject) who is not administered vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, and optionally an anti-CD20 antibody. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody). In some embodiments, the risk is reduced by at least 5%. In some embodiments, the risk is reduced by at least 10%. In some embodiments, the risk is reduced by at least 15%. In some embodiments, the risk is reduced by at least 20%. In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 30%. In some embodiments, the risk is reduced by at least 35%. In certain embodiments, treating PIRA comprises improving a PIRA indicator (e.g., T25FWT time or 9-HPT time or EDSS score, etc.) by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% as compared to the same indicator assessed in the same subject prior to the start of administration of vedolizumab or an equivalent amount of an isotopic variant, pharmaceutically acceptable salt, or solvate thereof (preferably vedolizumab calcium salt dihydrate as “Form A”). In some embodiments, the improvement is as compared to the same indicator assessed in the same subject within 1 week or within 0-28 days or within 6 weeks prior to the start of administration of vedolizumab or an equivalent amount of an isotopic variant, pharmaceutically acceptable salt, or solvate thereof. In other embodiments, treating PIRA comprises improving a PIRA indicator (e.g., T25FWT time or 9-HPT time or EDSS score, etc.) by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 40% as compared to the same indicator assessed in another subject with PIRA, wherein the other subject is not administered vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof. In some embodiments, the improvement is at least 5%.In some embodiments, the improvement is at least 10%. In some embodiments, the improvement is at least 15%. In some embodiments, the improvement is at least 20%. In some embodiments, the improvement is at least 25%. In some embodiments, the improvement is at least 30%. In some embodiments, the improvement is at least 35%. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody). In some embodiments, the PIRA sub-group is selected from: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof. In some embodiments, the PIRA sub-group is aSPMS. In some embodiments, the PIRA sub-group is n-aSPMS. In some embodiments, the PIRA sub-group is SPMS. In some embodiments, the PIRA sub-group is PPMS. In some embodiments, the PIRA sub-group is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0217] Also provided is a method of treating (e.g., slowing the progression of) PIRA in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vedocizumab as "Form A." Also provided is administering to the subject a dose of about 30 to 45 mg of vedocizumab, or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vedocizumab as "Form A," once daily during a maintenance period. Accordingly, provided herein is a method of treating (e.g., slowing the progression of) PIRA in a subject in need thereof, the method comprising administering to the subject a dose of about 30 to 45 mg of vedocizumab, or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vedocizumab as "Form A," once daily during a maintenance period. Also provided is a compound for use in a method of slowing the progression of PIRA in a subject in need thereof, wherein the compound is vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the method comprises administering to the subject a dose of about 30 to 45 mg of vedocizumab, or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vedocizumab as "Form A," once daily. In other embodiments, provided herein is a compound for use in a method of manufacturing a medicament for use in a method of treating (e.g., slowing the progression of) PIRA in a subject in need thereof, wherein the compound is vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the method comprises administering to the subject a dose of about 30 to 45 mg of vedocizumab, or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vedocizumab as "Form A," once daily during a maintenance period. In some embodiments, the progression of PIRA is assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combination thereof. In some embodiments, the progression of PIRA is assessed based on time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP) or based on time to onset of composite confirmed disability progression (e.g., 12-week or 24-week cCDP). In certain embodiments, the progression of PIRA is slowed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the progression is slowed by at least 5%. In some embodiments, the progression is slowed by at least 10%. In some embodiments, the progression is slowed by at least 15%. In some embodiments, the progression is slowed by at least 20%.In some embodiments, the progression is slowed by at least 25%. In some embodiments, the progression is slowed by at least 30%. In some embodiments, the progression is slowed by at least 35%. In some embodiments, the progression is slowed as measured by the onset of cCDP12 (e.g., an increase in time to cCDP12 onset) or the risk of cCDP12 (e.g., a reduction in the risk of experiencing a cCDP12 within a period of time). In some embodiments, the progression of the PIRA is slowed relative to another subject having PIRA (e.g., a comparative subject), wherein the other subject is not administered vedoflaxin, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody) and is not administered a DHODH inhibitor (e.g., vedoflaxin, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof). In certain embodiments, the total assessment period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks. In certain embodiments, the total assessment period is at least 120 weeks, e.g., the progression of PIRA is slowed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% as compared to another subject having PIRA who is not administered vedoflaxin, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, and optionally administered a CD20-directed cytolytic antibody within 120 weeks. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody). In some embodiments, the PIRA subgroup is selected from (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof. In some embodiments, the PIRA subgroup is aSPMS. In some embodiments, the PIRA subgroup is n-aSPMS. In some embodiments, the PIRA subgroup is SPMS. In some embodiments, the PIRA subgroup is PPMS. In some embodiments, the PIRA subgroup is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0218] In other embodiments, provided herein is a method of reducing disability in a subject having PIRA, comprising administering to the subject a therapeutically effective amount of vafidemstat or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vafidemstat calcium salt dihydrate as "polymorph A". In other embodiments, provided herein is a method of administering to the subject a dose of about 30 to 45 mg of vafidemstat or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vafidemstat calcium salt dihydrate as "polymorph A", once a day during a maintenance phase. In other embodiments, provided herein is a method of reducing disability in a subject having PIRA, comprising administering to the subject a dose of about 30 to 45 mg of vafidemstat or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vafidemstat calcium salt dihydrate as "polymorph A", once a day during a maintenance phase. In some embodiments, provided is a compound for use in a method of reducing disability in a subject having PIRA, wherein the compound is vafidemstat or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and the method comprises administering to the subject a dose of about 30 to 45 mg of vafidemstat or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vafidemstat calcium salt dihydrate as "polymorph A", once a day during a maintenance phase. In other embodiments, provided herein is a compound for use in the manufacture of a medicament for use in a method of reducing disability in a subject having PIRA, wherein the compound is vafidemstat or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the method comprises administering to the subject a dose of about 30 to 45 mg of vafidemstat or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vafidemstat calcium salt dihydrate as "polymorph A", once a day during a maintenance phase. Reducing disability can include reducing the psychological impact of MS, enhancing upper limb function, improving walking ability, reducing fatigue, improving work status, or reducing overall impression of MS severity, or any combination thereof. Reducing disability can also include reducing one or more symptoms of PIRA, or reducing one or more physical effects of PIRA on the subject. Reduction of disability, including for example one or more symptoms or physical effects or other aspects described herein, can be assessed as described herein, for example using MSIS-29, Neuro-QoL Upper Limb, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25EWT, EDSS, SDMT, MRI, NFL levels, GFAP levels, BDNF levels, or Nurr1 expression levels.In some embodiments, one or more of 9-HPT, T25FWT, or EDSS is used. In some embodiments, the reduction in disability comprises the subject can complete the T25FWT faster, the 9-HPT anchor is reduced (e.g. closer to “normal”), or the EDSS score is reduced. In certain embodiments, the reduction in disability comprises an improvement in one or more indicators of PIRA, such as indicators assessed using MSIS-29, Neuro-QoL Upper Limb, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25EWT, EDSS, SDMT, MRI, NFL levels, GFAP levels, BDNF levels, or Nurr1 expression levels. In certain embodiments, the improvement is at least a 5%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, or at least a 35% improvement in at least one PIRA indicator (e.g. T25FWT time or 9-HPT time or EDSS score) compared to the same indicator assessed in the same subject prior to the start of administration of verdofinitrilmod or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, preferably verdofinitrilmod calcium salt dihydrate as “Form A”. In some embodiments, two, three, four, five, or more indicators are improved, where each level of improvement is independent (e.g. one indicator is improved by at least 10% and another indicator is improved by at least 20%). In some embodiments, the improvement is at least 5%. In some embodiments, the improvement is at least 10%. In some embodiments, the improvement is at least 15%. In some embodiments, the improvement is at least 20%. In some embodiments, the improvement is at least 25%. In some embodiments, the improvement is at least 30%. In some embodiments, the improvement is at least 35%. In some embodiments, the improvement is compared to the same indicator assessed in the same subject within 1 week or within 0 to 28 days or within 6 weeks prior to the start of administration of verdofinitrilmod or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof. In some embodiments, the PIRA subgroup is selected from the following subgroups: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof. In some embodiments, the PIRA subgroup is aSPMS. In some embodiments, the PIRA subgroup is n-aSPMS.In some embodiments, the PIRA subgroup is SPMS. In some embodiments, the PIRA subgroup is PPMS. In some embodiments, the PIRA subgroup is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0219] In other embodiments, a method of delaying the onset of at least one progression event in a subject having PIRA is provided, the method comprising administering to the subject a therapeutically effective amount of verdolatrane or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably verdolatrane calcium salt dihydrate as "polymorph A". In other embodiments, a method of delaying the onset of at least one progression event in a subject having PIRA is provided, the method comprising administering to the subject a dose of about 30 to 45 mg of verdolatrane or an isotopically variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably verdolatrane calcium salt dihydrate as "polymorph A", once a day during a maintenance period. Also provided is a compound for use in a method of delaying the onset of at least one progression event in a subject having PIRA, wherein the compound is verdolatrane or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the method comprises administering to the subject a dose of about 30 to 45 mg of verdolatrane or an isotopically variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably verdolatrane calcium salt dihydrate as "polymorph A", once a day during a maintenance period. In other embodiments, a compound for use in the manufacture of a medicament for a method of delaying the onset of at least one progression event in a subject having PIRA is provided, wherein the compound is verdolatrane or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the method comprises administering to the subject a dose of about 30 to 45 mg of verdolatrane or an isotopically variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably verdolatrane calcium salt dihydrate as "polymorph A", once a day during a maintenance period. The progression event can include, for example, an increase in time required to complete 9-HPT or an increase in time required to complete T25FWT or an increase in EDSS score compared to baseline. In some embodiments, the increase in time required to complete 9-HPT compared to baseline is an increase of at least 20% (e.g., can be 20%, 25%, 30%, 35%, etc.). In some embodiments, the increase in time required to complete T25FWT compared to baseline is an increase of at least 20% (e.g., can be 20%, 25%, 30%, 35%, etc.). In other embodiments, the increase in EDSS score compared to baseline is an increase of at least 1.0 if baseline is less than or equal to 5.5 or an increase of at least 0.5 if baseline score is greater than 5.5 in a subject. In certain embodiments, the progression event is confirmed at a specific period of time after initial progression, for example, at least 12 weeks or at least 24 weeks.In certain embodiments, the baseline for determining a progression event is the same indicator (e.g., T25FWT, 9-HPT, EDSS, or a combination thereof) assessed in the same subject within 1 week or 0 to 28 days or 6 weeks prior to the initiation of the administration of vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof. In certain embodiments, the method, compound for use, or use of a compound in the manufacture of a medicament delays the onset of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the delay is at least 5%. In some embodiments, the delay is at least 10%. In some embodiments, the delay is at least 15%. In some embodiments, the delay is at least 20%. In some embodiments, the delay is at least 25%. In some embodiments, the delay is at least 25%. In some embodiments, the delay is at least 30%. In some embodiments, the delay is at least 35%. In some embodiments, the time to onset is delayed relative to another subject having PIRA (e.g., a comparator subject), wherein the other subject is not administered a DHODH inhibitor (e.g., vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof). In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody) and is not administered a DHODH inhibitor (e.g., vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof). In certain embodiments, the total assessment period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks. In certain embodiments, the total assessment period is at least 120 weeks, e.g., the period of time prior to the onset of at least one progression event assessed over 120 weeks is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% relative to another subject having PIRA who is not administered a DHODH inhibitor (e.g., vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof) and optionally administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody). In some embodiments, calculating the delay in the onset of at least one progression event can comprise, e.g., calculating the additional time prior to the occurrence of a progression event in a subject administered vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof relative to a subject who is not administered vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof (and optionally administered an anti-CD20 antibody).In some embodiments, the PIRA sub-group is selected from the following sub-groups: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof. In some embodiments, the PIRA sub-group is aSPMS. In some embodiments, the PIRA sub-group is n-aSPMS. In some embodiments, the PIRA sub-group is SPMS. In some embodiments, the PIRA sub-group is PPMS. In some embodiments, the PIRA sub-group is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0220] Further provided herein is a method of reducing the risk of having at least one progression event in a subject having PIRA, comprising administering to the subject a therapeutically effective amount of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof. Also provided herein is a method of reducing the risk of having at least one progression event in a subject having PIRA, comprising administering to the subject a dose of about 30 to 45 mg of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, once a day during a maintenance period. Further provided is a compound for use in a method of reducing the risk of having at least one progression event in a subject having PIRA, wherein the compound is vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the method comprises administering to the subject a dose of about 30 to 45 mg of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, once a day during a maintenance period. In other embodiments, provided is a compound for the manufacture of a medicament for reducing the risk of having at least one progression event in a subject having PIRA, wherein the compound is vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, and wherein the subject is administered a dose of about 30 to 45 mg of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, once a day during a maintenance period. A progression event can include, for example, an increase in time to complete 9-HPT compared to baseline or an increase in time to complete T25FWT compared to baseline or an increase in EDSS score compared to baseline. In some embodiments, the increase in time to complete 9-HPT compared to baseline is an increase of at least 20% (e.g., can be 20%, 25%, 30%, etc.). In some embodiments, the increase in time to complete T25FWT compared to baseline is an increase of at least 20% (e.g., can be 20%, 25%, 30%, etc.). In other embodiments, the increase in EDSS score compared to baseline is an increase of at least 1.0 (e.g., can be 1.0, 1.5, 2.0, etc.) if baseline is less than or equal to 5.5 or an increase of at least 0.5 (e.g., can be 0.5, 1.0, 1.5, etc.) if baseline score is greater than 5.5 in a subject. In certain embodiments, the progression event is sustained for a period of time, e.g., at least 12 weeks or at least 24 weeks (e.g., as CDP12, cCDP12, CDP24, or cCDP24).In certain embodiments, the baseline for determining a progression event is the same indicator (e.g., T25FWT, 9-HPT, EDSS, or a combination thereof) assessed in the same subject within 1 week or 0 to 28 days or 6 weeks prior to initiating administration of vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof. In certain embodiments, the method, compound for use, or use of a compound in the manufacture of a medicament reduces the risk of the subject having PIRA having at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the risk is reduced by at least 5%. In some embodiments, the risk is reduced by at least 10%. In some embodiments, the risk is reduced by at least 15%. In some embodiments, the risk is reduced by at least 20%. In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 30%. In some embodiments, the risk is reduced by at least 35%. In some embodiments, the reduction in the risk of having at least one progression event comprises reducing the risk of experiencing cCDP12 or reducing the risk of worsening according to EDSS. In some embodiments, the reduction in the risk of having at least one progression event is relative to another subject having PIRA, wherein the other subject is not administered a DHODH inhibitor (e.g., vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof). In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-directed cytolytic antibody) and is not administered a DHODH inhibitor (e.g., vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof). In certain embodiments, the total assessment period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks. In certain embodiments, the total assessment period is at least 120 weeks, e.g., a subject having PIRA administered vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof has a risk of at least one progression event within 120 weeks that is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% lower than another subject having PIRA who is not administered vedolizumab or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof and is optionally administered a CD20-directed cytolytic antibody.This reduction in the risk of at least one progression event can be calculated, for example, by calculating the rate of progression events (e.g., within 60 weeks or within 120 weeks) in one or more subjects having PIRA administered vedoflaxin, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, and comparing that rate of progression events to the rate of progression events in one or more subjects having PIRA not administered vedoflaxin, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, and optionally administered an anti-CD20 antibody (e.g., a CD20 directed cytolytic antibody). In some embodiments, the PIRA sub-group is selected from the following sub-groups: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof. In some embodiments, the PIRA sub-group is aSPMS. In some embodiments, the PIRA sub-group is n-aSPMS. In some embodiments, the PIRA sub-group is SPMS. In some embodiments, the PIRA sub-group is PPMS. In some embodiments, the PIRA sub-group is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0221] Further provided herein are methods of enhancing activity in a subject in need thereof, wherein the subject has PIRA, comprising administering to the subject a therapeutically effective amount of vofortamide or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vofortamide calcium salt dihydrate as "Polymorph A". Also provided herein are methods of enhancing activity in a subject in need thereof, wherein the subject has PIRA, comprising administering to the subject a dose of about 30 to 45 mg of vofortamide or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vofortamide calcium salt dihydrate as "Polymorph A", once a day during a maintenance period. Accordingly, provided herein are methods of enhancing activity in a subject in need thereof, wherein the subject has PIRA, comprising administering to the subject a dose of about 30 to 45 mg of vofortamide or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, preferably vofortamide calcium salt dihydrate as "Polymorph A", once a day during a maintenance period. The enhancement of activity in a subject can include, for example, an enhancement of walking ability, an enhancement of running ability, an enhancement of stair climbing ability, an enhancement of standing ability, an improvement in balance while walking or standing, an increase in the distance a subject is able to walk, a reduction in the effort required to walk, a reduction in the reliance on support (e.g., a cane, leaning on furniture, a walker, etc.) while walking indoors and / or outdoors, a reduction in the attention required to walk, or an increase in the evenness / steadiness of walking, or any combination of the foregoing enhancements. In some embodiments, one, two, or more of these aspects of activity are improved while one or more are not. For example, the enhancement of activity in a subject can include an enhancement of walking ability while one or more other components of activity are not improved. Such an enhancement of activity can be assessed, for example, using a subject questionnaire. In some embodiments, the enhancement of activity or one or more components of the enhancement of activity described herein can be assessed using the MSWS-12. In some embodiments, the enhancement of activity is assessed compared to the subject's activity (e.g., assessed using the MSWS-12) prior to the start of administration of vofortamide or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof. In some embodiments, the PIRA subgroup is selected from the following subgroups: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof.In some embodiments, the PIRA subgroup is aSPMS. In some embodiments, the PIRA subgroup is n-aSPMS. In some embodiments, the PIRA subgroup is SPMS. In some embodiments, the PIRA subgroup is PPMS. In some embodiments, the PIRA subgroup is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0222] In some embodiments provided herein, progression of PIRA can be assessed by one or more clinical or laboratory endpoints selected from MSIS-29, Neuro-QoL Upper Limb, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25EWT, EDSS, SDMT, MRI, NFL levels, GFAP levels, BDNF levels, or Nurr1 expression levels. Thus, for example, in some embodiments, progression of PIRA is assessed by one or more of EDSS, T25FWT, or 9-HPT. Further, in some embodiments, progression of PIRA is assessed by a sustained increase in one or more PIRA symptoms or signs, e.g., a sustained increase for at least 12 weeks (e.g., confirmed to still be increasing at least 12 weeks after the initial increase is observed) or at least 24 weeks (e.g., confirmed to still be increasing at least 24 weeks after the initial increase is observed). In certain embodiments, progression of PIRA is assessed by cCDP or CDP, e.g., cCDP-12, CDP-12, cCDP24, or CDP24, or any combination thereof. In some embodiments, progression of PIRA is assessed by cCDP12. In certain embodiments, progression of PIRA is assessed by EDSS. In certain embodiments, the risk of experiencing cCDP12 is reduced or the pre-onset time of cCDP12 is increased in combination with reducing the risk of experiencing CDP12 or in combination with increasing the pre-onset time of CDP12. In certain embodiments, the risk of experiencing cCDP12 is reduced or the pre-onset time of cCDP12 is increased in combination with reducing the risk of experiencing cCDP24. In other embodiments, the risk of experiencing cCDP12 is reduced in combination with both reducing the risk of experiencing CDP12 and reducing the risk of experiencing cCDP24. In other embodiments, the pre-onset time of cCDP12 is increased in combination with both increasing the pre-onset time of CDP12 and increasing the pre-onset time of cCDP24. In some embodiments, the PIRA subgroup is selected from the following subgroups: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) non-active PIRA; (j) clinically isolated syndrome (CIS); (k) conversion MS; or a combination thereof. In some embodiments, the PIRA subgroup is aSPMS. In some embodiments, the PIRA subgroup is n-aSPMS.In some embodiments, the PIRA subgroup is SPMS. In some embodiments, the PIRA subgroup is PPMS. In some embodiments, the PIRA subgroup is PMS. In some embodiments, the subject has POMS. In some embodiments, the subject has LOMS. In some embodiments, the subject has AOMS.

[0223] In some embodiments described herein, the response of a subject administered vofortradimezine, or an isotopic variant, pharmaceutically acceptable salt, or solvate thereof, can be compared to another subject administered an antibody directed against CD20, such as an anti-CD20 antibody. As used herein, an anti-CD20 antibody can include an antibody that binds to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. In some embodiments, the antibody is a humanized monoclonal antibody directed against B cells expressing CD20. In certain embodiments, binding of the anti-CD20 antibody to the cell surface of B lymphocytes can result in antibody-dependent cellular cytotoxicity and complement-mediated lysis. In certain embodiments, the anti-CD20 antibody is a CD20-directed cytolytic antibody. Examples of such antibodies can include, for example, ocrelizumab. Ocrelizumab is a recombinant, humanized, glycosylated, monoclonal IgGl antibody that selectively targets and depletes B cells expressing CD20.

[0224] In some embodiments of the methods, uses of compounds, or uses of compounds described herein, a therapeutically effective amount of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, is administered to a subject having PIRA, wherein the subject having PIRA has progressive disease from onset and is in a progressive stage at least 12 months prior to initiating administration of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof. In certain embodiments of the methods, uses of compounds, or uses of compounds described herein, about 30 to 45 mg of vedocizumab, or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof, is administered once daily to a subject having PIRA in the maintenance phase, wherein the subject having PIRA has progressive disease from onset and is in a progressive stage at least 12 months prior to initiating administration of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof. In some embodiments, the subject having PIRA has one or more T2 hyperintense lesions in one or more of the periventricular, cortical or juxtacortical, or subdural brain regions; two or more T2 hyperintense lesions in the spinal cord; or the presence of cerebrospinal fluid-specific oligoclonal bands. In certain embodiments, the subject having PIRA has at least two of one or more T2 hyperintense lesions in one or more of the periventricular, cortical or juxtacortical, or subdural brain regions; two or more T2 hyperintense lesions in the spinal cord; or the presence of cerebrospinal fluid-specific oligoclonal bands. In other embodiments, the subject having PIRA has progressive disease from onset and is in a progressive stage at least 12 months prior to initiating administration of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof; and has at least two of one or more T2 hyperintense lesions in one or more of the periventricular, cortical or juxtacortical, or subdural brain regions; two or more T2 hyperintense lesions in the spinal cord; or the presence of cerebrospinal fluid-specific oligoclonal bands. T2 hyperintense lesions can be assessed, for example, by MRI. The presence of cerebrospinal fluid-specific oligoclonal bands can be assessed, for example, by lumbar puncture. In other embodiments, the subject having PIRA can have an EDSS score of between 3.0 and 6.5 between initiating administration of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof. In some embodiments, the subject having PIRA is neurologically stable for at least 30 days prior to initiating administration of vedocizumab, or an isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof.In some such embodiments, the methods, compounds for use, or uses of compounds are for treating PIRA, treating (e.g., slowing the progression of) PIRA, reducing disability, delaying the onset of at least one progression event, reducing the risk of having at least one progression event, enhancing activity capacity, or increasing pre-cCDP12 time in a subject having PIRA in need thereof; and comprise administering to the subject a dosage of about 30 to 45 mg of vafidemstat or an equivalent amount of an isotopologue, a pharmaceutically acceptable salt, or a solvate thereof per day during a maintenance phase, preferably vafidemstat calcium salt dihydrate as "polymorphic form A".

[0225] Also provided herein are pharmaceutical compositions and formulations for use in the treatment methods described herein (e.g., treating PIRA, slowing the progression of PIRA, etc.) comprising vafidemstat or an isotopologue, a pharmaceutically acceptable salt, or a solvate thereof. In some embodiments, the pharmaceutical compositions and formulations further comprise one or more pharmaceutically acceptable carriers.

[0226] Vafidemstat or an isotopologue, a pharmaceutically acceptable salt, or a solvate thereof (preferably vafidemstat calcium salt dihydrate as "polymorphic form A") can be administered by any suitable means, including orally, parenterally, intrapulmonary, and intranasally, and, if needed for local treatment, also intralesionally. In certain embodiments, oral administration is used.

[0227] A pharmaceutically acceptable salt of a compound according to Formulae (I) to (V) or a compound according to Formula (VI) (preferably vafidemstat or an isotopologue thereof) can be used in the methods herein. The term "pharmaceutically acceptable salt" as used herein is intended to include salts of the active compounds that are relatively nontoxic to the subjects in which they are administered. Salts thereof can be prepared from a naturally acidic group as the salt-forming ion with or without additional salt-forming agents. Salts of the compounds of the present disclosure can be prepared using a variety of organic and inorganic counter-ions of

[0228] In some embodiments provided herein, an oral dose of a compound according to Formulae (I)-(V) or a compound according to Formula (VI) (preferably veduramfetamine) or an isotopolog, pharmaceutically acceptable salt, or solvate thereof is administered as one or more tablets or capsules. For example, in some embodiments, the maintenance phase of about 30-45 mg of veduramfetamine calcium salt dihydrate as "Polymorph A" is administered as one tablet once daily.

[0229] In other embodiments provided herein, an article of manufacture or kit comprising a compound according to Formulae (I)-(V) or a compound according to Formula (VI) (preferably veduramfetamine) or an isotopolog, pharmaceutically acceptable salt, or solvate thereof and a container are provided. In certain embodiments, a package insert comprising instructions for using the compound according to Formulae (I)-(V) or a compound according to Formula (VI) (preferably veduramfetamine) or an isotopolog, pharmaceutically acceptable salt, or solvate thereof is also included. Suitable containers for the kit include, for example, bottles, boxes, blister packs, or combinations thereof (e.g., blister packs in a box). In some embodiments, the container holds the formulation, and the label on, or associated with, the container can indicate that the contents are to be used for the indicated use. The article of manufacture or kit can further include other materials desirable from a commercial and user standpoint, including a package insert with instructions for use.

[0230] This specification is considered sufficient to enable one skilled in the art to practice the application. Various modifications of the application in addition to those described and depicted herein will become apparent to those skilled in the art from the foregoing description and will fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.

[0231] IV. Medical uses of the compounds

[0232] One aspect of the present disclosure relates to a compound according to Formulae (I)-(V) or a compound according to Formula (VI) for use in the treatment of a disease caused by lower levels of Nurr1 in the central nervous system of a subject in need thereof.

[0233] In some embodiments, the disease caused by lower levels of Nurr1 is Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia (FTD), Kennedy's disease, Krabbe disease, kuru, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum's disease, Sandhoff disease, Shy-Drager syndrome, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0234] In some embodiments, the disease caused by lower levels of Nurr1 is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

[0235] In some embodiments, the disease is Parkinson's disease.

[0236] In some embodiments, the disease is Alzheimer's disease.

[0237] In some embodiments, the disease is multiple sclerosis, in particular relapsing multiple sclerosis (RMS) such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive multiple sclerosis such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0238] In some embodiments, the subject in need of the above-mentioned method for treating MS is a human, in some embodiments in particular a female human.

[0239] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with pediatric-onset MS (POMS), meaning that the onset occurred before the age of 18.

[0240] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with late-onset MS (LOMS), meaning onset in the time period of 19-50 years of age.

[0241] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with adult-onset MS (AOMS), meaning onset at > 50 years of age.

[0242] The age at which the patient experiences the onset of MS appears to be a factor associated with PIRA: in one study, AOMS had a hazard ratio of 1.42 compared to POMS; LOMS had a hazard ratio of 2.98 compared to POMS (JAMA Neurol. 2024; 81 : 50).

[0243] Other factors associated with PIRA appear to be the length of time of the disease (the longer the disease phase, the higher the risk of PIRA) and the length of time of DMT treatment (the shorter the DMT treatment phase, the higher the risk of PIRA).

[0244] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with clinically isolated syndrome (CIS).

[0245] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients characterized as patients with conversion MS.

[0246] In some embodiments, the subject in need of the above-mentioned method for preventing and / or treating MS belongs to the group of patients who have not yet been diagnosed with MS, but who, if one or more indicators of an increased risk score (e.g. by biomarkers) and / or genetic predisposition and / or symptoms such as pre-MS symptoms are present. In general, the onset of MS means that a first demyelination event has already occurred. Since there are many cases, for example so-called benign MS patients who have not been detected for many years, it can be advantageous to include them in the treatment according to the application even before the detection of the MS disease, if they have a corresponding increased risk score, which can be determined by suitable biomarkers and genetic predispositions.

[0247] In some embodiments, the disease is progressive multiple sclerosis.

[0248] In some embodiments, the disease is primary progressive multiple sclerosis.

[0249] In some embodiments, the disease is non-active secondary progressive multiple sclerosis (non-active SPMS).

[0250] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS).

[0251] In some embodiments, the disease is relapsing-remitting multiple sclerosis.

[0252] In some embodiments, the disease is multiple sclerosis, wherein the disability is obtained by relapse-associated worsening (RAW).

[0253] In some embodiments, the disease is multiple sclerosis, wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0254] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), wherein the disability is obtained by relapse-associated worsening (RAW).

[0255] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0256] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), wherein the disability is obtained by relapse-associated worsening (RAW).

[0257] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0258] In some embodiments, the disease is primary progressive multiple sclerosis (PPMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0259] In some embodiments, the disease is non-active secondary progressive multiple sclerosis (non-active SPMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0260] In some embodiments, the disease is clinically isolated syndrome (CIS).

[0261] In some embodiments, the disease is conversion MS.

[0262] In some embodiments, the condition is PIRA.

[0263] In some embodiments, the disease is amyotrophic lateral sclerosis.

[0264] In some embodiments, the disease is schizophrenia.

[0265] In some embodiments, the disease is a drug addiction.

[0266] In some embodiments, the disease caused by lower levels of Nurr1 is cancer.

[0267] In some embodiments, the compound is a compound according to Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0268] (I),

[0269] wherein:

[0270] - A is a substituted or unsubstituted ring;

[0271] - Z 1 and Z 2 are each independently O, S, or NR 9 ;

[0272] - E is a linker or is absent;

[0273] - G is a linker or is absent;

[0274] - Y is a ring;

[0275] - R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 or NR 11 R 12 ;

[0276] - R 3 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0277] - each R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0278] - n is 0, 1, 2, 3, 4, or 5;

[0279] - q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0280] - r is 0 or 1,

[0281] which has one or more hydrogen atoms optionally replaced by deuterium. In some embodiments, the compound is a calcium salt, a hemi-calcium salt, a solvate, a disolvate, a hydrate, a dihydrate, a calcium salt hydrate, or a hemi-calcium salt dihydrate.

[0282] In some embodiments, the compound is a compound according to Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0283] (I),

[0284] wherein:

[0285] - Ring A is a 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted with 1 to 4 residues R 1 ;

[0286] - Z 1 and Z 2 are each independently O, S, or NR 9 ;

[0287] - E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene;

[0288] - G is O, S, SO2, NR 10 , or CH2;

[0289] - Y is aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0290] - R 1 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0291] - R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 , or NR 11 R 12 ;

[0292] - R 3 is H, halogen, -OR 13, -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0293] - each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0294] - n is 0 or 1;

[0295] - q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0296] - r is 0 or 1,

[0297] having one or more hydrogen atoms optionally replaced by deuterium.

[0298] In some embodiments, the compound is a compound according to Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0299] (II),

[0300] wherein:

[0301] - X is O, S, NR 9 , SO, or SO2;

[0302] - Z 2 is O, S, or NR 12 ;

[0303] - E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene;

[0304] - G is O, S, SO2, NR 10 , or CH2;

[0305] - Y is aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0306] - R 1 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14, alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted;

[0307] - each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted;

[0308] - m is 0, 1, 2, 3, or 4;

[0309] - n is 0 or 1; and

[0310] - q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0311] In some embodiments, the compound is a compound according to Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

[0312] (III),

[0313] wherein:

[0314] - E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene;

[0315] - Y is aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0316] - each R 1 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted; and

[0317] - each R 8 , R 13 , and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted.

[0318] In some embodiments, E is alkylene or cycloalkylene, each of which is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 1-naphthyl, 2-naphthyl, -2-naphthyl, anthryl, N-imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-

[0319] thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-

[0320] thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-

[0321] thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-

[0322] thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-

[0323] thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- A and R B are each independently H, D, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0324] each R 8 , R 13 , and R 14 is independently H, D, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;

[0325] x is 0, 1, 2, 3, or 4; and

[0326] - y is 0, 1, 2, 3, 4, or 5.

[0327] In some embodiments, the compound is a compound according to Formula (V), or a pharmaceutically acceptable salt or solvate thereof:

[0328] (V),

[0329] wherein:

[0330] - Ring A is , , , , , , or ;

[0331] - E is , , , , or ; and

[0332] - Y is , , , , , , or .

[0333] In some embodiments, the compound is

[0334] , , , , , , , or ,

[0335] or a pharmaceutically acceptable salt or solvate thereof.

[0336] In some embodiments, the compound is

[0337] ,

[0338] or an isotopic variant or pharmaceutically acceptable salt or solvate thereof.

[0339] In some embodiments, the compound is

[0340] ,

[0341] or a pharmaceutically acceptable salt or solvate thereof.

[0342] In some embodiments, the compound is

[0343] or a solvate thereof.

[0344] In some embodiments, the compound is

[0345] .

[0346] In some embodiments, the compound is a compound according to Formula (VI) or a pharmaceutically acceptable salt or solvate thereof:

[0347] (VI),

[0348] wherein:

[0349] - R 2 is NR 11 R 12 ;

[0350] - R 11 is selected from H, OH, optionally substituted alkyl, optionally substituted cycloalkyl, one or more hydrogen atoms of said alkyl or cycloalkyl being optionally replaced by deuterium;

[0351] - R 12 is selected from H or optionally substituted alkyl, one or more hydrogen atoms of said alkyl being optionally replaced by deuterium;

[0352] - Ring A is , , , , , , or ;

[0353] - E is , , , or ; and

[0354] - Y is , , , , , , or .

[0355] In some embodiments, the compound is a compound according to Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:

[0356] (VI),

[0357] wherein:

[0358] - R 2 is NHR 11 ;

[0359] - R 11 is selected from H or alkyl, one or more hydrogen atoms of said alkyl being optionally replaced by deuterium;

[0360] - Ring A is , , or ;

[0361] - E is , , , or ; and

[0362] - Y is , , , or .

[0363] In some embodiments, the compound is

[0364] , , , , , , , , , , , , , or ,

[0365] or a pharmaceutically acceptable salt or solvate thereof.

[0366] In some embodiments, each alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more R', wherein each R' is independently H, D, -CO2R", -CONHR", -CR"O, -SO2N(R")2, -NR"-CO-haloalkyl, -NR"-CO-alkyl, -NO2, -N3, -NR"-SO2-haloalkyl, -NR"-SO2-alkyl, -SO2-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, oxo, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl, or heteroaryl, wherein each R" is independently H, D, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, or aminoalkyl.

[0367] IV. Methods of Treatment

[0368] In one aspect, there is provided a method of treating a disease caused by lower levels of Nurr1 in the central nervous system of a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I) to (V) or a compound according to Formula (VI) described herein.

[0369] In one aspect, there is provided a method of treating a disease caused by lower levels of Nurr1 in the central nervous system of a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of Vdohydroxychloroquine or a solvate or pharmaceutically acceptable salt thereof.

[0370] In one aspect, there is provided a method of treating a disease caused by lower levels of Nurr1 in the central nervous system of a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of IMU-838, for example as polymorph A.

[0371] In some embodiments, the disease caused by lower levels of Nurr1 is Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia (FTD), Kennedy's disease, Krabbe disease, kuru, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum disease, Sandhoff disease, Shy-Drager syndrome, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0372] In some embodiments, the disease caused by lower levels of Nurr1 is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

[0373] In some embodiments, the disease is Parkinson's disease.

[0374] In some embodiments, the disease is Alzheimer's disease.

[0375] In some embodiments, the disease is multiple sclerosis, in particular relapsing multiple sclerosis (RMS) such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive multiple sclerosis such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0376] In some embodiments, the subject in need of the above-mentioned method for treating MS is a human, in some embodiments in particular a female human.

[0377] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with pediatric-onset MS (POMS), meaning that the onset occurred before the age of 18.

[0378] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with late-onset MS (LOMS), which means onset in the time period of 19-50 years.

[0379] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with adult-onset MS (AOMS), which means onset at > 50 years.

[0380] The age at which the patient experiences the onset of MS appears to be a factor associated with PIRA, for example: in one study, the risk ratio for AOMS compared to POMS was 1.42; the risk ratio for LOMS compared to POMS was 2.98 (JAMA Neurol. 2024; 81 : 50).

[0381] Other factors associated with PIRA appear to be the length of time of the disease (the longer the disease phase, the higher the risk of PIRA) and the length of time of DMT treatment (the shorter the DMT treatment phase, the higher the risk of PIRA).

[0382] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients with clinically isolated syndrome (CIS).

[0383] In some embodiments, the subject in need of the above-mentioned method for treating MS belongs to the group of patients characterized as patients with conversion MS.

[0384] In some embodiments, the subject in need of the above-mentioned method for preventing and / or treating MS belongs to the group of patients who have not yet been diagnosed with MS, but who have one or more indicators (e.g. by biomarkers) and / or genetic predispositions and / or symptoms such as pre-MS symptoms that increase the risk score. In general, the onset of MS means that the first demyelination event has already occurred. Since there are many cases, for example so-called benign MS patients who have not been detected for many years, it can be advantageous to include them in the treatment according to the application even before the MS disease has been detected, if they have a corresponding increase in the risk score, which can be determined by suitable biomarkers and genetic predispositions.

[0385] In some embodiments, the disease is progressive multiple sclerosis.

[0386] In some embodiments, the disease is primary progressive multiple sclerosis.

[0387] In some embodiments, the disease is non-active secondary progressive multiple sclerosis (non-active SPMS).

[0388] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS).

[0389] In some embodiments, the disease is relapsing-remitting multiple sclerosis.

[0390] In some embodiments, the disease is multiple sclerosis, wherein the disability is obtained by relapse-associated worsening (RAW).

[0391] In some embodiments, the disease is multiple sclerosis, wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0392] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), wherein the disability is obtained by relapse-associated worsening (RAW).

[0393] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0394] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), wherein the disability is obtained by relapse-associated worsening (RAW).

[0395] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0396] In some embodiments, the disease is primary progressive multiple sclerosis (PPMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0397] In some embodiments, the disease is non-active secondary progressive multiple sclerosis (non-active SPMS), wherein the disability is obtained by progression independent of relapse activity (PIRA).

[0398] In some embodiments, the disease is clinically isolated syndrome (CIS).

[0399] In some embodiments, the disease is conversion MS.

[0400] In some embodiments, the condition is PIRA.

[0401] In some embodiments, the disease is amyotrophic lateral sclerosis.

[0402] In some embodiments, the disease is schizophrenia.

[0403] In some embodiments, the disease is a drug addiction.

[0404] In some embodiments, the disease caused by lower levels of Nurr1 is a cancer.

[0405] In one aspect, a method of treating a disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I) to (V) or a compound according to Formula (VI) described herein.

[0406] In some embodiments, the change in the target gene (e.g., VMAT2), target protein (e.g., Nurr1), or peptide (e.g., NFL) relative to the initial value at the start of treatment is assessed after a treatment period of about 6 weeks, about 12 weeks, about 24 weeks, about 1 month, about 3 months, about 6 months, about 12 months.

[0407] In some embodiments, the change in the target gene (e.g., VMAT2), target protein (e.g., Nurr1), or peptide (e.g., NFL) relative to a healthy person of the same age, gender, and / or BMI is assessed at the start of treatment.

[0408] In one aspect, a method of modulating Nurr1 levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the Nurr1 levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the Nurr1 levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0409] In one aspect, a method of reducing plasma NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the plasma NFL levels in the subject are reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more compared to the levels at the start of treatment. In embodiments, the plasma NFL levels in the subject are reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more compared to the levels at the start of treatment.

[0410] In one aspect, a method of reducing serum NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the serum NFL levels in the subject are reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more compared to the levels at the start of treatment. In embodiments, the serum NFL levels in the subject are reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more compared to the levels at the start of treatment.

[0411] In one aspect, a method of reducing CSF NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the CSF NFL levels in the subject are reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more compared to the levels at the start of treatment. In embodiments, the CSF NFL levels in the subject are reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more compared to the levels at the start of treatment.

[0412] In one aspect, a method of reducing plasma high NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the plasma NFL levels in the subject are reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI. In embodiments, the plasma NFL levels in the subject are reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI.

[0413] In one aspect, a method of reducing serum high NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the serum NFL levels in the subject are reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI. In embodiments, the serum NFL levels in the subject are reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI.

[0414] In one aspect, a method of reducing high NFL levels in CSF is provided. In one aspect, a method of reducing plasma NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the plasma NFL levels in the subject are reduced by about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50% or more compared to the levels at the start of treatment. In some embodiments, the plasma NFL levels in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more compared to the levels at the start of treatment.

[0415] In one aspect, a method of reducing serum NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the serum NFL levels in the subject are reduced by about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50% or more compared to the levels at the start of treatment. In some embodiments, the serum NFL levels in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more compared to the levels at the start of treatment.

[0416] In one aspect, a method of reducing CSF NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the CSF NFL levels in the subject are reduced by about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50% or more compared to the levels at the start of treatment. In some embodiments, the CSF NFL levels in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more compared to the levels at the start of treatment.

[0417] In one aspect, a method of reducing plasma high NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the plasma NFL levels in the subject are reduced by about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50% or more relative to the levels in a healthy person of the same age, biological sex, and / or BMI. In some embodiments, the plasma NFL levels in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI.

[0418] In one aspect, a method of reducing serum high NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the serum NFL levels in the subject are reduced by about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50% or more relative to the levels in a healthy person of the same age, biological sex, and / or BMI. In some embodiments, the serum NFL levels in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI.

[0419] In one aspect, a method of reducing CSF high NFL levels in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the CSF NFL levels in the subject are reduced by about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 20%, about 30%, about 40%, about 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI. In some embodiments, the CSF NFL levels in the subject are reduced by at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to the levels in a healthy person of the same age, sex, and / or BMI.

[0420] In one aspect, a method of increasing Pitx3 levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the Pitx3 levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the Pitx3 levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0421] In one aspect, a method of increasing VMAT2 levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the VMAT2 levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the VMAT2 levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0422] In one aspect, a method of increasing AADC levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the AADC levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the AADC levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0423] In one aspect, a method of increasing DAT levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the DAT levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the DAT levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0424] In one aspect, a method of increasing BDNF levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the BDNF levels or activity in the subject are increased by about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, about 30 fold, about 35 fold, about 40 fold, about 45 fold, about 50 fold, about 60 fold, about 70 fold, about 80 fold, about 90 fold, about 100 fold or more. In some embodiments, the BDNF levels or activity in the subject are increased by at least 1.2 fold, at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, at least 10 fold, at least at least 15 fold, at least 20 fold, at least 25 fold, at least 30 fold, at least 35 fold, at least 40 fold, at least 45 fold, at least 50 fold, at least 60 fold, at least 70 fold, at least 80 fold, at least 90 fold, at least 100 fold or more.

[0425] In one aspect, a method of increasing GDNF levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the GDNF levels or activity in the subject are increased by about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, about 30 fold, about 35 fold, about 40 fold, about 45 fold, about 50 fold, about 60 fold, about 70 fold, about 80 fold, about 90 fold, about 100 fold or more. In some embodiments, the GDNF levels or activity in the subject are increased by at least 1.2 fold, at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, at least 10 fold, at least at least 15 fold, at least 20 fold, at least 25 fold, at least 30 fold, at least 35 fold, at least 40 fold, at least 45 fold, at least 50 fold, at least 60 fold, at least 70 fold, at least 80 fold, at least 90 fold, at least 100 fold or more.

[0426] In one aspect, a method of increasing GDNF receptor C-RET levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the GDNF receptor C-RET levels or activity in the subject are increased by about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, about 30 fold, about 35 fold, about 40 fold, about 45 fold, about 50 fold, about 60 fold, about 70 fold, about 80 fold, about 90 fold, about 100 fold or more. In some embodiments, the GDNF receptor C-RET levels or activity in the subject are increased by at least 1.2 fold, at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, at least 10 fold, at least at least 15 fold, at least 20 fold, at least 25 fold, at least 30 fold, at least 35 fold, at least 40 fold, at least 45 fold, at least 50 fold, at least 60 fold, at least 70 fold, at least 80 fold, at least 90 fold, at least 100 fold or more.

[0427] In one aspect, a method of increasing GFAP levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the GFAP levels or activity in the subject are increased by about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 2 fold, about 3 fold, about 4 fold, about 5 fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, about 10 fold, about 15 fold, about 20 fold, about 25 fold, about 30 fold, about 35 fold, about 40 fold, about 45 fold, about 50 fold, about 60 fold, about 70 fold, about 80 fold, about 90 fold, about 100 fold or more. In some embodiments, the GFAP levels or activity in the subject are increased by at least 1.2 fold, at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, at least 10 fold, at least at least 15 fold, at least 20 fold, at least 25 fold, at least 30 fold, at least 35 fold, at least 40 fold, at least 45 fold, at least 50 fold, at least 60 fold, at least 70 fold, at least 80 fold, at least 90 fold, at least 100 fold or more.

[0428] In one aspect, a method of increasing tyrosine hydroxylase (TH) levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the TH levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the TH levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0429] In one aspect, a method of increasing SOD levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the SOD levels or activity in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the SOD levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0430] In one aspect, a method of reducing the level or activity of TNFa in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of TNFa in the subject is reduced by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the level or activity of TNFa in the subject is reduced by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0431] In one aspect, a method of reducing the level or activity of iNOS in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of iNOS in the subject is reduced by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the level or activity of iNOS in the subject is reduced by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0432] In one aspect, a method of reducing IL-1β levels or activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the IL-1β levels or activity in the subject are reduced by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the IL-1β levels or activity in the subject are reduced by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0433] In some embodiments, the method comprises increasing dopamine levels in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the dopamine levels in the subject are increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the dopamine levels or activity in the subject are increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0434] In some embodiments, the method comprises using the compound to increase the development of dopaminergic neurons compared to a control (e.g., in the absence of the compound described herein). In some embodiments, the level of development of the dopaminergic neurons is increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the level of development of dopaminergic neurons in the subject is increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0435] In some embodiments, the method comprises using the compound to increase the maintenance of dopaminergic neurons compared to a control (e.g., in the absence of the compound described herein). In some embodiments, the level of maintenance of the dopaminergic neurons is increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the level of maintenance of dopaminergic neurons in the subject is increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0436] In some embodiments, the method comprises increasing survival of dopaminergic neurons using the compound compared to a control (e.g., in the absence of the compound described herein). In some embodiments, the level of survival of the dopaminergic neurons is increased by about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold or more. In some embodiments, the level of survival of dopaminergic neurons in the subject is increased by at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold or more.

[0437] In embodiments, the method comprises stabilizing Nurr1 monomers using a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the method comprises stabilizing Nurr1 homodimers using a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the method comprises stabilizing head-to-head Nurr1 homodimers using a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the method comprises stabilizing Nurr1 heterodimers using a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0438] In embodiments, the method comprises contacting Nurr1 monomers with a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the method comprises contacting Nurr1 homodimers with a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the method comprises contacting head-to-head Nurr1 homodimers with a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the method comprises contacting Nurr1 heterodimers with a compound according to Formulae (I)-(V) or a compound according to Formula (VI) described herein. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0439] In embodiments, the method comprises binding a Nurr1 monomer to a compound according to formula (I)-(V) or a compound according to formula (VI) described herein. In embodiments, the method comprises binding a Nurr1 homodimer to a compound according to formula (I)-(V) or a compound according to formula (VI) described herein. In embodiments, the method comprises binding a head-to-tail Nurr1 homodimer to a compound according to formula (I)-(V) or a compound according to formula (VI) described herein. In embodiments, the method comprises binding a Nurr1 heterodimer to a compound according to formula (I)-(V) or a compound according to formula (VI) described herein. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0440] In embodiments, the method comprises using a compound according to formula (I)-(V) or a compound according to formula (VI) described herein to exclude the formation of a Nurr1:RXR heterodimer.

[0441] In embodiments, the method comprises binding Nurr1 and inducing binding of Nurr1 to a NBRE, NuRE, or DR-5 response element. In embodiments, the method comprises binding Nurr1 and inducing binding of Nurr1 to a NBRE. In embodiments, the method comprises binding Nurr1 and inducing binding of Nurr1 to a NuRE. In embodiments, the method comprises binding Nurr1 and inducing binding of Nurr1 to a DR-5 response element.

[0442] In embodiments, a compound according to formula (I)-(V) or a compound according to formula (VI) stabilizes a Nurr1 monomer. In embodiments, a compound according to formula (I)-(V) or a compound according to formula (VI) stabilizes a Nurr1 homodimer. In embodiments, a compound according to formula (I)-(V) or a compound according to formula (VI) stabilizes a head-to-tail Nurr1 homodimer. In embodiments, a compound according to formula (I)-(V) or a compound according to formula (VI) stabilizes a Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0443] In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) stabilizes Nurr1 monomer relative to a control (e.g., in the absence of the compound). In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) stabilizes Nurr1 homodimer relative to a control (e.g., in the absence of the compound). In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) stabilizes head-to-tail Nurr1 homodimer relative to a control (e.g., in the absence of the compound). In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) stabilizes Nurr1 heterodimer relative to a control (e.g., in the absence of the compound). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0444] In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) contacts Nurr1 monomer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) contacts Nurr1 homodimer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) contacts head-to-tail Nurr1 homodimer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) contacts Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0445] In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) binds Nurr1 monomer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) binds Nurr1 homodimer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) binds head-to-tail Nurr1 homodimer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) binds Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0446] In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) excludes formation of Nurr1 :RXR heterodimer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) inhibits formation of Nurr1 :RXR heterodimer. In embodiments, a compound according to Formulae (I) to (V) or a compound according to Formula (VI) bound to Nurr1 inhibits binding of the resulting compound:Nurr1 complex to RXR.

[0447] In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) acts as an agonist of Nurr1 monomer. In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) acts as an agonist of Nurr1 homodimer. In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) acts as an agonist of head-to-tail Nurr1 homodimer. In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) acts as an agonist of Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRa.

[0448] In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) binds to Nurr1 and induces binding of Nurr1 to NBRE, NuRE, or DR-5 response element. In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) binds to Nurr1 and induces binding of Nurr1 to NBRE. In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) binds to Nurr1 and induces binding of Nurr1 to NuRE. In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) binds to Nurr1 and induces binding of Nurr1 to DR-5 response element.

[0449] In embodiments, lower levels of Nurr1 result in impaired function or activity of Nurr1. In embodiments, lower levels of Nurr1 can be restored by administration of the compound according to Formulae (I) to (V) or the compound according to Formula (VI). In embodiments, the compound according to Formulae (I) to (V) or the compound according to Formula (VI) acts as a Nurr1 agonist.

[0450] V. Pharmaceutical Compositions

[0451] In some embodiments, there is provided a pharmaceutical composition comprising a compound according to Formulae (I) to (V) or the compound according to Formula (VI) described herein and a pharmaceutically acceptable excipient.

[0452] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound according to Formulae (I) to (V) or the compound according to Formula (VI).

[0453] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent, wherein the second agent is an agent for treating a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the second agent is a Parkinson’s disease drug, such as levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromocriptine, pergolide, pramipexole, ropinirole, trihexephendyl, benztropine, biperiden, procyclidine, tolcapone, or entacapone. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0454] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent, wherein the second agent is an agent for treating an inflammatory disease, such as acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent.

[0455] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent, wherein the second agent is an anticancer agent.

[0456] VI. Treatment Dose and Duration

[0457] In some embodiments, the present application provides a method of treating a subject, such as a human patient in need thereof, comprising administering, in particular orally administering, to the subject a compound herein, in particular a compound according to formulae (I) to (V) or a compound according to formula (VI) and / or a pharmaceutically acceptable salt thereof and / or a solvate, in particular a hydrate, thereof and / or a solvate, in particular a hydrate, of a pharmaceutically acceptable salt thereof, at a daily dose of about 12 to 120 pmol, such as about 12.3 pmol to about 38.2 pmol, about 76.5 pmol, or about 115 pmol, for example the daily dose can be about 12.3 pmol to about 38.2 pmol, about 25.5 pmol, or about 26.5 pmol.

[0458] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient vedourafenib and / or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof and / or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, in a daily dose of about 12 to 120 pmol of vedourafenib or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, thereby treating the human patient, preferably the daily dose is about 12.3 pmol to about 38.2 pmol, about 76.5 pmol or about 115 pmol, more preferably the daily dose is about 12.3 pmol to about 38.2 pmol, most preferably the daily dose is about 26.5 pmol.

[0459] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient vedourafenib and / or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof and / or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, in a daily dose of about 115 pmol of vedourafenib or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, thereby treating the human patient.

[0460] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient vedourafenib and / or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof and / or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, in a daily dose of about 76.5 pmol of vedourafenib or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, thereby treating the human patient.

[0461] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient vedourafenib and / or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof and / or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, in a daily dose of about 12 to 38 pmol of vedourafenib or a pharmaceutically acceptable salt and / or solvate (in particular hydrate) thereof or a solvate (in particular hydrate) of a pharmaceutically acceptable salt thereof, thereby treating the human patient.

[0462] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient vedouriclamide and / or a pharmaceutically acceptable salt and / or solvate (particular hydrate) thereof and / or a solvate (particular hydrate) of a pharmaceutically acceptable salt thereof, at a daily dose of about 25.5 pmol of vedouriclamide or a pharmaceutically acceptable salt and / or solvate (particular hydrate) thereof or a solvate (particular hydrate) of a pharmaceutically acceptable salt thereof, thereby treating the human patient.

[0463] In the following table, the number of pmol of the active moiety of vedouriclamide is converted to the number of mg of vedouriclamide free acid (i.e. the active moiety) and vedouriclamide calcium salt dihydrate:

[0464]

[0465] The daily dose in the following embodiments is based on the active moiety, i.e. vedouriclamide free acid.

[0466] In some embodiments, the present application provides a method of treating a subject, e.g. a human patient in need thereof, comprising orally administering to the subject vedouriclamide calcium salt dihydrate having the following structure as "Polymorph A" at a dose of about 5 mg to about 45 mg:

[0467] ,

[0468] For example, the dose is about 5 mg to about 15 mg, about 30 mg or about 45 mg, about 5 mg to about 15 mg, about 45 mg or about 10 mg. In some embodiments, the administration is performed daily.

[0469] In some embodiments, the present application provides a method of treating a subject, e.g. a human patient in need thereof, comprising orally administering to the human patient vedouriclamide calcium salt dihydrate having the following structure as "Polymorph A" at a daily dose of about 10 mg:

[0470] .

[0471] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient vedouriclamide calcium salt dihydrate having the following structure as "Polymorph A" in the form of a tablet or capsule at a daily dose of about 45 mg:

[0472] .

[0473] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient, in the form of a tablet or capsule, vedoflaxin calcium salt dihydrate as "Polymorph A" having the structure below at a daily dose of about 30 mg:

[0474] .

[0475] In some embodiments, the administration is performed every day.

[0476] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient, in the form of a tablet or capsule, vedoflaxin calcium salt dihydrate as "Polymorph A" having the structure below at a daily dose of about 15 mg during the first week of treatment:

[0477] .

[0478] In some embodiments, the present application provides a method of treating a human patient in need thereof, comprising orally administering to the human patient, in the form of a tablet or capsule, vedoflaxin calcium salt dihydrate as "Polymorph A" having the structure below at a daily dose of about 22.5 mg during the first week of treatment:

[0479] .

[0480] VIII. DEFINITIONS

[0481] Throughout this specification, substituents of compounds of the disclosure are disclosed in groups or ranges. Specifically, the present disclosure includes each and every subcombination of the members of these groups and ranges. The following is a non-limiting list of definitions of terms.

[0482] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs.

[0483] The term "level or activity" refers to the expression level of the respective target's mRNA or protein or an activity resulting from the expression level of the mRNA or protein regulated by the respective target. For certain target genes and proteins, the activity can also be measured using PET scans or SPECT. In the case of dopamine or its metabolites, "activity" means increase or decrease of the respective molecule.

[0484] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, disease treatment or biomarker / target gene outcome as set forth below. The therapeutically effective amount can vary depending on the intended application or the subject and disease condition being treated, e.g., body weight (as assessed by body mass index (BMI)), age, and / or sex, severity of disease condition, mode of administration, etc., response to biomarker or Nurr1 target gene, etc., which can be readily determined by one of ordinary skill in the art. The specific dose will vary depending on, e.g., the particular compound chosen, the dosing regimen being followed, whether it is administered in combination with other agents, the time of administration, the duration of treatment, the tissue to which it is administered, and the physical delivery system carrying it.

[0485] The term "subject" as used herein refers to any member of the animal kingdom, including humans. In some embodiments, "subject" refers to a human at any stage of development. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, a cow, a primate, or a pig). In some embodiments, a subject includes, but is not limited to, a mammal, a bird, a reptile, an amphibian, a fish, or a worm. In some embodiments, a subject can be a transgenic animal, a genetically engineered animal, or a clone.

[0486] In some embodiments, a subject can be any member of the animal kingdom. For example, a subject can be a human, a non-human primate such as a chimpanzee and other apes and monkey species; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and experimental animals including rats, mice, and guinea pigs. A subject can be a subject of any age. For example, a subject can be an elderly, an adult, an adolescent, a pre-adolescent child, a child, a toddler, and an infant. In some embodiments, a subject is a patient.

[0487] The subject can have a certain age, for example, about 1 to about 5 years old, about 5 to about 10 years old, about 10 to about 15 years old, about 15 to about 20 years old, about 20 to about 25 years old, about 25 to about 30 years old, about 30 to about 35 years old, about 35 to about 40 years old, about 40 to about 45 years old, about 45 to about 50 years old, about 50 to about 55 years old, about 55 to about 60 years old, about 60 to about 65 years old, about 65 to about 70 years old, about 70 to about 75 years old, about 75 to about 80 years old, about 80 to about 85 years old, about 85 to about 90 years old, about 90 to about 95 years old, about 95 to about 100 years old, about 1 to 8 years old, about 1 to 10 years old, about 1 to 12 years old, about 1 to 14 years old, about 1 to 16 years old, about 1 to 18 years old, about 1 to 20 years old, about 20 to 40 years old, about 20 to 60 years old, about 20 to 80 years old, about 20 to 100 years old, about 40 to 80 years old, or about 60 to 80 years old.

[0488] In some embodiments, the subject is at least about 1 year old, at least about 5 years old, at least about 10 years old, at least about 12 years old, at least about 14 years old, at least about 16 years old, at least about 18 years old, at least about 20 years old, at least about 25 years old, at least about 30 years old, at least about 40 years old, at least about 50 years old, at least about 60 years old, at least about 70 years old, or at least about 80 years old. In some embodiments, the subject is no more than about 1 year old, no more than about 5 years old, no more than about 10 years old, no more than about 12 years old, no more than about 14 years old, no more than about 16 years old, no more than about 18 years old, no more than about 20 years old, no more than about 25 years old, no more than about 30 years old, no more than about 40 years old, no more than about 50 years old, no more than about 60 years old, no more than about 70 years old, or no more than about 80 years old.

[0489] In some embodiments, the subject in need of the above methods of treating MS belongs to the group of patients with pediatric-onset MS (POMS), meaning onset before the age of 18.

[0490] In some embodiments, the subject in need of the above methods of treating MS belongs to the group of patients with late-onset MS (LOMS), meaning onset within the time period of 19-50 years of age.

[0491] In some embodiments, the subject in need of the above methods of treating MS belongs to the group of patients with adult-onset MS (AOMS), meaning onset at >50 years of age.

[0492] The subject can have a certain body mass index (BMI), for example, about 15 kg / m 2 to about 18 kg / m 2 , about 15 kg / m 2 to about 18.5 kg / m 2 , about 18.5 kg / m 2 to about 24.9 kg / m2 about 25 kg / m 2 about 26 kg / m 2 about 27 kg / m 2 about 28 kg / m 2 about 29 kg / m 2 about 30 kg / m 2 about 31 kg / m 2 about 32 kg / m 2 about 33 kg / m 2 about 34 kg / m 2 about 35 kg / m

[0493] The terms "agonist," "activator," "upregulator," and the like refer to an agent that is capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the agonist. In certain cases, expression or activity is 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more than the expression or activity in the absence of the agonist.

[0494] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the target of the molecule (e.g., the target can be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) physical state relative to the absence of the composition.

[0495] The term "expression" includes any step involved in the production of a polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using routine techniques for detecting proteins (e.g., ELISA, Western blot, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0496] The term "modulate" is used according to its ordinary meaning and refers to the act of changing or altering one or more properties. "Modulate" refers to the process of changing or altering one or more properties. For example, when applied to the effect of a modulator on a target protein, modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. For example, when applied to the effect of a modulator on a target gene, modulate means to change by increasing or decreasing the expression of the gene or the activity of the gene.

[0497] The term "abnormal" as used herein means different from normal. When used to describe enzyme activity, abnormal means an activity greater than or less than the mean of normal controls or normal, non-diseased control samples. In one embodiment, the abnormal level differs from the level of a healthy subject by at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, more preferably at least 50%. Specifically, the level of upregulation is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, more preferably at least 50% higher than the level of a healthy subject. Specifically, the level of downregulation is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, more preferably at least 50% lower than the level of a healthy subject. When used to describe target gene levels, abnormal means gene expression greater than or less than the mean of normal controls or normal, non-diseased control samples. Abnormal activity can mean an amount of activity that results in a disease, wherein restoring the abnormal activity to a normal or non-disease related amount (e.g. by using the methods described herein) results in a reduction of the disease or one or more symptoms of the disease.

[0498] "Day" preferably means a period of about 24 hours. It can be about 22-26 hours. Most preferably, day is a period of 24 hours.

[0499] "Month" preferably means a period of about 28 days, about 29 days, about 30 days, or about 31 days. It can be about 26-33 days. Most preferably, month is a period of 30 days.

[0500] The term "evening" as used herein means the period of time from late afternoon to early night, preferably 16:00 to 23:00 local time.

[0501] The term "morning" as used herein means the period of time from dawn to about midday, preferably 5:00 to 12:00 local time.

[0502] The term "about" as used herein with respect to numerical values, numbers, ranges and / or amounts preferably means "approximately" and / or "circa". The meaning of these terms is well known in the art and preferably includes a variance, deviation and / or variability of plus or minus 15%, in particular plus or minus 10% of the respective numerical value, number, range and / or amount.

[0503] "Treatment" as used herein preferably includes a sequential succession of "induction treatment" and "maintenance treatment". For example, a treatment according to the present application comprises an induction treatment of about one week, wherein a semi-daily dose is administered, followed by a maintenance treatment, wherein a full daily dose is administered (see e.g. WO 2019 / 101888).

[0504] "Daily dose" preferably refers to the total dose of a compound according to formulae (I) to (V) or a compound according to formula (VI) (preferably vedocizumab) or a pharmaceutically acceptable salt or solvate thereof, which is orally administered to a patient per administration day. The daily dose can be achieved by one or more administrations per day, e.g. once a day, twice a day or three times a day. Preferably, it is achieved or realized by a single administration per day, which preferably consists of one or more tablets or capsules, preferably a tablet or capsule as described herein.

[0505] "Relapse" preferably relates to a problem in the nervous system that occurs over a short period of time, usually a few days, but sometimes as short as a few hours or even minutes. These attacks most often involve motor, sensory, visual or coordination problems early in the disease. Later, bladder, bowel, sexual and cognitive problems can show up. Sometimes, attacks last for weeks. A typical MS relapse includes a period of worsening, with the onset of neurologic deficits, followed by a plateau, in which the patient does not get any better but also does not get any worse, followed by a recovery period. Recovery usually begins within a few weeks.

[0506] "Annualized relapse rate" is the average number of relapses per year in a group of patients in a clinical study. See "Multiple Sclerosis Coalition. The Use Of Disease - Modifying Therapies In Multiple Sclerosis: Principles and Current Evidence Summary". Available at http: / / www.nationalmssociety.org / getmedia / 1e64b96c-9e55-400e-9a64-0cdf5e2d60fe / summaryDMTpaper_-final.

[0507] “Hazard ratio” is a measure of the change over time in the frequency of a particular event in one group compared to the frequency of occurrence in another group. A hazard ratio of exactly 1.0 means that the study drug provides no reduction in risk compared to the control treatment.

[0508] The “Expanded Disability Status Scale” (EDSS) is a clinician-reported outcome measure used to quantify the level of disability in subjects with MS over time. The EDSS is based on a standard neurological examination that includes functional systems (vision, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and brain [or mental]) that are rated and scored as Functional System Scores (FSS), and walking, which is scored as a walk score. Each FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6, and the walk score ranges from 0 to 12. These ratings can then be used in conjunction with observations and information about walking and use of assistive devices to determine a total EDSS score. The EDSS is a measure of disability ranging from 0 points (normal) to 10.0 points (death) in half-point increments (Kurtzke, Neurology 1983;33:1444). In some embodiments of the methods provided herein, erectile dysfunction and fatigue are not included in the EDSS score. Generally, a decrease in EDSS score corresponds to improvement in disease, and conversely, an increase in EDSS score corresponds to worsening of disease.

[0509] The “9-Hole Peg Test” (9-HPT) is a quantitative measure of upper extremity (arm and hand) function (Arch. Phys. Med. Rehabil. 1988;69:850). The test apparatus consists of a container with nine pegs and a block containing nine holes. The subject picks up each of the nine pegs one at a time and places them in the nine holes as quickly as possible. Once all the pegs are in the holes, the subject removes them one at a time as quickly as possible and replaces them in the container. The total time to complete the task is recorded. Both the dominant and non-dominant hands are tested twice (two successful completion of the dominant hand test followed immediately by two successful completion of the non-dominant hand test). The two trials for each hand are averaged, converted to the reciprocal of the average time for each hand, and then the two reciprocals are averaged. The 9-HPT can be performed as described, e.g., in the Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring Manual (National Multiple Sclerosis Society, 2001). For example, a meaningful change in upper extremity function can be indicated by a 20% worsening in the average 9-HPT time compared to baseline.

[0510] The“Timed 25-Foot Walk Test” (T25FWT) is a quantitative measure of ambulatory ability and leg function based on timed 25-foot walking. Subjects are instructed to start at one end of a clearly marked 25-foot course and are instructed to walk the 25 feet as quickly and safely as possible, and the time taken for the subject to complete the walk from start to finish of the 25 feet is timed. In some embodiments, the task is performed immediately again by having the subject walk the same distance back, and the times for both trials are averaged to yield a score for the T25FWT. Subjects can use assistive devices (e.g., a cane or wheelchair) when performing the task. The T25FWT can be performed, for example, as described in the MSFC Administration and Scoring Manual. For example, a clinically meaningful change in ambulatory ability and leg function can be indicated by a 20% worsening in the average T25FWT time compared to baseline.

[0511] The“Symbol Digit Modalities Test” (SDMT) is a test used to assess the presence of cognitive impairment and / or changes in cognitive function over time and in response to treatment. The SDMT can be particularly sensitive to the slowing of information processing that is common in MS (Mult. Scler. 2017; 23:721). The SDMT includes a substitution task. Using reference keys, subjects have 90 seconds to pair specific numbers with given geometric figures. Responses can be collected verbally, and the number of correct responses is considered the SDMT score. For example, a clinically meaningful change in cognitive processing can be indicated by a 4-point decrease in the SDMT score compared to baseline.

[0512] The“Columbia-Suicide Severity Rating Scale” (C-SSRS) is a tool used to assess a subject’s lifetime suicidal ideation and can be used to track suicidal events throughout treatment or a portion thereof. A structured interview prompts recollection of suicidal ideation, including intensity of ideation, behaviors, and attempts with actual / potential lethality. A“baseline” C-SSRS can include, for example, a C-SSRS collected prior to the initiation of administration of a compound of Formula (I)-(V) or a compound according to Formula (VI), or an isotopically- varied, pharmaceutically acceptable salt, or solvate thereof, particularly veduroxstat. Such a score can be compared to a subsequent C-SSRS collected, for example, after the initiation of administration of a compound of Formula (I)-(V) or a compound according to Formula (VI), or an isotopically- varied, pharmaceutically acceptable salt, or solvate thereof, particularly veduroxstat. In some embodiments, a comparison between different assessment periods, which can occur, for example, during a clinician visit, can be described as a C-SSRS“since last visit.”

[0513] “EQ-5D-5L” is a validated self-reported health status questionnaire that can be used to calculate health utility scores for use in health economic analyses (Qual. Life Res. 2011;20: 1727; Qual. Life Res. 2013;22: 1717). The EQ-5D-5L has two components: a five-item health profile that assesses mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, and a visual analog scale (VAS) that measures health status. The EQ-5D-5L is designed to capture the subject’s current health status. Published weighting systems can allow for the creation of a single composite score of a subject’s health status. The “Multiple Sclerosis Impact Scale-29 Version 2” (MSIS-29, Version 2) is a 29-item subject-reported measure of the psychosocial impact of MS (Brain 2001; 124: 962). Subjects are asked to rate how much their functioning and health have been affected on a 4-point scale from “not at all” (1) to “extremely” (4) over the past 14 days. The physical score is the sum of items 1-20, which is then converted to a 0-100 scale. The psychological score is the sum of items 21-29, converted to a 0-100 scale. Higher scores can indicate greater impact of MS. Clinically meaningful impact is indicated by a change of at least 7.5 points on the physical scale in the MSIS-29 Version 1. In the MSIS-29 Version 2, this degree of change can also indicate a meaningful impact.

[0514] The “12-item Multiple Sclerosis Walking Scale” (MSWS-12) is a 12-item self-reported measure to gauge the impact of MS on an individual’s walking ability over the past 2 weeks. Each item is scored on a 5-point Likert scale, and the total score is converted to a 0-100 scale, with higher scores indicating greater impact of MS on walking ability.

[0515] “Quality of Life in Neurological Disorders in Upper Limbs” (Fine Motor Skills and Activities of Daily Living; Upper Limb Neuro-QoL) is a 20-item questionnaire to assess upper limb function involving subjects with MS at each stage of their development (Qual. Life Res. 2012;21: 475). Items include assessments of dressing, cooking, eating, cleaning, and writing, for which subjects rate their performance on a 5-point Likert scale from “no difficulty at all” (5) to “unable to complete” (1). Item scores are added, multiplied by 20, and divided by 20 minus the number of any unanswered items. Scores range from 20-100, with higher scores indicating better upper limb function. According to the NINDS User Manual (2015), a score can be calculated as long as at least 50% of the items are answered.

[0516] “PROMIS FatigueMS” is an 8-item scale developed for use as a measure of fatigue in subjects with MS (Qual. Life Res. 2012;21:1021), with a recall period of the previous 7 days. It contains 5-point Likert scales, yielding a score between 1 and 5 for each scored question. The total raw score is the sum of the values for each scored question. The range of total raw scores is 8-40 points. Scores can also be converted to PROMIS T-scores, with a mean of 50 and a standard deviation of 10. The range of T-scores is 34.7-81.3 points. Higher scores indicate more severe fatigue.

[0517] “Patient Global Impression of Change” (PGI-C) is a single-item assessment of the subject’s impression of change in their MS symptoms compared to a time point 6 months ago. The subject responds on a 7-point Likert scale, from “very much better” (1) to “very much worse” (7). The PGI-C is used as an anchor to determine clinically meaningful change in MSIS-29.

[0518] “Patient Global Impression of Severity” (PGI-S) is a single-item assessment of the subject’s impression of the severity of their MS symptoms over the past 7 days. The subject responds on a 5-point Likert scale, from “none” (1) to “very severe” (5). The PGI-S is used as an anchor to determine clinically meaningful change in MSIS-29.

[0519] “Work Productivity and Activity Impairment: Multiple Sclerosis” (WPAI:MS) is a 6-item scale. Subjects estimate the amount of time their work and daily activities were affected by their MS over the past 7 days (Pharmacoeconomics 1993;4:353). The WPAI:MS assessment evaluates absenteeism and “presenteeism,” which refers to the time subjects were present at work or activities but believed their health negatively affected their ability to perform at normal levels. Higher scores indicate more severe productivity impairment.

[0520] “Confirmed disability progression” (CDP) refers to an increase in a subject’s EDSS score that is sustained over a specified period of time. This can be assessed, for example, by calculating a subject’s EDSS score, determining that the score has increased compared to a previous score (e.g., a baseline score, which can be a score obtained prior to the subject’s initiation of administration of a compound of Formula (I)-(V) or a compound according to Formula (VI) or an isotopolog, pharmaceutically acceptable salt, or solvate thereof, particularly vedolizumab), and then confirming that the score is still increasing after a specified period of time from the initial increase (e.g., by reevaluating the subject and recalculating again). For example, 12-week confirmed disability progression (CDP12) refers to an EDSS score that is still increasing at least 12 weeks after the initial increase (e.g., confirmed by recalculating the EDSS score at least 12 weeks after the initial increase). 24-week confirmed disability progression (CDP24) refers to an EDSS score that is still increasing at least 24 weeks after the initial increase (e.g., confirmed by recalculating the EDSS score at least 24 weeks after the initial increase). The initial increase can be compared to a baseline EDSS score (e.g., prior to initiation of administration of a compound of Formula (I)-(V) or a compound according to Formula (VI) or an isotopolog, pharmaceutically acceptable salt, or solvate thereof, particularly vedolizumab), or can be compared to a previous EDSS score that has remained stable over time (e.g., within 12, 24, 36, 48, or 60 weeks). In some embodiments, CDP refers to an increase of >1.0 point from baseline EDSS score in subjects with a baseline EDSS score of <5.5 points, or an increase of >0.5 point from baseline EDSS score in subjects with a baseline EDSS score of >5.5 points. Pre-CDP time (e.g., pre-CDP12 or pre-CDP24 time) refers to the period of time from establishment of a previous EDSS score (e.g., from a baseline EDSS score prior to initiation of administration of vedolizumab or an isotopolog, pharmaceutically acceptable salt, or solvate thereof) to the time at which a sustained increase in EDSS score is observed.

[0521] “Comprehensive confirmed disability progression” (cCDP) is a comprehensive measure of disability progression using a combination of EDSS, 9-HPT, and T25FWT. It assesses the progression of disability in a subject over a specified time period, which is determined by the first occurrence of a progression event. A progression event can include any of the following: CDP (e.g., an increase of >1.0 points from baseline EDSS score in subjects with baseline EDSS score of <5.5 points, or an increase of >0.5 points from baseline EDSS score in subjects with baseline EDSS score of >5.5 points); completion of the 9-hole peg test (9-HPT) in >20% more time than baseline; or timed 25-foot walk test (T25FWT) in >20% more time than baseline; wherein the occurrence of a progression event is confirmed after a specified time period from the initial occurrence. For example, comprehensive 12-week sustained disability progression (cCDP12) refers to the occurrence of at least one progression event at an initial time point, and the same progression event is confirmed at least 12 weeks later (e.g., by reevaluating the subject using the same test). Comprehensive 24-week confirmed disability progression (cCDP12) refers to the occurrence of at least one progression event at an initial time period, and the same progression event is confirmed at least 24 weeks later. cCDP pre-onset time (e.g., cCDP12 or cCDP24 pre-onset time) refers to the time period from the establishment of a prior assessment score (e.g., a baseline score prior to the start of administration of vedolizumab or an isotope variant, pharmaceutically acceptable salt, or solvate thereof) to the observation of an initial progression event. Without wishing to be bound by theory, cCDP12 requires at least one of the following: 1) an increase of >1.0 points from a baseline (BL) score of <5.5 points, or an increase of >0.5 points from a BL score of >5.5 points (confirmed disability progression); 2) completion of the 9-hole peg test in 20% more time than BL; 3) timed 25-foot walk test in 20% more time than BL, compared to EDSS-based endpoints that emphasize lower extremity function. Thus, cCDP 12 is a more sensitive assessment of disability, particularly in early stages of the disease. Using cCDP12 as the primary outcome can provide a clearer, more complete picture of disability progression or improvement compared to EDSS alone.

[0522] “Confirmed disease worsening” (CDW) measures the increase in a patient’s EDSS score is sustained over a predetermined time period, which means that the patient’s level of physical disability has increased, as described in Drugs 2015; 75: 947.

[0523] In some embodiments, the confirmed disease progression is measured by Kurtzke Expanded Disability Status Scale (EDSS) score in a subject in need thereof having MS.

[0524] In some embodiments, the confirmed disease progression is an increase in EDSS score of at least 1 point.

[0525] In some embodiments, the MS patient has a confirmed disease progression of an increase in EDSS score of at least 0.5 points.

[0526] In some embodiments, the hazard ratio of no confirmed disability worsening is reduced by 20-60%.

[0527] In some embodiments, the hazard ratio of no confirmed disability worsening is reduced by 30-50%.

[0528] In some embodiments, the hazard ratio of no confirmed disability worsening is reduced by at least 30%.

[0529] In some embodiments, the hazard ratio of no confirmed disability worsening is reduced by at least 40%.

[0530] In some embodiments, the hazard ratio of no confirmed disability worsening is reduced by at least 50%.

[0531] The term "brain atrophy" describes one of the most devastating consequences of MS. Brain atrophy can be seen at the earliest stages of MS and can lead to irreversible neurological and cognitive impairment. Progressive loss of brain tissue volume can be detected in vivo in a sensitive and reproducible manner by MRI. See, e.g., Lancet Neurol. 2006; 5: 158.

[0532] The "efficacy" of the treatment according to the application can preferably be measured based on changes in the disease progression in response to the use according to the application. For example, MS treatment efficacy can be measured by the frequency of relapses in RRMS and whether new lesions in the CNS are present as detected using methods such as MRI techniques (Neurology 1996; 47 (Suppl 4): S217; Ann. Neurology 1997; 41 : 125).

[0533] Preferably, observation of a reduction and / or suppression of MRI T1 gadolinium-enhancing lesions (areas believed to represent active inflammation) gives the primary efficacy variable. Active lesions show up as bright white on MRI scans after administration of intravenous imaging contrast (gadolinium). Secondary efficacy variables preferably include MRI T1 enhancing brain lesion volume, MRI T1 enhancing lesion number, MRI T2 lesion volume (believed to represent total disease burden, i.e. demyelination, gliosis, inflammation, and axonal loss), MRI T1 enhancing low intensity lesion volume (believed to represent mainly demyelination and axonal loss), time to progression of MS, frequency and severity of exacerbations, and time to exacerbation, Expanded Disability Status Scale score, and Scripps Neurological Rating Scale (SNRS) score (Neurology 1984; 34: 1368). Methods for early accurate diagnosis of multiple sclerosis and tracking disease progression are described in Mattson, Expert Rev. Neurother. 2002; 2: 319.

[0534] White matter lesions on brain MRI in MS can lead to misdiagnosis, particularly when trying to subdivide patients into subgroups. A subset of MS lesions show paramagnetic rims on susceptibility-weighted MRI sequences, reflecting iron accumulation in microglial cells. These paramagnetic rim lesions have been proposed as a marker of compartmentalized smoldering disease (AJR 2022; 219: 120). Paramagnetic rim lesion detection occurs rarely in other neurological conditions (52% of MS cases versus 7% of non-MS cases) and has high specificity (93%) in differentiating MS from non-MS (Ann Neurol. 2020; 88: 1034). Paramagnetic rim lesions can be an emerging marker of chronic neuroinflammation in MS and can help to assign MS patients to subgroups, e.g. PPMS.

[0535] The term "effective amount" as used herein includes a dosage sufficient to produce a desired result on the indicated disorder, condition, or mental state. The desired result can include subjective or objective improvement of the dosage recipient.

[0536] The term "administering" as used herein includes activities associated with providing an amount of a compound according to Formula (I) to (V) or a compound according to Formula (VI) (preferably vedourabine) or a pharmaceutically acceptable salt or solvate thereof to a patient. Administering includes providing a unit dose of a composition set forth herein to a patient in need thereof. Administering includes providing an effective amount of a compound, e.g., vedourabine and / or a pharmaceutically acceptable salt and / or solvate (particularly hydrate) thereof and / or a solvate (particularly hydrate) of a pharmaceutically acceptable salt thereof, over a specified period of time, e.g., about 6, 9, 12, 15 months or more or about 1, 2, 3, 4, 5 years or more.

[0537] "Disease" or "disorder" refers to a state of being or health condition of a patient or subject that can be treated with a compound or method provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is a cancer.

[0538] In some embodiments, the level of Nurr1, the level of activity of a Nurr1 downstream gene, or the level of a Nurr1 downstream protein (e.g., NCAM, CFB, LTA, A2M, HSD11B1, BHLHE41, MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNF alpha, iNOS, or IL-1 beta) is measured in a subject and then compared to a similar value obtained from a healthy control subject of the same biological sex, similar or identical body mass index (BMI), or similar or identical age as the subject. For example, the healthy control subject can be within ±1 year, ±2 years, ±3 years, ±4 years, ±5 years, ±10 years, ±15 years, ±20 years, or ±30 years of the subject's age. In some embodiments, the healthy control subject has a BMI within ±1 kg / m2, ±2 kg / m2, ±3 kg / m2, ±4 kg / m2, ±5 kg / m2, ±10 kg / m2, ±15 kg / m2, or ±20 kg / m2of the subject's BMI. 2 2 2 2 2 2 2 2 ​​​​​​​Within. When measuring the level of a protein (e.g., Nurr1) or gene, age, BMI, and biological sex can be assessed independently in the subject or healthy control subject.

[0539] In some embodiments, the level of Nurr1 in a sample, the level of activity of a Nurr1 downstream gene, or the level of a Nurr1 downstream protein (e.g., NCAM, CFB, LTA, A2M, HSD11B1, BHLHE41, MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNF alpha, iNOS, or IL-1 beta) is measured in a subject more than once, and then compared to the level of Nurr1, the level of activity of a Nurr1 downstream gene, or the level of a Nurr1 downstream protein in another sample from the subject to monitor a decrease or reduction in the level over time.

[0540] In some embodiments, the level of Nurr1 in a sample, the level of activity of a Nurr1 downstream gene, or the level of a Nurr1 downstream protein (e.g., GDNF, GFAP, or VMAT2) is measured in a subject more than once, and then compared to the level of Nurr1, the level of activity of a Nurr1 downstream gene, or the level of a Nurr1 downstream protein in another sample from the subject to monitor a decrease or reduction in the level over time.

[0541] Non-limiting examples of psychiatric disorders include anxiety, depression, bipolar disorder, dementia, schizophrenia, and other psychoses.

[0542] Non-limiting examples of central nervous system disorders or diseases include nervous system diseases or disorders that affect the structure or function of the brain or spinal cord, which together form the central nervous system (CNS), such as addiction, encephalitis, Parkinson’s disease, and multiple sclerosis.

[0543] Non-limiting examples of neurodegenerative diseases or disorders include diseases or disorders in which the function of the nervous system of a subject becomes impaired, such as, for example, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia (FTD), Kennedy's disease, Krabbe disease, kuru, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive nuclear palsy (PSP), Refsum disease, Sandhoff disease, Shy-Drager syndrome, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, and tabes dorsalis.

[0544] Multiple sclerosis (MS) can be divided into relapsing MS (RMS) and progressive MS (PMS). Relapsing-remitting MS (RRMS) and active secondary progressive MS (active SPMS) are mainly driven by focal inflammatory disease, characterized by the presence of magnetic resonance imaging (MRI) lesions and relapses. However, from a recent meta-analysis on a large patient database it is known that disability worsening in these two subtypes is driven by relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). RRMS is characterized by relapses and MRI lesions dominating the clinical course. Active SPMS (aSPMS) is characterized by relapses and less lesions and continuous disability progression (see Figure 8 ).

[0545] Primary progressive MS (PPMS) and non-active secondary progressive MS (non-active SPMS or n-aSPMS) are two major progressive forms of MS, characterized by continuous disability worsening, with or without any MRI lesions or relapses present. From a recent meta-analysis on a large patient database it is known that disability worsening in these two subtypes is almost completely driven by PIRA. Non-active SPMS is characterized by continuous disability progression, while relapses have ceased. PPMS is characterized by disability worsening from the start (see Figure 8 ).

[0546] Definitions and subcategories of PPMS and SPMS can vary. In one exemplary definition, all SPMS can be considered to belong to the PMS category, and thus all SPMS patients are considered PMS patients, with no distinction between aSPMS and n-aSPMS. In another exemplary definition, active SPMS can be considered to belong to the RMS category, while non-active SPMS can be considered to belong to the PMS category. Thus, the terms “n-aSPMS” and “SPMS” are used synonymously in the present invention.

[0547] PIRA, compared to RAW, can be separated as follows (JAMA Neurol. 2023;80:151): A PIRA event can be defined as experiencing a confirmed disability worsening (CDW) on the EDSS scale at 6 months in the period free of relapses (PFR). PFR is the time between two consecutive relapses, starting 3 months after a relapse (or 6 months after the first demyelination event). The first EDSS score obtained at least 6 months after the first attack or 3 months after any other attack is called the baseline EDSS score and the re-baseline EDSS score, respectively. The re-baseline EDSS score is set not to be lower than the first recorded (baseline) EDSS score. A confirmed disability accumulation (CDA) is defined as an increase in the EDSS score of 1.5, 1.0, or 0.5 if the baseline / re-baseline EDSS score is 0, 1.0 to 5.0, or greater than 5.0, respectively. The date of PIRA is the date of confirmation of CDA. Any other CDA episode that does not meet the PIRA criteria (i.e., occurring outside the PFR) is considered a RAW event. Those patients with at least 1 CDA but without any PIRA event are considered RAW patients.

[0548] In the clinical study by Kopp et al. (Mult. Scler. Relat. Disord. 2021;56:103319), the following inclusion criteria applied to a population of MS with a clinical SPMS diagnosis assigned by a MS neurologist and to RRMS patients meeting the MSBase definition for diagnosis of transition to SPMS. This m-EXPAND criterion identified patients with recent EDSS score worsening that can not be explained with a recent relapse:

[0549] (a) EDSS of 3.0 to 6.5, inclusive (at the landmark date + / - 6 months); and

[0550] (b) EDSS progression in the last 2 years prior to data extraction, defined as EDSS progression of 1 point or more in patients with EDSS score below 6.0, or EDSS progression of >0.5 points in patients with EDSS score > 6.0, without relapse in the 6 months prior to progression, and with EDSS > 3.0 at the time of progression; and

[0551] (c) disability progression.

[0552] Currently, there are no FDA-approved treatment options for SPMS other than mitoxantrone. However, the treatment with mitoxantrone does not distinguish between relapsing activity (active SPMS vs. non-active SPMS). Notably, mitoxantrone treatment is associated with significant toxicities, including cardiac toxicity and secondary malignancies, which limit the length of treatment to ~3 years (lifetime dose of 140 mg / m 2 ). Furthermore, the patient population in this trial primarily had relapsing SPMS, and the benefit in non-active SPMS is not known. Siponimod, natalizumab, and interferon beta-1b are approved for active SPMS but have not shown benefit in non-active SPMS. For PPMS patients, ocrelizumab has been approved, but it carries a black box warning for progressive multifocal leukoencephalopathy and immune-mediated colitis due to a strong dampening of the immune response. Other treatment options currently being tested in clinical trials, such as fingolimod with the risk of liver injury, also do not offer the good safety profile of vidofludimus. Thus, given the lack of effective therapies for the entire PIRA, there is an urgent unmet need.

[0553] MS usually begins with a clinically isolated syndrome (CIS). This is the first onset of symptoms caused by inflammation and damage to the myelin sheath that covers nerves in the brain or spinal cord. In CIS, the individual has an attack suggestive of demyelination, but does not meet the criteria for MS. Between 30% and 70% of individuals who experience CIS will later develop MS.

[0554] There is also another subset of MS patients, MS patients that shift between relapsing MS and PIRA. For this disease, the term “shifting MS” is used in this document. Shifting MS patients can be identified by one or more of the following test methods:

[0555] (a) Symbol Digital Modalities Test (SDMT),

[0556] (b) Multiple Sclerosis Functional Composite Score (MSFC),

[0557] (c) EDSS,

[0558] (d) Timed 25-Foot Walk (T25FW),

[0559] (e) 9-Hole Peg Test (9HPT),

[0560] (f) MS Pro Discuss TM clinical tool,

[0561] (g) integration of several tests such as EDSS, Timed 25-Foot Walk (T25FW), SDMT and 9-Hole Peg Test (9HPT), MS ProDiscuss TM Composite score of clinical tools.

[0562] The term "neuroprotection" as used herein refers to the relative preservation of neuronal structure and / or function, i.e. a therapeutic strategy to slow down or stop otherwise irreversible loss of neurons over time. In the case of a persistent injury (neurodegenerative injury), relative preservation of neuronal integrity means that the rate of neuronal loss decreases over time. It is a widely explored therapeutic option for many CNS disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury and intake of neurotoxins (i.e. methamphetamine overdose). Neuroprotection aims to stop or at least slow down (lessen) neuronal loss to prevent or slow down disease progression and secondary injuries. Although there are differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include reduced delivery of oxygen and glucose to the brain, energy failure, elevated levels of oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation and protein aggregation.

[0563] The term "inflammatory disease" or "inflammatory disorder" as used herein refers to an inflammatory disease or disorder, e.g. can be a disease or disorder characterized by abnormal inflammation (e.g. elevated levels of inflammation compared to a control, such as a healthy person not suffering from the disease). Non-limiting examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, type 1 diabetes, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0564] Non-limiting examples of cancers include neoplasm, malignant tumor, leukemia, lymphoma, carcinoma, sarcoma, thyroid cancer, cancer of the endocrine system, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, ovarian cancer, sarcoma, stomach or uterine cancer, melanoma, mesothelioma, medulloblastoma, colorectal cancer, pancreatic cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary carcinoma of the thyroid, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary carcinoma of the thyroid, hepatocellular cancer, and prostate cancer.

[0565] Non-limiting examples of leukemia include a progressive malignant disease of the hematopoietic organs characterized by distorted proliferation and development of leukocytes and precursor cells in the blood and bone marrow, such as acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythoblastic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid cell leukemia, lymphosarcellar cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblast leukemia, monocyte leukemia, myeloblast leukemia, myelocytic leukemia, myelogenous leukemia, myelomonocytic leukemia, myelomonocytic leukemia, myelosis, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0566] Non-limiting examples of lymphomas include cancers affecting hematopoietic and lymphoid tissues, non-Hodgkin's lymphoma (NHL), Hodgkin's disease, high grade NHL, low grade NHL, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0567] Non-limiting examples of sarcomas include tumors made of embryonic connective tissue and the like, and are generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, interstitial sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B-cells, lymphosarcoma, immunoblastic sarcoma of T-cells, Jenson's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

[0568] Non-limiting examples of melanomas include tumors arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0569] Non-limiting examples of cancer include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar cystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus cancer, cribriform carcinoma, armored carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, sclerosing carcinoma, embryonal carcinoma, cerebral carcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, trichomeal stromal carcinoma, hematologic carcinoma, hepatocellular carcinoma, Schulte's cell carcinoma, hyaline chondrocyte carcinoma, adrenaloid carcinoma, infantile embryonal carcinoma, carcinoma in situ. Intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma Cancer, preinvasive carcinoma, acanthosis nigra, soft carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider carcinoma, sclerosing carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spherical cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, linear carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0570] In some embodiments, this disclosure provides a composition comprising a molecular population, wherein each molecule of said population is independently a compound of formula (I), (II), (III), (IV), (V), or (VI), wherein a proportion of each molecule in said population independently contains deuterium atoms. The deuterium incorporation level can be any value, such as natural abundance or a level greater than or less than natural abundance. The protium level in the sample can be any value, such as natural abundance or a level greater than or less than natural abundance. The tritium level can be any value, such as natural abundance or a level greater than or less than natural abundance.

[0571] It should be recognized that variations in the abundance of natural isotopes occur in synthesized compounds, depending on the source of the chemical materials used in the synthesis. Therefore, formulations of compounds according to formulas (I) through (V) or according to formula (VI) will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Comp. Biochem. Physiol. 1998;119A:725.

[0572] When a chemical name or structure does not specify whether a particular position in a compound that is normally occupied by hydrogen is isotopically enriched, it means that the particular position is occupied by hydrogen at natural abundance. For example, the term "phenyl" or In the absence of further specification of isotopic enrichment, it is indicated that all hydrogen atoms are present at natural abundance.

[0573] In some embodiments, a certain proportion of each molecule in the population is substituted with a deuterium atom at the same position. The proportion of molecules in the population that contain a deuterium atom at a particular atomic position can be represented by an isotopic enrichment factor wherein wherein is the abundance of deuterium at that position within the population of molecules, is the natural abundance of deuterium at the position. The proportion of molecules in the population that contain a deuterium atom at a particular atomic position can alternatively be represented by the mole percent of the population that is substituted with deuterium at that atomic position (i.e., % deuterium incorporation).

[0574] Non-limiting examples of isotopic enrichment factors include at least 835 (12.5% deuterium incorporation), at least 1670 (25% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0575] Non-limiting examples of deuterium abundance in a sample of a compound of the present application include natural abundance, and an abundance that is at least 3340 times the natural deuterium abundance (i.e., at least 50.1% deuterium incorporation), at least 3500 times the natural deuterium abundance (52.5% deuterium incorporation), at least 4500 times the natural deuterium abundance (67.5% deuterium incorporation), at least 5000 times the natural deuterium abundance (75% deuterium incorporation), at least 5500 times the natural deuterium abundance (82.5% deuterium incorporation), at least 6000 times the natural deuterium abundance (90% deuterium incorporation), at least 6333.3 times the natural deuterium abundance (95% deuterium incorporation), at least 6466.7 times the natural deuterium abundance (97% deuterium incorporation), at least 6600 times the natural deuterium abundance (99% deuterium incorporation), at least 6633.3 times the natural deuterium abundance (99.5% deuterium incorporation), or any other abundance.

[0576] When a particular position in a compound of the present application (e.g. a compound represented by formulae (I) to (V) or a compound according to formula (VI) or a pharmaceutically acceptable salt and / or solvate thereof) is specifically designated by name or structure as "H" or "hydrogen", the position is understood to have hydrogen taking the natural abundance isotopic composition.

[0577] The percentage of deuterium incorporation can be obtained by quantitative analysis (peak area) using e.g. mass spectrometry or by comparison of the signal from an internal standard or other non-deuterated 1 H signals to the remaining residual 1 H-NMR signals.

[0578] The term "compound" when referring to any compound of the present disclosure (including a compound represented by formulae (I) to (V) or a compound according to formula (VI) or a pharmaceutically acceptable salt and / or solvate thereof) refers to a collection of molecules having the same chemical structure except for possible isotopic variations between constituent hydrogen atoms of the molecule. The relative amounts of isotopic variations in a compound of the present application will depend on a variety of factors including the isotopic purity of the deuterated reagents used to prepare the compound and the efficiency of incorporation of deuterium in the various synthetic steps used to prepare the compound.

[0579] "D" and "d" both refer to deuterium. "H" refers to hydrogen.

[0580] "Substituted by deuterium" means that one or more hydrogen atoms are replaced by a corresponding number of deuterium atoms.

[0581] Within the scope of the present application, "isotopic variant" refers to a deuterated variant of a compound of formulae (I) to (V) or a compound according to formula (VI) (preferably vedoradiamid), or a pharmaceutically acceptable salt or solvate thereof.

[0582] Any formula or structure given herein is also intended to represent deuterated compounds additionally comprising other isotopically labeled atoms. Examples of other isotopes that can be incorporated into a compound of the present disclosure include isotopes of hydrogen, i.e., tritium or 3 H), and isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, and without limitation 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The present disclosure also includes isotopically-labelled compounds, for example those into which radioactive isotopes such as 3 H, 13 C and14 Various isotopically-labelled compounds of C. Such isotopically- labelled compounds are useful in metabolic studies, receptor binding assays, detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0583] Halogen can be, for example, fluorine, chlorine, bromine and iodine, in some embodiments fluorine or chlorine, in some embodiments fluorine.

[0584] If not otherwise mentioned, alkyl is preferably straight-chain or branched-chain alkyl having 1 to 10 carbon atoms (C1-C10-alkyl), preferably 1 to 8 carbon atoms (C1-C8-alkyl), more preferably 1 to 6 carbon atoms (C1-C6-alkyl), in particular 1 to 4 carbon atoms (C1-C4-alkyl). 1-10 -alkyl), preferably 1 to 8 carbon atoms (C 1-8 -alkyl), more preferably 1 to 6 carbon atoms (C 1-6 -alkyl), in particular 1 to 4 carbon atoms (C 1-4 -alkyl). Non-limiting examples of straight-chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Branched-chain alkyl groups include any straight-chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched-chain alkyl groups include isopropyl, isobutyl, sec-butyl and tert-butyl. Preferred alkyl groups are selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl or hexyl. More preferably, alkyl is selected from methyl, ethyl, isopropyl or tert-butyl. Unless otherwise mentioned, the term "alkyl" also means to include those alkyl derivatives which are defined in more detail below as "unsaturated alkyl". Unsaturated alkyl is alkyl having one or more double bonds (i.e. "alkenyl") or triple bonds (i.e. "alkynyl"), preferably vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers.

[0585] The alkyl groups in the compounds of formulae (I) to (IV) can optionally be substituted with one or more substituents R' (in some embodiments with fluorine).

[0586] Non-limiting examples of alkyl and alkylene groups include straight-chain, branched-chain and cyclic alkyl and alkylene groups. The alkyl or alkylene group can be, for example, substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19, C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 group. Non-limiting examples of alkyl groups can be C 1-4 -alkyl.

[0587] The term "alkylene", "alkenylene", "alkynylene", "arylene", "heteroarylene" or "cycloalkylene" means that the respective group is divalent and links the attached residues to the rest of the molecule. Furthermore, in the context of the present application, C1-alkylene means a methylene linker, C2-alkylene means an ethylene linker or a methyl substituted methylene linker and the like. In the context of the present application, alkylene preferably denotes methylene, ethylene or propylene. Similarly, the term "arylene" is a divalent aryl group, which can be substituted as defined for aryl groups.

[0588] Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl. Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cyclic alkyl groups (i.e., "cycloalkyl groups") include saturated or partially unsaturated mono-, bi-, fused-, bridged-, and spiro-bicyclic rings, as well as higher fused-, bridged-, and spiro-systems, preferably comprising 3 to 10 carbon atoms in the ring system, more preferably 3 to 8 carbon atoms, even more preferably 3 to 6 carbon atoms, wherein each atom (i.e., skeletal atom) forming the ring system is a carbon atom. Cyclic alkyl groups can be substituted with any number of linear, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-1-yl, cycloprop-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopent-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctyl, 2,5-dimethylcyclopent-1-yl, 3,5-dichlorocyclohex-1-yl, 4-hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1-yl, octahydroindenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, 1,3-dimethyl[2.2.1]hept-2-yl, bicyclo[2.2.2]octyl, and bicyclo[3.3.3]undecyl. Cycloalkyl groups can optionally be substituted with one or more substituents R', wherein R' is as defined below.

[0589] R' is independently H, D, -CO2R", -CONHR", -CR"O, -SO2N(R")2, -NR"-CO-haloalkyl, -NR"-CO-alkyl, -NO2, -N3, -NR"-SO2-haloalkyl, -NR"-SO2-alkyl, -SO2-alkyl, -CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, -OH, oxo, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halo, haloalkyl, haloalkoxy, aryl, arylalkyl, or heteroaryl.

[0590] R" is independently H, D, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, or aminoalkyl.

[0591] Non-limiting examples of deuterated alkyl groups include mono-, di-, tri-, up to per-deuterated alkyl groups.

[0592] Non-limiting examples of alkenyl and alkenyl groups include straight-chain, branched, and cyclic alkenyl groups. One or more alkenes of the alkenyl group can be, for example, E, Z, cis, trans, terminal, or external methylene. The alkenyl or alkenyl group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9 ... 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 20 C 21 C 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 C 32 C 33 C 34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 C 42 C 43 C 44 C 45 C 46 C 47 C 48 C 49 Or C 50 Non-limiting examples of groups, alkenyl groups, and alkenyl groups include vinyl, propen-1-en-1-yl, isopropenyl, buten-4-yl, 2-chlorovinyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7-methyloct-3,5-dien-2-yl.

[0593] Non-limiting examples of ynyl or ynylene groups include straight-chain, branched, and cyclic ynyl groups. The triple bond in the ynyl or ynylene group can be internal or terminal. The ynyl or ynylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C8, C9, C16, C18, C19 ... 10 C 11 C 12 C 13 C14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 . Non-limiting examples of alkynyl or alkynylene groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, and 2-methyl-hex-4-yn-1-yl, 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5-ethylhept-3-yn-1-yl.

[0594] Haloalkyl can be any alkyl group substituted with any number of halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms. Non-limiting examples of haloalkyl groups can be C 1-4 Haloalkyl. Haloalkenyl can be any alkenyl group substituted with any number of halogen atoms. Haloalkynyl can be any alkynyl group substituted with any number of halogen atoms. In one embodiment, haloalkyl is CF3.

[0595] Alkoxy can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. Non-limiting examples of alkoxy groups can be C 1-4 Alkoxy. Ether or ether group includes alkoxy. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. Non-limiting examples of deuterated alkyl groups include mono-deuterated, di-deuterated, tri-deuterated, up to per-deuterated alkyl groups.

[0596] Alkylthio means a S-alkyl group, the alkyl group being as defined above.

[0597] Hydroxyalkyl means a HO-alkyl group, the alkyl group being as defined above.

[0598] Haloalkoxy means an alkoxy group, the alkoxy group being as defined above, substituted by 1 to 5, preferably 3, halogen atoms; OCF3is preferred.

[0599] Hydroxyalkylamino means a (HO-alkyl)2-N- group or a HO-alkyl-NH- group, the alkyl group being as defined above.

[0600] Alkylamino means a -HN-alkyl or a -N-dialkyl group, the alkyl group being as defined above.

[0601] Aminoalkyl means a H2N-alkyl-, monoalkylaminoalkyl or dialkylaminoalkyl group, the alkyl group being as defined above.

[0602] Aryl groups can be heterocyclic or non-heterocyclic. Aryl groups can be monocyclic or polycyclic. Aryl groups can be substituted with any number of substituents described herein (e.g., hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms). The aryl group can be optionally substituted with one or more substituents R', where R' is as defined above. Preferred R' residues are fluoro, OCH3, and OCD3. Non-limiting examples of aryl groups include phenyl, tolyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thienyl, and furanyl. Non-limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl.Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N- diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,N- dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4- aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, 4-(N- ethylamino)phenyl, and 4-(N,N-diethylamino)phenyl.

[0603] Arylalkyl refers to an alkyl group substituted with 1 to 3 (preferably 1) aryl groups, the alkyl and aryl groups being as defined above.

[0604] Heterocyclyl can be any ring containing non-carbon ring atoms (e.g., N, O, S, P, Si, B, or any other heteroatom). Heterocyclyl can be substituted with any number of substituents (e.g., alkyl and halogen atoms). Heterocycles can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran. In one embodiment, heterocyclyl contains 1, 2, 3, or 4 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O, or S. Sulfur atoms in heterocycles can be oxidized to S=O or SO2. Carbon atoms in heterocycles can be oxidized to C=O.

[0605] Non-limiting examples of heterocyclyl groups include: heterocyclic ring units having a monocyclic ring containing one or more heteroatoms, non-limiting examples of which include diaziridinyl, aziridinyl, azetidinyl, oxetanyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, thiazolidinonyl, oxazolinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, thiazolidinonyl, The heterocyclic unit comprises: oxaliplatinyl, hydantoinyl, tetrahydrofuranyl, pyrrolylyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-oneyl, 2,3,4,5-tetrahydro-1H-azheptatrienyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline; and ii) a heterocyclic unit having two or more rings (one of which is a heterocycle), non-limiting examples of which include hexahydro-1H-pyrrolopyrrolylyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indoleyl, 1,2,3,4-tetrahydroquinoline, and decahydro-1H-cyclooctyl[b]pyrroleyl. The heterocyclic group may optionally be substituted with one or more substituents R', wherein R' is defined below. Heterocyclic groups can be attached to the rest of the molecule via carbon, nitrogen (e.g., in morpholine or piperidine), or sulfur atoms. An example of an S-linked heterocyclic alkyl group is a cyclic sulfonylimide amide.

[0606] .

[0607] A heteroaryl group may include an aromatic group containing at least one heteroatom. In one embodiment, the heteroaryl group comprises 1, 2, 3, or 4 heteroatoms, wherein the heteroatoms are independently selected from N, O, or S. Non-limiting examples of heteroaryl groups include: i) heteroaryl rings containing a monocyclic ring, including non-limiting examples of 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazine, thiazolyl, 1H-imidazolyl, etc. azole group, iso Azolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing two or more fused rings (one of which is a heteroaryl ring), non-limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyridolo[2,3-d]pyrimidinyl; 4,5,6,7-tetrahydro-1H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxyquinolinyl, and isoquinolinyl.

[0608] When applied to an alkyl group containing 1 to 4 carbon atoms, non-limiting examples of groups having one or more hydrogen atoms optionally replaced by deuterium include the following residues: -CD3, -CH2D, -CHD2, CD3CH2(CH2). n - CD3CH2(CHD) n - CD3CH2(CD2) n -、CH2DCH2(CH2) n -, CH2DCH2(CHD)n -, CH2DCH2(CD2) n -, CHD2CH2(CH2) n -, CHD2CH2(CHD) n -, CHD2CH2(CD2) n -, CD3CHD(CH2) n -, CD3CHD(CHD) n -, CD3CHD(CD2) n -, CH2DCHD(CH2) n -, CH2DCHD(CHD) n -, CH2DCHD(CD2) n -, CHD2CHD(CH2) n -, CHD2CHD(CHD) n -, CHD2CHD(CD2) n -, CH3CHD(CH2) n -, CH3CHD(CHD) n -, CH3CHD(CD2) n -, CD3CD2(CH2) n -, CD3CD2(CHD) n -, CD3CD2(CD2) n -, CH2DCD2(CH2) n -, CH2DCD2(CHD) n -, CH2DCD2(CD2) n -, CHD2CD2(CH2) n -, CHD2CD2(CHD) n -, CHD2CD2(CD2) n -, CH3CD2(CH2) n -, CH3CD2(CHD) n -, CH3CD2(CD2) n - (wherein n is an integer from 0 to 2), CH3CH2(CHD) m -, CH3CH2(CD2) m - (wherein m is an integer from 1 to 2), and -CD(CD3)2, -CH(CD3)2and -C(CD3)3.

[0609] Furthermore, the compounds of the present application are in part affected by tautomerism. For example, if a heteroaryl group containing a nitrogen atom in the ring is substituted with a hydroxyl group on the carbon atom adjacent to said nitrogen atom, the following tautomerism can occur:

[0610] .

[0611] In some embodiments, the compounds described herein exist as tautomers. In cases where tautomerism is possible, a chemical equilibrium of tautomers can exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Non-limiting examples of tautomeric equilibria include:

[0612] .

[0613] When ring A is a partially saturated ring, the double bond in ring A is located at the depicted position: In the case where ring A is a 5-membered heteroaromatic ring, then the double bond is within the delocalized pi-system, and can exist in mesomeric forms. One example is the following mesomeric form of thiophene: .

[0614] Cycloalkyl or heterocyclyl can be attached directly or spirocyclically, for example, when cyclohexane is substituted with the heterocyclyl oxetane, the following structures are possible:

[0615] and .

[0616] The present disclosure provides for the use of a pharmaceutically acceptable salt of any of the therapeutic compounds described herein. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt can be an organic acid or an inorganic acid. The base added to the compound to form the base addition salt can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

[0617] Metal salts can be produced by adding an inorganic base to a compound of the present disclosure. The inorganic base consists of a metal cation and a basic counterion, such as hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0618] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0619] Ammonium salts can be produced by adding ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, benzhydrylamine, piperazine, pyridine, pyrazole, pyrazole, imidazole, pyrazine, or piperazine.

[0620] In some embodiments, the ammonium salt is a triethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a morpholine salt, a piperidine salt, a N-methylmorpholine salt, a piperidine salt, a N-methylpiperidine salt, a benzhydrylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyrazole salt, an imidazole salt, a pyrazine salt, or a piperazine salt.

[0621] Acid addition salts can be produced by adding an acid to a compound of the present disclosure. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid. In some embodiments, the salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a nitrite, a sulfate, a sulfite, a phosphate, an isonicotinate, a lactate, a salicylate, a tartrate, an ascorbate, a gentisinate, a gluconate, a glucuronate, a saccharate, a formate, a benzoate, a glutamate, a pantothenate, an acetate, a propionate, a butyrate, a fumarate, a succinate, a methanesulfonate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, a citrate, an oxalate, or a maleate.

[0622] In some embodiments, a compound of the present disclosure exists in the form of a solvate, for example, including water (hydrate) or a pharmaceutically acceptable solvent such as an alcohol for example, ethanol as a solvent. Stoichiometric, sub-stoichiometric, super-stoichiometric, or non-stoichiometric amounts of solvent are bound by non-covalent intermolecular forces. When the solvent is water, the "solvate" is a "hydrate." It is understood that a "pharmaceutically acceptable salt" can also optionally contain a "solvate."

[0623] The term "polymorph" as used herein refers to a crystalline form of a compound or salt, hydrate, or solvate thereof, that takes a specific crystal packing arrangement. All polymorphs have the same elemental composition. The term "crystalline" as used herein refers to a solid form consisting of an orderly arrangement of its constituent units. Different crystalline forms of the same compound or salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid state, which results in different crystal symmetries and / or unit cell parameters. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.

[0624] The term "effective amount" is intended to include an amount of a compound that, when administered, is sufficient to prevent or to some extent alleviate one or more symptoms of the disorder, disease, or condition being treated. The term "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0625] "IMU-838" (also known as "Calcium Vidorazolidum" is a calcium salt of Vidorazolidum, in some embodiments including pharmaceutically acceptable solvates, hydrates, crystals, and polymorphs.

[0626] An illustrative structure of IMU-838 is a dihydrate of 2-(((3-fluoro-3'- methoxy(l,l'-biphenyl)-4-yl)amino)carbonyl)-l-cyclopenten-l-carboxylic acid calcium salt (2: 1), which structure is as follows:

[0627] .

[0628] Polymorph Form A of IMU-838 is a crystalline material having the structure described above. In some embodiments, Polymorph Form A of IMU-838 is characterized by an X-ray powder diffraction pattern having characteristic peaks at 5.91°, 9.64°, 16.78°, 17.81°, 19.81°, and 25.41° 2Θ (±0.2°). In some embodiments, Polymorph Form A of IMU-838 is characterized by an X-ray diffraction pattern as shown in FIG. 1. Figure 7

[0629] Enumerated Embodiments

[0630] In the above context, the following consecutively numbered embodiments provide further specific aspects of the application:

[0631] Embodiment 1 : A compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof,

[0632] (I),

[0633] ​wherein:

[0634] - Ring A is a 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted by 1 to 4 residues R 1 ;

[0635] - Z 1 and Z 2 are each independently O, S or NR 9 ;

[0636] - E is alkylene, alkenylene, alkynylene, arylene, heteroarylene or cycloalkylene;

[0637] - G is O, S, SO2, NR 10 or CH2;

[0638] - Y is aryl, heteroaryl, heterocyclyl or cycloalkyl;

[0639] - R 1 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclyl;

[0640] - R 2 is H, OR 11 , NR 11 OR 11 , NR 11 SO2R 11 or NR 11 R 12 ;

[0641] - R 3 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclyl;

[0642] - each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclyl;

[0643] - n is 0 or 1 ;

[0644] - q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0645] - r is 0 or 1,

[0646] having one or more hydrogen atoms optionally replaced by deuterium, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection in a subject having a neurodegenerative disease.

[0647] Embodiment 2: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 1, wherein the subject exhibits an abnormal level of a biomarker associated with a neurodegenerative disorder prior to the administration.

[0648] Embodiment 3: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 1 or 2, wherein the compound is a compound of Formula (II):

[0649] (II),

[0650] wherein:

[0651] - X is O, S, NR 9 , SO, or SO2;

[0652] - Z 2 is O, S, or NR 12 ;

[0653] - E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene;

[0654] - G is O, S, SO2, NR 10 , or CH2;

[0655] - Y is aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0656] - R 1 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl;

[0657] - each R 8 , R 9 , R 10 , R 11 , R 12 , R 13and R 14 independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;

[0658] - m is 0, 1, 2, 3, or 4;

[0659] - n is 0 or 1; and

[0660] - q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0661] Embodiment 4: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 3, wherein the compound is a compound of Formula (III):

[0662] (III),

[0663] wherein:

[0664] - E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene;

[0665] - Y is aryl, heteroaryl, heterocyclyl, or cycloalkyl;

[0666] - R 1 is H, halogen, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl; and

[0667] - each R 8 , R 13 , and R 14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl.

[0668] Embodiment 5: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 4, wherein the compound is a compound of Formula (IV):

[0669] (IV),

[0670] wherein:

[0671] - each R A and R B is independently H, D, halogen, -OR 13 , -SR 13, -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl;

[0672] - each R 8 , R 13 , and R 14 is independently H, D, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl;

[0673] - x is 0, 1, 2, 3, or 4; and

[0674] - y is 0, 1, 2, 3, 4, or 5.

[0675] Embodiment 6: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 5, wherein the compound is a compound of Formula (V):

[0676] (V),

[0677] wherein:

[0678] - Ring A is , , , , , , or ;

[0679] - E is , , , , or ; and

[0680] - Y is , , , , , , or .

[0681] Embodiment 7: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 6, wherein the compound is

[0682] , , 、 、 、 、 、 or .

[0683] Embodiment 7a: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 1, wherein the compound is a compound of Formula (VI):

[0684] (VI),

[0685] wherein:

[0686] - R 2 is NR 11 R 12 ;

[0687] - R 11 is selected from H, OH, optionally substituted alkyl, optionally substituted cycloalkyl, one or more hydrogen atoms of said alkyl or cycloalkyl being optionally replaced by deuterium;

[0688] - R 12 is selected from H or optionally substituted alkyl, one or more hydrogen atoms of said alkyl being optionally replaced by deuterium;

[0689] - Ring A is 、 、 、 、 、 、 or ;

[0690] - E is 、 、 、 or ; and

[0691] - Y is 、 、 、 、 、 、 or .

[0692] Embodiment 7b: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 1 or 7a, wherein the compound is a compound of Formula (VI):

[0693] (VI),

[0694] wherein:

[0695] - R 2 is NHR 11 ;

[0696] - R 11 is selected from H or alkyl, one or more hydrogen atoms of said alkyl being optionally replaced by deuterium;

[0697] - Ring A is , , or ;

[0698] - E is , , , or ; and

[0699] - Y is , , , or .

[0700] Embodiment 7c: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 1, 7a or 7b, wherein the compound is

[0701] , , , , , , , , , , , , , or .

[0702] Embodiment 8: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 7c, wherein the compound is

[0703] .

[0704] Embodiment 9: The compound of Formula (I) or a solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 8, wherein the compound is

[0705] .

[0706] Embodiment 10: The compound of Formula (I) or a solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 9, wherein the compound is

[0707] Embodiment 11 : The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 10, wherein the neurodegenerative disorder is selected from the group consisting of an inflammatory disorder, non-inflammatory disease exacerbation, neuronal loss, a psychiatric disorder, a neurological disorder, a central nervous system disorder, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, PIRA, amyotrophic lateral sclerosis, schizophrenia, brain atrophy, and drug addiction, and wherein the neuroprotection is slowing or halting the loss of dopaminergic neurons.

[0708] Embodiment 12: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 11, wherein the therapeutically effective amount is about 5 mg to about 100 mg.

[0709] Embodiment 13: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 12, wherein the administration is oral.

[0710] Embodiment 14: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 13, wherein the administration is oral by a solid dosage form.

[0711] Embodiment 15: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 14, wherein the administration is over a first period and a second period, wherein:

[0712] a) the first period comprises at least five consecutive days of once-daily dosing of the compound in a first period amount, wherein the first period amount of the compound is about 5 mg to about 50 mg;

[0713] b) the second period follows the first period; and

[0714] c) the second period comprises once-daily dosing of the compound in a second period amount, wherein the second period amount is greater than the first period amount.

[0715] Embodiment 16: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 15, wherein:

[0716] a) the first period is five to ten consecutive days of once-daily dosing of the compound in a first period amount, wherein the first period amount of the compound is about 15 mg to about 25 mg;

[0717] b) the second period follows the first period; and

[0718] c) the second period comprises once-daily dosing of the compound in a second period amount, wherein the second period amount is about 40 mg to about 50 mg,

[0719] and wherein the subject is a human.

[0720] Embodiment 17: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 2 to 16, wherein the biomarker is Nurr1.

[0721] Embodiment 18: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 2 to 16, wherein the biomarker is miR-132.

[0722] Embodiment 19: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 2 to 16, wherein the abnormal level of a biomarker associated with a neurodegenerative disorder is down-regulated Nurr1.

[0723] Embodiment 20: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 2 to 16, wherein the abnormal level of a biomarker associated with a neurodegenerative disorder is up-regulated miR-132.

[0724] Embodiment 21 : The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is Parkinson’s disease.

[0725] Embodiment 22: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is multiple sclerosis, in particular relapsing multiple sclerosis (RMS) such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive multiple sclerosis such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0726] Embodiment 22a. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is active SPMS.

[0727] Embodiment 22b. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is PPMS.

[0728] Embodiment 22c. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is non-active SPMS.

[0729] Embodiment A12d. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is PIRA.

[0730] Embodiment 22e. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is clinically isolated syndrome (CIS).

[0731] Embodiment 22f. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 20, wherein the neurodegenerative disorder is relapsing remitting MS.

[0732] Embodiment 23: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 16, wherein the neurodegenerative disorder is drug addiction.

[0733] Embodiment 24: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 23, wherein the subject exhibits an abnormal level of a biomarker associated with drug addiction, wherein the biomarker is dopamine.

[0734] Embodiment 25: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 23 or 24, wherein the drug addiction is cocaine addiction.

[0735] Embodiment 26: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 23 or 24, wherein the drug addiction is amphetamine addiction.

[0736] Embodiment 27: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 17, wherein the method comprises:

[0737] a) obtaining the level of Nurr1 in the subject; and

[0738] b) deciding whether to administer a Nurr1 agonist to the subject based on the level of Nurr1 in the subject.

[0739] Embodiment 28: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 27, wherein the level of Nurr1 in the subject is no more than about 90%, preferably about 80%, more preferably about 70%, even more preferably about 60%, more preferably about 50% of the level in a healthy subject of the same age, sex, and / or BMI, and the decision is to administer the Nurr1 agonist to the subject.

[0740] Embodiment 29: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 27, wherein the level of Nurr1 in the subject is at least 98%, preferably at least 95% of the level in a healthy subject of the same age, sex, and / or BMI, and the decision is not to administer the Nurr1 agonist to the subject.

[0741] Embodiment 30: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 27, wherein the level of Nurr1 in the subject is no more than about 90%, preferably about 80%, more preferably about 70%, even more preferably about 60%, more preferably about 50% of the level in a healthy subject of the same age, sex, and / or BMI, and further comprising identifying the subject as having the neurodegenerative disorder.

[0742] Embodiment 31 : The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 27, wherein the level of Nurr1 in the subject is at most 95%, preferably at least 90%, more preferably at least 80%, even more preferably at least 70%, more preferably at least 60%, more preferably at least 50% of the level in a healthy subject of the same age, sex, and / or BMI, and further comprising identifying the subject as having the neurodegenerative disorder.

[0743] Embodiment 32: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 27 to 31, wherein the method further comprises administering a therapeutically effective amount of the Nurr1 agonist to the subject based on the level of Nurr1 in the subject.

[0744] Embodiment 33: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 17, wherein the method comprises:

[0745] a) obtaining a level of Nurr1 in a subject undergoing a therapy for a neurodegenerative disorder; and

[0746] b) deciding whether to start or continue the therapy for the neurodegenerative disorder based on the level of Nurr1 in the subject, wherein the therapy is Nurr1 agonism.

[0747] Embodiment 34: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 33, wherein the level of Nurr1 in the subject is no more than about 90%, preferably about 80%, more preferably about 70%, even more preferably about 60%, more preferably about 50% of the level in a healthy subject of the same age, sex and / or BMI, and the decision is to start or continue the therapy.

[0748] Embodiment 35: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 33, wherein the level of Nurr1 in the subject is at least 98%, preferably at least 95% of the level in a healthy subject of the same age, sex and / or BMI, and the decision is not to start the therapy.

[0749] Embodiment 36: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 33, wherein the level of Nurr1 in the subject is no more than about 90%, preferably about 80%, more preferably about 70%, even more preferably about 60%, more preferably about 50% of the level in a healthy subject of the same age, sex and / or BMI, and further comprising identifying that the subject needs to start or continue treatment for the neurodegenerative disorder.

[0750] Embodiment 37: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 33, wherein the level of Nurr1 in the subject is at most 95%, preferably at least 90%, more preferably at least 80%, even more preferably at least 70%, more preferably at least 60%, more preferably at least 50% of the level in a healthy subject of the same age, sex, and / or BMI, and further comprising identifying that the subject needs to start or continue treatment for the neurodegenerative disorder.

[0751] Embodiment 38: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 33, wherein the neurodegenerative disorder therapy comprises administering to the subject a therapeutically effective amount of a Nurr1 agonist for the neurodegenerative disorder.

[0752] Embodiment 39: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 27-38, wherein obtaining the level of Nurr1 in the subject comprises obtaining an assay result of an ex vivo biological sample of the subject, wherein the assay determines the level of Nurr1 in the ex vivo biological sample of the subject.

[0753] Embodiment 40: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 27-38, wherein obtaining the level of Nurr1 in the subject comprises performing an assay of an ex vivo biological sample of the subject, wherein the assay determines the level of Nurr1 in the ex vivo biological sample of the subject.

[0754] Embodiment 41: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 39 or 40, wherein the assay determines the level of Nurr1 in the ex vivo biological sample of the subject by determining the concentration of Nurr1 in the ex vivo biological sample of the subject.

[0755] Embodiment 42: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 39 or 40, wherein the assay determines the level of Nurr1 in the ex vivo biological sample of the subject by determining the level of Nurr1 activity in the ex vivo biological sample of the subject.

[0756] Embodiment 43: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 39-40, wherein the assay is (a) a real-time PCR assay of expression of Nurr1 gene relative to a related housekeeping gene / internal control (e.g., GAPDH), (b) an immunoassay (e.g., ELISA) using a suitable antibody for Nurr1 protein, or (c) a Western blot of Nurr1 protein from a tissue selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, or peripheral blood mononuclear cells.

[0757] Embodiment 44: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 39-43, wherein the ex vivo biological sample is a blood sample.

[0758] Embodiment 45: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1-17, wherein the method comprises:

[0759] a) obtaining a protein level in a subject, wherein the protein is downstream of Nurr1 in a biological pathway of the subject; and

[0760] b) deciding whether to administer a Nurr1 agonist to the subject based on the protein level in the subject.

[0761] Embodiment 46: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 45, wherein the protein level in the subject indicates that the protein is upregulated.

[0762] Embodiment 47: A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 45, wherein the protein level in the subject indicates that the protein is downregulated.

[0763] Embodiment 48: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 45 to 47, wherein the protein is selected from BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNF alpha, iNOS, and IL-1 beta.

[0764] Embodiment 49: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 45 to 48, wherein the method further comprises administering to the subject a therapeutically effective amount of the Nurr1 agonist based on the level of the protein in the subject.

[0765] Embodiment 50: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 1 to 17, wherein the method comprises:

[0766] a) obtaining a level of a protein in a subject undergoing a therapy for a neurodegenerative disorder, wherein the protein is downstream of Nurr1 in a biological pathway of the subject, wherein the therapy is Nurr1 agonism; and

[0767] b) deciding whether to continue the therapy for the neurodegenerative disorder based on the level of the protein in the subject.

[0768] Embodiment 51: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 50, wherein the level of the protein in the subject is higher than the level prior to the therapy.

[0769] Embodiment 52: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to embodiment 50, wherein the level of the protein in the subject is lower than the level prior to the therapy.

[0770] Embodiment 53: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of embodiments 50 to 52, wherein the protein is selected from BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNF alpha, iNOS, and IL-1 beta.

[0771] Embodiment 54: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to Embodiment 53, wherein the method further comprises determining the protein level in the subject is higher than the level prior to the therapy.

[0772] Embodiment 55: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 45-54, wherein obtaining the protein level in the subject comprises obtaining an assay result of an ex vivo biological sample of the subject, wherein the assay determines the protein level in the ex vivo biological sample of the subject.

[0773] Embodiment 56: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of Embodiments 45-54, wherein obtaining the protein level in the subject comprises performing an assay of an ex vivo biological sample of the subject, wherein the assay determines the protein level in the ex vivo biological sample of the subject.

[0774] Embodiment 57: The compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative disorder an...

Claims

1. A compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating a neurodegenerative condition and / or a method of neuroprotection in a subject having a neurodegenerative disease, wherein the compound is of Formula (V): wherein: R1is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH (V)， ​ - Ring A is , , , , , , or ; - E is , , , , or ; ​ - Y is , , , , , , or . ​ ​ , , , , , , , or . ​ 。 ​ 。 ​ ​ ​ ​ ​ ​ 12. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 1 to 7, wherein the neuroprotection is slowing or preventing neuron loss induced by multiple sclerosis.

13. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 1 to 7, wherein the neuroprotection is slowing or preventing dopaminergic neuron loss induced by multiple sclerosis.

14. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 1 to 7, wherein the neurodegenerative disorder is Parkinson’s disease.

15. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 1 to 14, wherein the method comprises: determining the level or activity of Nurr1 in an ex vivo biological sample of the subject using an assay selected from (a) a real-time PCR assay of Nurr1 gene expression relative to a related housekeeping gene / internal control (e.g. GAPDH), (b) an immunoassay (e.g. ELISA) using a suitable antibody for Nurr1 protein, or (c) a Western blot of Nurr1 protein from a biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, or peripheral blood mononuclear cells; and administering to the patient an effective amount of the compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof if the test sample from the patient comprises a level of Nurr1 no greater than about 90% of the level in a healthy subject of the same age, gender and / or BMI.

16. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 1 to 14, wherein the method comprises: a) obtaining a level of a protein in a subject, wherein the protein is downstream of Nurr1 in a biological pathway of the subject; and b) deciding whether to administer a Nurr1 agonist to the subject based on the level of the protein in the subject.

17. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to claim 16, wherein the protein is selected from BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNFa, iNOS and IL-1 beta.

18. The compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to claim 4, which is and wherein the disorder is PIRA.

19. The compound of Formula (V) for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to claim 5, which is and wherein the disorder is PIRA.

20. The compound of Formula (V) for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to claim 18 or 19, wherein the neurodegenerative disorder is multiple sclerosis, wherein disability is obtained by progression independent of relapsing activity (PIRA).

21. The compound of Formula (V) for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 18 to 20, wherein the therapeutically effective amount is about 5 mg to about 100 mg.

22. The compound of Formula (V) for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 18 to 21, wherein the administration is oral by solid dosage form.

23. The compound of Formula (V) for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 18 to 22, wherein the administration is carried out over a first period and a second period, wherein: a) the first period is five to ten consecutive days of once daily dosing of the compound in a first period amount, wherein the first period amount of the compound is about 15 mg to about 25 mg; b) the second period is subsequent to the first period; and c) the second period comprises once daily dosing of the compound in a second period amount, wherein the second period amount is about 30 mg to about 50 mg.

24. The compound of Formula (V) for use in a method of treating a neurodegenerative disorder and / or a method of neuroprotection according to any one of claims 18 to 23, wherein the method is intended to arrest or slow disease progression and secondary damage by halting or at least slowing (reducing) neuronal loss.

25. A method of treating multiple sclerosis (MS) in a patient diagnosed with progression independent of relapses (PIRA), the method comprising administering to the subject a compound of Formula (V), wherein the compound is: 。 26. A method of treating multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound of Formula (V), wherein: the compound is ; and the MS is characterized by progression independent of relapses (PIRA).

27. A method of treating progression independent of relapses (PIRA) in a subject with multiple sclerosis (MS), the method comprising administering to the subject a compound of Formula (V), wherein the compound is 。 28. A method of treating multiple sclerosis (MS) in a subject, the method comprising administering to the subject a compound of Formula (V), wherein: the compound is ; and the subject has MS characterized by progression independent of relapses (PIRA).

29. The method of claim 25, wherein the patient has no evidence of relapse in 24 months.

30. The method of any one of claims 25-29, wherein the MS is progressive MS (PMS).

31. The method of claim 30, wherein the PMS is characterized by few or no active lesions.

32. The method of any one of claims 25-29, wherein the MS is primary progressive MS (PPMS).

33. The method of any one of claims 25-29, wherein the MS is non-active secondary progressive MS (n-aSPMS).

34. The method of claim 33, wherein the n-aSPMS is characterized by no lesion within 12 months.

35. The method of any one of claims 25-29, wherein the MS is active secondary progressive MS (a-SPMS).

36. The method of any one of claims 25-35, wherein the method reduces serum NFL levels in the subject compared to a control.

37. The method of any one of claims 25-36, wherein the method reduces serum GFAP levels in the subject compared to a control.

38. The method of any one of claims 25-37, wherein the method reduces percent brain volume change (PBVC) in the subject compared to a control.

39. The method of any one of claims 25-38, wherein the method reduces rate of change in brain parenchymal fraction (BPF) in the subject compared to a control.

40. The method of any one of claims 25-39, wherein the method increases time to confirmed disability worsening, e.g., based on the Expanded Disability Status Scale (EDSS), in the subject compared to a control.

41. The method of any one of claims 25-40, wherein the method halts and / or slows disease progression and secondary damage by halting or at least slowing (lessening) neuronal loss.

42. The method of any one of claims 25-41, wherein the compound is administered in a therapeutically effective amount of about 5 mg to about 100 mg.

43. The method of any one of claims 25-42, wherein the compound is administered orally via a solid dosage form.

44. The method of any one of claims 25-43, wherein the compound is administered over a first period and a second period, wherein: a) the first period is five to ten consecutive days of once daily dosing of the compound at a first period amount, wherein the first period amount of the compound is about 15 mg to about 25 mg; b) the second period is after the first period; and c) the second period comprises once daily dosing of the compound at a second period amount, wherein the second period amount is about 30 mg to about 50 mg.

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